[177LU] Lutetium-PSMA I&T Compositions and Dosimetry, Kits, Methods of Making Same, and Methods of Using Same

Abstract

The present disclosure provides: 177 The present invention relates to pharmaceutical compositions containing Lu-PSMA I&T and methods of administering the same. Administration of the compositions results in a low absorbed radiation dose per gram of tissue in a human patient, including the kidney, gastrointestinal tract, left colon, liver, rectum, red bone marrow, spleen, lacrimal gland, and salivary gland. The compositions, methods, and kits described herein contain 177Lu-PSMA I&T suitable for administration to a human patient, with a radiochemical purity of 95% or greater and a molar ratio of PSMA I&T to 177Lu of 3.0:1.0 to 8.0:1.0 and / or 4.4:1.0 to 7.6:1.0.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This invention claims priority to the following U.S. provisional patent applications: Nos. 63 / 529,986, 63 / 620,262, 63 / 626,839, 63 / 671,633, 63 / 671,625, 63 / 677,137, and 63 / 677,276, filed July 31, 2023, January 12, 2024, January 30, 2024, July 15, 2024, July 15, 2024, July 30, 2024, and July 30, 2024, respectively, which are incorporated herein in their entirety, including all tables, figures, and claims.

[0002] The present disclosure provides an injectable 177 Lu] Lutetium-PSMA I&T ([ 177 Lu]Lu-PSMA I&T or 177 Composition of the Lu-PSMA I&T solution, and 177 Regarding kits containing Lu-PSMA I&T. 177 The Lu-PSMA I&T solution and / or kit thereof can be used for prostate cancer radioligand therapy (PRLT). 177 The present invention relates to a method of administering a composition comprising Lu-PSMA I&T to a human patient in need thereof. [Background technology]

[0003] Prostate cancer (PC) is the most frequent non-skin cancer and the second leading cause of cancer death in adult men. Overall, increasing survival rates for patients with metastatic castration-resistant prostate cancer (mCRPC) has been challenging, and there is a clinical need for effective treatment strategies for mCRPC patients.

[0004] Prostate-specific membrane antigen (PSMA) is highly expressed on prostate epithelial cells and is strongly upregulated in prostate cancer, making PSMA a promising molecular target for the diagnosis and therapy of PC, including mCRPC. 177 Lu-PSMA-617 and177 Lu-PSMA I&Ts are small molecule inhibitors of PSMA that are highly desirable for targeted radionuclide therapy due to their low toxicity. However, there are currently no studies available to treat prostate cancer. 177 The use of these small molecule inhibitors targeting PSMA with Lu may also result in undesirable absorbed doses of radiation to healthy organs.

[0005] can be administered to a patient that is not targeted for the treatment of cancer (e.g., prostate cancer), minimizing the unwanted cumulative absorbed dose of radiation to the patient's healthy organ tissues 177 There remains a need for improved formulations containing Lu-PSMA I&T. 177 Provided herein is a solution to overcome these and other problems in the art by providing Lu-PSMA I&T compositions. Further provided herein are improved therapeutic agents that result in a lower cumulative absorbed dose of radiation per administration. 177 Lu-PSMA I&T compositions and administration methods are provided. Also provided herein are improved Lu-PSMA I&T compositions that provide a lower cumulative absorbed dose of radiation and / or a lower dose per administration to critical individual organs (e.g., kidney, lacrimal gland, salivary gland, and liver). 177 Lu-PSMA I&T compositions and administration methods are provided. Importantly, the improved compositions and methods described herein surprisingly allow for longer treatment cycles and / or lower cumulative absorbed dose radiation levels than the prior art. Summary of the Invention [Means for solving the problem]

[0006] especially, 177 Provided herein are compositions comprising Lu-PSMA I&Ts and methods of administering the same to a human patient in need thereof.

[0007] The compositions, methods, and kits described herein include 177Lu-PSMA I&T suitable for administration to human patients, with a radiochemical purity of 95% or greater and a molar ratio of PSMA I&T to 177Lu of 3.0:1.0 to 8.0:1.0 and / or 4.4:1.0 to 7.6:1.0. This is highly surprising and unexpected, as our own initial testing suggested that this embodiment was not feasible and would require a molar ratio of PSMA I&T to 177Lu of at least 11.0:1.0 or greater to maintain a radiochemical purity of 95% or greater for 72 hours or longer. Indeed, our own initial predictions indicated that anything below an 11.0:1.0 ratio would likely have unacceptable radiochemical purity (e.g., less than 95%) upon formation and would continue to deteriorate in a manner that would be further unacceptable for human patients 24 hours after formation, 48 hours after formation, 72 hours after formation, or 96 hours after formation. See the PSMA:Lu-177 (mol / mol) graph below, which shows inadequate predicted radiochemical formation in formulations below 11.0:1.0. [ka]

[0008] However, utilizing the unique parameters described herein, provided herein are compositions, methods, and kits described herein comprising 177Lu-PSMA I&T suitable for administration to a human patient, with a radiochemical purity of 95% or greater and a molar ratio of PSMA I&T to 177Lu of 3.0:1.0 to 8.0:1.0 and / or 4.4:1.0 to 7.6:1.0, wherein the composition is stable for 72 hours or more.

[0009] In another embodiment, the compositions, methods, and kits described herein comprise 177Lu-PSMA I&T suitable for administration to a human patient, having a radiochemical purity of 95% or greater and a ratio of PSMA I&T to [177Lu]Lu3+ (units: μg:mCi) of about 0.20 to about 0.60. In another embodiment, the compositions, methods, and kits described herein comprise 177Lu-PSMA I&T suitable for administration to a human patient, having a radiochemical purity of 95% or greater and a ratio of PSMA I&T to [177Lu]Lu3+ (units: μg:mCi) of 0.60 or less. This is also highly surprising and unexpected, as our own initial testing suggested that this embodiment was not feasible and would require a PSMA I&T to [177Lu]Lu3+ ratio (units: μg:mCi) of at least 0.70 to maintain 95% or greater radiochemical purity for 72 hours or greater. See the PSMA:Lu-177 (mol / mol) graph below, which shows inadequate predicted radiochemical formation in formulations below 0.60. [ka]

[0010] However, utilizing the unique parameters described herein, provided herein are compositions, methods, and kits described herein comprising 177Lu-PSMA I&T suitable for administration to a human patient, with a radiochemical purity of 95% or greater and a ratio of PSMA I&T to [177Lu]Lu3+ (units: μg:mCi) of about 0.20 to about 0.64, about 0.20 to about 0.63, about 0.20 to about 0.62, about 0.20 to about 0.61, or about 0.20 to about 0.60, wherein the composition is stable for 72 hours or more.

[0011] In some embodiments, the composition comprises a PSMA I&T ratio of about 1.0:1 to about 8.0:1, about 1.5:1 to about 8.0:1, about 2.0:1 to about 8.0:1, about 2.5:1 to about 8.0:1, about 3.0:1 to about 8.0:1, about 3.5:1 to about 8.0:1, about 4.0:1.0 to about 8.0:1.0, about 4.5:1.0 to about 5.5:1.0, or about 5.0:1.0 to about 6.0:1.0. 177 In some embodiments, the composition has a molar ratio of PSMA I&T to Lu of about 4.0:1.0, about 4.5:1.0, about 5.0:1.0, about 5.5:1.0, about 6.0:1.0, about 6.5:1.0, about 7.0:1.0, about 7.5:1.0, or about 8.0:1.0. 177 In some embodiments, the composition has a molar ratio of PSMA I&T to Lu of about 5.1:1.0 to about 5.9:1.0, about 5.2:1.0 to about 5.8:1.0, about 5.3:1.0 to about 5.7:1.0, or about 5.4:1.0 to about 5.6:1.0. 177 The molar ratio of Zn to Lu is:

[0012] In some embodiments, the composition comprises about 7.1 GBq to about 7.6 GBq 177 In some embodiments, the composition comprises 7.4±15% GBq of Lu-PSMA I&T. 177 Lu-PSMA I&T, 7.4±10% GBq 177 Lu-PSMA I&T, or 7.4±5%GBq 177 In one example, the composition comprises about 7.4 GBq of Lu-PSMA I&T. 177 Includes Lu-PSMA I&T.

[0013] 1. A method comprising: 177Further provided herein is a method, comprising administering to a human patient in need thereof a radiopharmaceutical composition comprising Lu-PSMA I&T, wherein the absorbed radiation dose per gram of tissue in the kidney of the human patient is from about 0.2 Gy / GBq to about 0.6 Gy / GBq, from about 0.25 Gy / GBq to about 0.55 Gy / GBq, from about 0.3 Gy / GBq to about 0.5 Gy / GBq, or from about 0.35 Gy / GBq to about 0.45 Gy / GBq. In some embodiments, the absorbed radiation dose per gram of tissue in the kidney of a human patient is 0.60 Gy / GBq or less, 0.55 Gy / GBq or less, 0.50 Gy / GBq or less, 0.45 Gy / GBq or less, 0.40 Gy / GBq or less, 0.35 Gy / GBq or less, 0.30 Gy / GBq or less, 0.25 Gy / GBq or less, 0.20 Gy / GBq or less, or 0.15 Gy / GBq or less. In some embodiments, the average absorbed radiation dose per gram of tissue in the kidney of a human patient is about 0.39±0.15 Gy / GBq, about 0.40±0.15 Gy / GBq, about 0.41±0.15 Gy / GBq, about 0.42±0.15 Gy / GBq, about 0.43±0.15 Gy / GBq, about 0.44±0.15 Gy / GBq, or about 0.45±0.15 Gy / GBq. In some embodiments, the average absorbed radiation dose per gram of tissue in the kidney of a human patient is 0.39 Gy / GBq or less, 0.40 Gy / GBq or less, 0.41 Gy / GBq or less, or 0.42 Gy / GBq or less. In some embodiments, the standard deviation of the mean absorbed radiation dose per gram of tissue in the kidney of a human patient is 0.19 Gy / GBq or less, 0.18 Gy / GBq or less, 0.17 Gy / GBq or less, 0.16 Gy / GBq or less, or 0.15 Gy / GBq or less. In some embodiments, the absorbed radiation dose is measured by SPECT imaging, two-dimensional imaging, or a combination thereof.

[0014] 1. A method comprising: 177Provided herein are methods comprising administering to a human patient in need thereof a radiopharmaceutical composition comprising Lu-PSMA I&T, wherein the absorbed radiation dose per gram of tissue in the lacrimal gland of the human patient is about 0.01 Gy / GBq to about 1.5 Gy / GBq. In some embodiments, the absorbed radiation dose per gram of tissue in the lacrimal gland of the human patient is 1.5 Gy / GBq or less, 1.4 Gy / GBq or less, 1.3 Gy / GBq or less, 1.2 Gy / GBq or less, 1.1 Gy / GBq or less, 1.0 Gy / GBq or less, 0.9 Gy / GBq or less, 0.8 Gy / GBq or less, 0.7 Gy / GBq or less, 0.6 Gy / GBq or less, 0.5 Gy / GBq or less, 0.4 Gy / GBq or less, 0.3 Gy / GBq or less, 0.2 Gy / GBq or less, or 0.1 Gy / GBq or less. In some embodiments, the absorbed radiation dose per gram of tissue in the lacrimal gland of a human patient is about 0.1 Gy / GBq to about 0.8 Gy / GBq. In some embodiments, the absorbed radiation dose per gram of tissue in the lacrimal gland of a human patient is about 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5 Gy / GBq. In some embodiments, the average absorbed radiation dose per gram of tissue in the lacrimal gland of a human patient is 0.37±0.36 Gy / GBq, 0.38±0.36 Gy / GBq, 0.39±0.36 Gy / GBq, or 0.40±0.36 Gy / GBq. In some embodiments, the average absorbed radiation dose per gram of tissue in the lacrimal gland of the human patient is 0.40 Gy / GBq or less, 0.50 Gy / GBq or less, 0.60 Gy / GBq or less, 0.70 Gy / GBq or less, 0.80 Gy / GBq or less, 0.90 Gy / GBq or less, or 1.0 Gy / GBq or less. In some embodiments, the standard deviation of the average absorbed radiation dose per gram of tissue in the lacrimal gland of the human patient is 0.37 Gy / GBq or less. In some embodiments, the absorbed radiation dose is measured by SPECT imaging, two-dimensional imaging, or a combination thereof.

[0015] 1. A method comprising: 177Further provided herein are methods comprising administering to a human patient in need thereof a radiopharmaceutical composition comprising Lu-PSMA I&T, wherein the absorbed radiation dose per gram of tissue in the salivary gland of the human patient is about 0.01 Gy / GBq to about 1.0 Gy / GBq. In some embodiments, the absorbed radiation dose per gram of tissue in the salivary gland of the human patient is 1.0 Gy / GBq or less, 0.9 Gy / GBq or less, 0.8 Gy / GBq or less, 0.7 Gy / GBq or less, 0.6 Gy / GBq or less, 0.5 Gy / GBq or less, 0.4 Gy / GBq or less, 0.3 Gy / GBq or less, 0.2 Gy / GBq or less, or 0.1 Gy / GBq or less. In some aspects, the absorbed radiation dose per gram of tissue in the salivary gland of the human patient is about 0.1 Gy / GBq to about 0.5 Gy / GBq. In some embodiments, the absorbed radiation dose per gram of tissue in the salivary glands of a human patient is about 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or about 1.0 Gy / GBq. In some embodiments, the average absorbed radiation dose per gram of tissue in the salivary glands of a human patient is about 0.17±0.16 Gy / GBq, 0.18±0.16 Gy / GBq, 0.19±0.16 Gy / GBq, or 0.20±0.16 Gy / GBq. In some embodiments, the average absorbed radiation dose per gram of tissue in the salivary glands of a human patient is 0.18 Gy / GBq or less, 0.19 Gy / GBq or less, 0.20 Gy / GBq or less, 0.21 Gy / GBq or less, 0.22 Gy / GBq or less, 0.23 Gy / GBq or less, 0.24 Gy / GBq or less, 0.25 Gy / GBq or less, 0.26 Gy / GBq or less, 0.27 Gy / GBq or less, 0.28 Gy / GBq or less, 0.29 Gy / GBq or less, or 0.30 Gy / GBq or less. In some embodiments, the standard deviation of the mean absorbed radiation dose per gram of tissue in the salivary glands of a human patient is 0.25 Gy / GBq or less, 0.24 Gy / GBq or less, 0.23 Gy / GBq or less, 0.22 Gy / GBq or less, 0.21 Gy / GBq or less, 0.20 Gy / GBq or less, 0.19 Gy / GBq or less, 0.18 Gy / GBq or less, 0.17 Gy / GBq or less, or 0.16 Gy / GBq or less.In some embodiments, the absorbed radiation dose is measured by SPECT imaging, two-dimensional imaging, or a combination thereof.

[0016] 1. A method comprising: 177 Further provided herein are methods comprising administering to a human patient in need thereof a radiopharmaceutical composition comprising Lu-PSMA I&T, wherein the absorbed radiation dose per gram of tissue in the left colon of the human patient is about 0.01 Gy / GBq to about 1.6 Gy / GBq. In some embodiments, the absorbed radiation dose per gram of tissue in the left colon of the human patient is 1.6 Gy / GBq or less, 1.5 Gy / GBq or less, 1.4 Gy / GBq or less, 1.3 Gy / GBq or less, 1.2 Gy / GBq or less, 1.1 Gy / GBq or less, 1.0 Gy / GBq or less, 0.9 Gy / GBq or less, 0.8 Gy / GBq or less, 0.7 Gy / GBq or less, 0.6 Gy / GBq or less, 0.5 Gy / GBq or less, 0.4 Gy / GBq or less, 0.3 Gy / GBq or less, 0.2 Gy / GBq or less, or 0.1 Gy / GBq or less. In some embodiments, the absorbed radiation dose per gram of tissue in the left colon of a human patient is about 0.1 Gy / GBq to about 0.8 Gy / GBq. In some embodiments, the absorbed radiation dose per gram of tissue in the left colon of a human patient is about 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, or about 1.6 Gy / GBq. In some embodiments, the average absorbed radiation dose per gram of tissue in the left colon of a human patient is 0.45±0.31 Gy / GBq, 0.46±0.31 Gy / GBq, or 0.47±0.31 Gy / GBq. In some embodiments, the average absorbed radiation dose per gram of tissue in the left colon of a human patient is 0.47 Gy / GBq or less.

[0017] 1. A method comprising: 177Further provided herein are methods comprising administering to a human patient in need thereof a radiopharmaceutical composition comprising Lu-PSMA I&T, wherein the absorbed radiation dose per gram of tissue in the rectum of the human patient is about 0.01 Gy / GBq to about 1.5 Gy / GBq. In some embodiments, the absorbed radiation dose per gram of tissue in the rectum of the human patient is 1.5 Gy / GBq or less, 1.4 Gy / GBq or less, 1.3 Gy / GBq or less, 1.2 Gy / GBq or less, 1.1 Gy / GBq or less, 1.0 Gy / GBq or less, 0.9 Gy / GBq or less, 0.8 Gy / GBq or less, 0.7 Gy / GBq or less, 0.6 Gy / GBq or less, 0.5 Gy / GBq or less, 0.4 Gy / GBq or less, 0.3 Gy / GBq or less, 0.2 Gy / GBq or less, or 0.1 Gy / GBq or less. In some embodiments, the absorbed radiation dose per gram of tissue in the rectum of a human patient is about 0.1 Gy / GBq to about 0.8 Gy / GBq. In some embodiments, the absorbed radiation dose per gram of tissue in the rectum of a human patient is about 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, or about 1.5 Gy / GBq. In some embodiments, the average absorbed radiation dose per gram of tissue in the rectum of a human patient is 0.44±0.30 Gy / GBq. In some embodiments, the absorbed radiation dose is measured by SPECT imaging, two-dimensional imaging, or a combination thereof.

[0018] 1. A method comprising: 177 administering to a human patient in need thereof a radiopharmaceutical composition comprising Lu-PSMA I&T, 177 Further provided herein are methods wherein the ratio of Lu-PSMA I&T activity is about 0.5 or less within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. In some embodiments, the method comprises administering the composition to a human patient in a systemic manner. 177 The percent activity of Lu-PSMA I&T is 0.5 or less, 0.4 or less, 0.3 or less, 0.2 or less, or 0.1 or less within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. In some embodiments, the percent activity of Lu-PSMA I&T is 0.5 or less, 0.4 or less, 0.3 or less, 0.2 or less, or 0.1 or less in a human patient's system. 177The percentage of activity of the Lu-PSMA I&T is less than about 0.5, 0.4, 0.3, 0.2, 0.1, or 0.1 within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. In some embodiments, the percentage of activity of the Lu-PSMA I&T is less than about 0.5, 0.4, 0.3, 0.2, 0.1, or 0.1 within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. 177 The ratio of activity of the Lu-PSMA I&T is about 0.4 or less within 48 hours or 168 hours after administration of the composition. In some embodiments, the ratio of activity of the Lu-PSMA I&T is about 0.4 or less within 48 hours or 168 hours after administration of the composition. 177 The ratio of activity of Lu-PSMA I&T is less than about 0.4, about 0.3, about 0.2, about 0.1, or 0.1 within 48 hours or 168 hours after administration of the composition. In some embodiments, the ratio of activity of Lu-PSMA I&T is less than about 0.4, about 0.3, about 0.2, about 0.1, or 0.1 within 48 hours or 168 hours after administration of the composition. 177 The Lu-PSMA I&T activity rate is about 0.2 or less within 168 hours after administration of the composition. In some embodiments, administration is by injection. In some embodiments, the activity rate is measured by SPECT imaging, two-dimensional image-based dosimetry, or a combination thereof. The method comprises: 177 administering to a human patient in need thereof a radiopharmaceutical composition comprising Lu-PSMA I&T, 177 Further provided herein are methods wherein the ratio of activity of the Lu-PSMA I&T is about 0.05 or less within 24 hours, within 48 hours, or within 168 hours after administration of the composition.

[0019] 1. A method comprising: 177 administering to a human patient in need thereof a radiopharmaceutical composition comprising Lu-PSMA I&T, 177 Further provided herein are methods wherein the ratio of Lu-PSMA I&T activity is about 0.05 or less within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. 177 The percent activity of Lu-PSMA I&T is 0.05 or less, 0.04 or less, 0.03 or less, 0.02 or less, or 0.01 or less within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. In some embodiments, the percent activity of Lu-PSMA I&T in the kidney of a human patient is 0.05 or less, 0.04 or less, 0.03 or less, 0.02 or less, or 0.01 or less within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. 177The rate of activity of Lu-PSMA I&T is less than about 0.05, about 0.04, about 0.03, about 0.02, about 0.01, or 0.01 within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. In some embodiments, the rate of activity of Lu-PSMA I&T in the kidney of a human patient is less than about 0.05, about 0.04, about 0.03, about 0.02, about 0.01, or 0.01 within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. 177 The ratio of activity of the Lu-PSMA I&T is about 0.040 or less within 48 hours or 168 hours after administration of the composition. In some embodiments, the ratio of activity of the Lu-PSMA I&T in the kidney of a human patient is about 0.040 or less within 48 hours or 168 hours after administration of the composition. 177 The ratio of activity of Lu-PSMA I&T is about 0.040 or less, about 0.035 or less, or about 0.030 or less within 48 hours or 168 hours after administration of the composition. In some embodiments, the ratio of activity of Lu-PSMA I&T in the kidney of a human patient is about 0.040 or less, about 0.035 or less, or about 0.030 or less within 48 hours or 168 hours after administration of the composition. 177 The percent activity of Lu-PSMA I&T is less than about 0.04, 0.03, 0.02, 0.01, or 0.01 within 48 hours or 168 hours after administration of the composition. In some embodiments, the percent activity of Lu-PSMA I&T in the kidney of a human patient is less than about 0.04, 0.03, 0.02, 0.01, or 0.01 within 48 hours or 168 hours after administration of the composition. 177 The ratio of activity of the Lu-PSMA I&T is about 0.03 or less within 168 hours after administration of the composition. In some embodiments, the ratio of activity of the Lu-PSMA I&T in the kidney of a human patient is about 0.03 or less within 168 hours after administration of the composition. 177 The percent activity of Lu-PSMA I&T is less than about 0.03, 0.02, 0.01, or 0.01 within 168 hours after administration of the composition. In some embodiments, administration is by injection. In some embodiments, the percent activity is measured by SPECT imaging, two-dimensional imaging, or a combination thereof.

[0020] 1. A method comprising: 177 administering to a human patient in need thereof a radiopharmaceutical composition comprising Lu-PSMA I&T, 177 Further provided herein are methods wherein the ratio of Lu-PSMA I&T activity is about 0.08 or less within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. In some embodiments, the ratio of Lu-PSMA I&T activity in the red bone marrow of a human patient is about 0.08 or less within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. 177The percent activity of Lu-PSMA I&T is 0.08 or less, 0.07 or less, 0.06 or less, 0.05 or less, 0.04 or less, 0.03 or less, 0.02 or less, 0.01 or less, or less within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. In some embodiments, the percent activity of Lu-PSMA I&T in red bone marrow of a human patient is 0.08 or less, 0.07 or less, 0.06 or less, 0.05 or less, 0.04 or less, 0.03 or less, 0.02 or less, 0.01 or less, or less within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. 177 The percent activity of Lu-PSMA I&T is less than about 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01, or 0.01 within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. In some embodiments, the percent activity of Lu-PSMA I&T in red bone marrow of a human patient is less than about 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01, or 0.01 within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. 177 The ratio of activity of the Lu-PSMA I&T is about 0.06 or less within 48 hours or 168 hours after administration of the composition. In some embodiments, the ratio of activity of the Lu-PSMA I&T in the red bone marrow of a human patient is about 0.06 or less within 48 hours or 168 hours after administration of the composition. 177 The percent activity of Lu-PSMA I&T is less than about 0.06, 0.05, 0.04, 0.03, 0.02, 0.01, or 0.01 within 48 hours or 168 hours after administration of the composition. In some embodiments, the percent activity of Lu-PSMA I&T in red bone marrow of a human patient is less than about 0.06, 0.05, 0.04, 0.03, 0.02, 0.01, or 0.01 within 48 hours or 168 hours after administration of the composition. 177 The ratio of activity of Lu-PSMA I&T is about 0.04 or less within 168 hours after administration of the composition. In some embodiments, the ratio of activity of Lu-PSMA I&T in red bone marrow of a human patient is about 0.04 or less within 168 hours after administration of the composition. 177 The percent activity of Lu-PSMA I&T is less than about 0.04, 0.03, 0.02, 0.01, or 0.01 within 168 hours after administration of the composition. In some embodiments, administration is by injection. In some embodiments, the percent activity is determined by SPECT imaging, two-dimensional imaging, or a combination thereof.

[0021] 1. A method comprising: 177 administering to a human patient in need thereof a radiopharmaceutical composition comprising Lu-PSMA I&T, 177 Further provided herein are methods wherein the ratio of Lu-PSMA I&T activity is about 0.015 or less within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. 177The percent activity of Lu-PSMA I&T is 0.015 or less, 0.014 or less, 0.013 or less, 0.012 or less, 0.011 or less, 0.010 or less, 0.009 or less, 0.008 or less, 0.007 or less, 0.006 or less, 0.005 or less, 0.004 or less, 0.003 or less, 0.002 or less, 0.001 or less, or less within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. In some embodiments, the percent activity of Lu-PSMA I&T in the salivary glands of a human patient is 0.015 or less, 0.014 or less, 0.013 or less, 0.012 or less, 0.011 or less, 0.010 or less, 0.009 or less, 0.008 or less, 0.007 or less, 0.006 or less, 0.005 or less, 0.004 or less, 0.003 or less, 0.002 or less, 0.001 or less, or less, or less, within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. 177 The percent activity of Lu-PSMA I&T is less than about 0.015, 0.014, 0.013, 0.012, 0.011, 0.010, 0.009, 0.008, 0.007, 0.006, 0.005, 0.004, 0.003, 0.002, 0.001, or 0.001 within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. In some embodiments, the percent activity of Lu-PSMA I&T in the salivary glands of a human patient is less than about 0.015, 0.014, 0.013, 0.012, 0.011, 0.010, 0.009, 0.008, 0.007, 0.006, 0.005, 0.004, 0.003, 0.002, 0.001, or 0.001 within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. 177 The ratio of activity of the Lu-PSMA I&T is about 0.007 or less within 48 hours or 168 hours after administration of the composition. In some embodiments, the ratio of activity of the Lu-PSMA I&T in the salivary glands of a human patient is about 0.007 or less within 48 hours or 168 hours after administration of the composition. 177 The percent activity of Lu-PSMA I&T is less than about 0.007, 0.006, 0.005, 0.004, 0.003, 0.002, 0.001, or 0.001 within 48 hours or 168 hours after administration of the composition. In some embodiments, the percent activity of Lu-PSMA I&T in the salivary glands of a human patient is less than about 0.007, 0.006, 0.005, 0.004, 0.003, 0.002, 0.001, or 0.001 within 48 hours or 168 hours after administration of the composition. 177 The ratio of activity of Lu-PSMA I&T is about 0.004 or less within 168 hours after administration of the composition. In some embodiments, the ratio of activity of Lu-PSMA I&T in the salivary glands of a human patient is about 0.004 or less within 168 hours after administration of the composition. 177 The percent activity of Lu-PSMA I&T is less than about 0.004, 0.003, 0.002, 0.001, or 0.001 within 168 hours after administration of the composition. In some embodiments, administration is by injection. In some embodiments, the percent activity is measured by SPECT imaging, two-dimensional imaging, or a combination thereof.

[0022] 1. A method comprising: 177 administering to a human patient in need thereof a radiopharmaceutical composition comprising Lu-PSMA I&T, 177Further provided herein are methods wherein the ratio of activity of Lu-PSMA I&T is about 0.10 or less within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. 177 The percent activity of Lu-PSMA I&T is 0.10 or less, 0.09 or less, 0.08 or less, 0.07 or less, 0.06 or less, 0.05 or less, 0.04 or less, 0.03 or less, 0.02 or less, 0.01 or less, or less within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. In some embodiments, the human patient has less than about 0.10, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01, or 0.01 ... 177 The ratio of activity of the Lu-PSMA I&T is about 0.10 or less within 48 hours or 168 hours after administration of the composition. In some embodiments, the ratio of activity of the Lu-PSMA I&T in the gastrointestinal tract of a human patient is about 0.10 or less within 48 hours or 168 hours after administration of the composition. 177 The percent activity of the Lu-PSMA I&T is less than about 0.10, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01, or 0.01 within 48 hours or 168 hours after administration of the composition. In some embodiments, the percent activity of the Lu-PSMA I&T in the gastrointestinal tract of a human patient is less than about 0.10, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01, or 0.01 within 48 hours or 168 hours after administration of the composition. 177 The ratio of activity of the Lu-PSMA I&T is about 0.05 or less within 168 hours after administration of the composition. In some embodiments, the ratio of activity of the Lu-PSMA I&T in the gastrointestinal tract of a human patient is about 0.05 or less within 168 hours after administration of the composition. 177 The percent activity of Lu-PSMA I&T is less than about 0.05, 0.04, 0.03, 0.02, 0.01, or 0.01 within 168 hours after administration of the composition. In some embodiments, administration is by injection. In some embodiments, the percent activity is measured by SPECT imaging, two-dimensional imaging, or a combination thereof.

[0023] 1. A method comprising: 177 administering to a human patient in need thereof a radiopharmaceutical composition comprising Lu-PSMA I&T, 177Further provided herein are methods wherein the ratio of Lu-PSMA I&T activity is about 0.04 or less within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. 177 The rate of activity of Lu-PSMA I&T is 0.04 or less, 0.03 or less, 0.02 or less, 0.01 or less, or less within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. In some embodiments, the rate of activity of Lu-PSMA I&T in the liver of a human patient is 0.04 or less, 0.03 or less, 0.02 or less, 0.01 or less, or less within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. 177 The percent activity of Lu-PSMA I&T is less than about 0.04, 0.03, 0.02, 0.01, or 0.01 within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. In some embodiments, the percent activity of Lu-PSMA I&T in the liver of a human patient is less than about 0.04, 0.03, 0.02, 0.01, or 0.01 within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. 177 The ratio of activity of the Lu-PSMA I&T is about 0.02 or less within 48 hours or 168 hours after administration of the composition. In some embodiments, the ratio of activity of the Lu-PSMA I&T in the liver of a human patient is about 0.02 or less within 48 hours or 168 hours after administration of the composition. 177 The rate of activity of the Lu-PSMA I&T is less than about 0.02, 0.01, or 0.01 within 48 hours or 168 hours after administration of the composition. In some embodiments, the rate of activity of the Lu-PSMA I&T in the liver of a human patient is less than about 0.02, 0.01, or 0.01 within 48 hours or 168 hours after administration of the composition. 177 The percent activity of Lu-PSMA I&T is about 0.01 or less within 168 hours after administration of the composition. In some embodiments, administration is by injection. In some embodiments, the percent activity is measured by SPECT imaging, two-dimensional imaging, or a combination thereof.

[0024] 1. A method comprising: 177 administering to a human patient in need thereof a radiopharmaceutical composition comprising Lu-PSMA I&T, 177 Further provided herein are methods wherein the percent activity of Lu-PSMA I&T is about 0.004 or less within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. 177The percent activity of Lu-PSMA I&T is 0.004 or less, 0.003 or less, 0.002 or less, 0.001 or less, or less within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. In some embodiments, the percent activity of Lu-PSMA I&T in the spleen of a human patient is 0.004 or less, 0.003 or less, 0.002 or less, 0.001 or less, or less within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. 177 The percent activity of Lu-PSMA I&T is less than about 0.004, 0.003, 0.002, 0.001, or 0.001 within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. In some embodiments, the percent activity of Lu-PSMA I&T in the spleen of a human patient is less than about 0.004, 0.003, 0.002, 0.001, or 0.001 within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. 177 The ratio of activity of Lu-PSMA I&T is about 0.002 or less within 48 hours or 168 hours after administration of the composition. In some embodiments, the ratio of activity of Lu-PSMA I&T in the spleen of a human patient is about 0.002 or less within 48 hours or 168 hours after administration of the composition. 177 The percent activity of Lu-PSMA I&T is less than about 0.002, 0.001, or 0.001 within 48 hours or 168 hours after administration of the composition. In some embodiments, the percent activity of Lu-PSMA I&T in the spleen of a human patient is less than about 0.002, 0.001, or 0.001 within 48 hours or 168 hours after administration of the composition. 177 The percent activity of Lu-PSMA I&T is about 0.001 or less within 168 hours after administration of the composition. In some embodiments, administration is by injection. In some embodiments, the percent activity is measured by SPECT imaging, two-dimensional imaging, or a combination thereof.

[0025] 1. A method comprising: 177 administering to a human patient in need thereof a radiopharmaceutical composition comprising Lu-PSMA I&T, 177 Further provided herein are methods wherein the percent activity of Lu-PSMA I&T is about 0.0004 or less within 24 hours, 48 ​​hours, or 168 hours after injection of the composition. 177 The percent activity of Lu-PSMA I&T is 0.0004 or less, 0.0003 or less, 0.0002 or less, 0.0001 or less, or less within 24 hours, 48 ​​hours, or 168 hours after injection of the composition. In some embodiments, the percent activity of Lu-PSMA I&T in the spleen of a human patient is 0.0004 or less, 0.0003 or less, 0.0002 or less, 0.0001 or less, or less within 24 hours, 48 ​​hours, or 168 hours after injection of the composition. 177The percent activity of Lu-PSMA I&T is less than about 0.0004, 0.0003, 0.0002, 0.0001, or 0.0001 within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. In some embodiments, the percent activity of Lu-PSMA I&T in the spleen of a human patient is less than about 0.0004, 0.0003, 0.0002, 0.0001, or 0.0001 within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. 177 The percent activity of Lu-PSMA I&T is about 0.0002 or less within 48 hours or 168 hours after administration of the composition. In some embodiments, the percent activity of Lu-PSMA I&T in the spleen of a human patient is about 0.0002 or less within 48 hours or 168 hours after administration of the composition. 177 The percent activity of Lu-PSMA I&T is less than about 0.0002, 0.0001, or 0.0001 within 48 hours or 168 hours after administration of the composition. In some embodiments, the percent activity of Lu-PSMA I&T in the spleen of a human patient is less than about 0.0002, 0.0001, or 0.0001 within 48 hours or 168 hours after administration of the composition. 177 The percent activity of Lu-PSMA I&T is less than about 0.0001 within 168 hours after administration of the composition. In some embodiments, administration is by injection. In some embodiments, the percent activity is measured by SPECT imaging, two-dimensional imaging, or a combination thereof.

[0026] The various features, aspects, and advantages of the present disclosure will be better understood from the following detailed description when read in conjunction with the accompanying drawings, in which like characters represent like parts throughout. [Brief explanation of the drawings]

[0027] [Figure 1A] The structural formula of the precursor PSMA I&T is presented. [Figure 1B] The structural formula of the R isomer of 177Lu-PSMA I&T is presented. [Figure 2] FIG. 1 is a flow chart diagram of an exemplary method for preparing the disclosed radiopharmaceutical compositions. [Figure 3A] 1 is a flowchart of the synthesis procedure for 177Lu-PSMA I&T in one embodiment. [Figure 3B] 1 is a flowchart of the synthesis procedure for 177Lu-PSMA I&T in one embodiment. [Figure 4]Drawings of exemplary product vials are shown. The pharmaceutical product is carried in Type 1 glass, sterile, pyrogen-free glass vials with fluorine-coated bromobutyl rubber septa. The septa are sealed with crimped aluminum capsules. The glass vials containing the radiopharmaceutical are kept in lead-shielded containers during transport. The shipping container, including the lead shielding and outer packaging, conforms to Type A requirements (IAEA standards). [Figure 5] 1 shows the radiochemical purity of 177Lu-PSMA I&T measured by HPLC at different time points. [Figure 6A] 1 shows HPLC radiochromatograms of a high activity formulation containing 42.5 mg / ml ascorbic acid at a pH of 7±0.1 at 0 and 71 hours after EOS, as detailed in the Examples. [Figure 6B] 1 shows HPLC radiochromatograms of a high activity formulation containing 42.5 mg / ml ascorbic acid at a pH of 7±0.1 at 0 and 71 hours after EOS, as detailed in the Examples. [Figure 7A] 1 shows HPLC radiochromatograms of a high activity concentration formulation containing 42.4 mg / ml ascorbic acid at a pH of 4.5±0.1 at 0 and 71 hours after EOS, as detailed in the Examples. [Figure 7B] 1 shows HPLC radiochromatograms of a high activity concentration formulation containing 42.4 mg / ml ascorbic acid at a pH of 4.5±0.1 at 0 and 71 hours after EOS, as detailed in the Examples. [Figure 8A] 1 shows HPLC radiochromatograms of a high activity formulation containing 42.5 mg / ml ascorbic acid at a pH of 3.5±0.1 at 0 and 90 hours after EOS, as detailed in the Examples. [Figure 8B] 1 shows HPLC radiochromatograms of a high activity formulation containing 42.5 mg / ml ascorbic acid at a pH of 3.5±0.1 at 0 and 90 hours after EOS, as detailed in the Examples. [Figure 9A]1 shows HPLC radiochromatograms of a low activity formulation containing 21 mg / ml ascorbic acid at a pH of 4.5±0.1 at 0 and 92 hours after EOS, as detailed in the Examples. [Figure 9B] 1 shows HPLC radiochromatograms of a low activity formulation containing 21 mg / ml ascorbic acid at a pH of 4.5±0.1 at 0 and 92 hours after EOS, as detailed in the Examples. [Figure 10A] 1 shows HPLC radiochromatograms of a low activity formulation containing 31 mg / ml ascorbic acid at a pH of 5±0.1 at 0 and 71 hours after EOS, as detailed in the Examples. [Figure 10B] 1 shows HPLC radiochromatograms of a low activity formulation containing 31 mg / ml ascorbic acid at a pH of 5±0.1 at 0 and 71 hours after EOS, as detailed in the Examples. [Figure 11A] 1 shows HPLC radiochromatograms of a low activity formulation containing 31 mg / ml ascorbic acid at a pH of 4.5±0.1 at 0 hours and 93 hours after EOS, as detailed in the Examples. [Figure 11B] 1 shows HPLC radiochromatograms of a low activity formulation containing 31 mg / ml ascorbic acid at a pH of 4.5±0.1 at 0 hours and 93 hours after EOS, as detailed in the Examples. [Figure 12] An embodiment of the present invention is presented. [Figure 13] An embodiment of the present invention is presented. [Figure 14] Shown are maximum intensity projections of Cycle 1 SPECT / CT images acquired for one patient (80-001) at 4, 24, 48, and 168 hours post-injection. [Figure 15] Not specified. [Figure 16] Shown are whole-body time-activity curves expressed as percentage of injected activity for each patient imaged in cycle 1. The curve with the slowest washout belongs to the patient with superscan. [Figure 17] Renal time activity curves expressed as percentage of injected activity for each patient imaged in cycle 1 are shown. [Figure 18] Shown are red bone marrow time activity curves expressed as percentage of injected activity for each patient imaged in cycle 1. The highest curve is that of patient (42-030) with a superscan, reflecting a higher dose to the bone marrow due to widespread metastatic disease in the bone. [Figure 19] Shown are salivary gland time activity curves expressed as percentage of injected activity for each patient imaged in cycle 1. No salivary glands were within the SPECT field of view for patient 12-004. [Figure 20] Shown are gastrointestinal time-activity curves expressed as percent of injected activity for each patient imaged in cycle 1. Two patients (80-004 and 25-005) did not have significant uptake in the gastrointestinal tract and are not included here. [Figure 21] Liver time activity curves expressed as percentage of injected activity for each patient imaged in cycle 1 are shown. [Figure 22] Spleen time activity curves expressed as percentage of injected activity for each patient imaged in cycle 1 are shown. [Figure 23] Shown are lacrimal gland time activity curves expressed as percentage of injected activity for each patient imaged in cycle 1. The lacrimal glands of five patients (42-027, 80-018, 66-024, 25-009, and 12-004) were not within the SPECT field of view. [Figure 24] Shown are the mean time-activity curves for cycle 1 for all source organs on a semi-logarithmic scale. [Figure 25] On a semi-logarithmic scale, plasma time activity curves in percent injected activity per liter are shown for cycle 1 patients (n=27). [Figure 26] Plasma time activity curves in percent injected activity per liter are presented for cycle 3 patients (n=15). [Figure 27] Organ depictions for representative patients are presented. DETAILED DESCRIPTION OF THE INVENTION

[0028] It will be understood that, for simplicity and clarity of illustration, reference numerals have been repeated among different figures, where appropriate, to indicate corresponding or analogous elements. Additionally, numerous specific details have been set forth in order to provide a thorough understanding of the examples described herein. However, those skilled in the art will understand that the examples described herein may be practiced without these specific details. In other instances, methods, procedures, and components have not been described in detail so as not to obscure the relevant features being described. Additionally, the specification should not be considered as limiting the scope of the embodiments described herein. The figures are not necessarily to scale, and the proportions of certain parts may be exaggerated to better illustrate the details and features of the present disclosure.

[0029] Disclosed herein are small molecule inhibitors of PSMA that possess the favorable attributes of large monoclonal antibodies with reduced negative factors such as low permeability and toxicity. 177 Includes Lu-PSMA I&T. 177 Lu-PSMA I&T is a short-lived radiolabeled material from which the product is formulated immediately after final synthesis.

[0030] The headings included herein are for ease of reference only and are not intended to limit the disclosure in any way.

[0031] Additional features and advantages of the present disclosure will be set forth in the description that follows, and in part will be obvious from the description, or may be learned by practice of the principles disclosed herein. The features and advantages of the present disclosure may be realized and obtained by means of the instruments and combinations particularly pointed out in the appended claims. These and other features of the present disclosure will become more fully apparent from the following specification and appended claims, or may be learned by practice of the principles set forth herein. All publications, patents, and patent applications cited herein, whether supra or infra, are hereby incorporated by reference in their entirety.

[0032] I. Definition Definitions that apply throughout the above disclosure are presented here. As used herein, the terms "comprising," "having," and "including" are used interchangeably in their open, non-limiting sense. The terms "a," "an," and "the" are understood to encompass plural and singular. Thus, the term "a mixture thereof" also relates to "mixtures thereof."

[0033] In general, provided ranges are intended to include all specific ranges within a given range and combinations of subranges between given ranges. Thus, a range of 1 to 5 specifically includes 1, 2, 3, 4, and 5, as well as subranges such as 2 to 5, 3 to 5, 2 to 3, 2 to 4, and 1 to 4. All ranges and values ​​disclosed herein are inclusive and combinable. For example, any value or point described herein within a range described herein can serve as a minimum or maximum value for deriving subranges, etc.

[0034] As used herein, "about" refers to numerical values, including integers, fractions, percentages, etc., whether explicitly stated or not. The term "about" generally refers to a range of numerical values, e.g., ±0.5-1%, ±1-5%, or ±5-10% of the recited value, that are considered equivalent to (e.g., have the same function or result as) the recited value.

[0035] As used herein, "PSMA" refers to prostate-specific membrane antigen, also known as folate hydrolase I or glutamate carboxypeptidase II, which is a type II transmembrane protein anchored to the cell membrane of prostate epithelial cells. PSMA is highly expressed on prostate epithelial cells and is strongly upregulated in prostate cancer. PSMA expression level is directly correlated with androgen independence, metastasis, and the progression of prostate cancer. Therefore, PSMA is currently a promising molecular target for the diagnosis and therapy of metastatic prostate cancer.

[0036] As used herein, "lutetium-177" and "177Lu" are used interchangeably. 177Lu is a beta- and gamma-emitting radionuclide with a physical half-life of 6.7 days. It has maximum and average beta particle energies of 0.498 MeV and 0.133 MeV, respectively. The maximum and average soft tissue penetration depths of 177Lu are 1.7 mm and 0.23 mm, respectively. There are two major gamma emission lines: 113 keV (6% relative abundance) and 208 keV (11% relative abundance).

[0037] As used herein, "177Lu-PSMA-617" refers to a DOTA derivative of the Glu-urea-Lys motif being developed at the German Cancer Research Center (DKFZ) Heidelberg, Germany for the treatment of patients with metastatic prostate cancer.

[0038] As used herein, "[Lu]Lu-PSMA I&T" and "Lu-PSMA I&T" refer to Lu-PSMA for imaging and therapy (I&T), which is a third generation derivative of the Lu-PSMA compound used herein. The chemical name of 177Lu-PSMA I&T is (3S,7S,26R,29R,32R,37R)-29-benzyl-32-(4-hydroxy-3-iodobenzyl)-5,13,20,28,31,34-hexaoxo-37-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)-4,6,12,21,27,30,33-heptaazaheptatriacontane-1,3,7,26,37-pentacarboxylic acid; lutetium-177(III). The chemical structure of 177Lu-PSMA I&T is provided in Figure 1B.

[0039] The term "half-life" as used herein refers to biological half-life, e.g., the time required for the blood or plasma concentration of a drug to decrease by half. This decrease in drug concentration reflects its excretion or elimination after absorption is complete and distribution reaches an equilibrium or quasi-equilibrium state. The half-life of a drug in blood can be determined graphically from a pharmacokinetic plot of the drug's blood concentration-time plot, typically after intravenous administration to a sample population. Half-life can also be determined using mathematical calculations well known in the art. Furthermore, as used herein, the term "half-life" also includes the "apparent half-life" of a drug. The apparent half-life can be a composite number that accounts for contributions from processes other than elimination, such as absorption, reuptake, or enterohepatic recycling.

[0040] As used herein, "PRLT" refers to prostate radioligand therapy, and "RLT" refers to radioligand therapy. PRLT in this context involves the systemic intravenous administration of specific radiopharmaceuticals composed of a beta-emitting radionuclide chelated to a small molecule for the purpose of delivering cytotoxic radiation to cancer cells. All compositions and methods described herein can be used to treat PRLT and / or cancer.

[0041] As used herein, the term "CRPC" refers to castration-resistant prostate cancer. In some instances, patients with CRPC may have castrate serum testosterone levels of <50 μg / L or 1.7 nmol / L, as well as one of the following progression patterns: biochemical progression or radiological progression, as defined below. All compositions and methods described herein can be used to treat CRPC and / or cancer.

[0042] As used herein, the term "biochemical progression" refers to three consecutive rises in PSA at one-week intervals, two rises of 50% above the nadir, and a PSA >2 μg / l.

[0043] As used herein, the term "RAC" refers to radioactivity concentration.

[0044] As used herein, the term "radiologic progression" refers to the appearance of new lesions, i.e., either two or more new bone lesions or soft tissue lesions on a bone scan using Response Evaluation Criteria in Solid Tumors (RECIST).

[0045] As used herein, the terms "end of synthesis," "post-formulation," and "end of formulation" are used interchangeably to mean when the process of preparing a composition is complete, which may include quality control by qualified personnel and the time after release of the drug product.

[0046] The term "active agent" or "drug," as used herein, refers to any chemical substance that elicits a biochemical response when administered to a human or animal. A drug may act as a substrate or product of a biochemical reaction, or the drug may interact with a cellular receptor to elicit a physiological response, or the drug may bind to a receptor and block it from eliciting a physiological response.

[0047] The term "adverse event" (AE) is any undesirable medical occurrence in a subject administered an investigational drug, which does not necessarily have a causal relationship to the treatment. An AE can be any untoward or unintended sign (e.g., abnormal laboratory finding), symptom, or disease temporarily associated with the use of the drug, whether or not considered a related drug. This includes any newly occurring event or a pre-existing condition that has increased in severity or frequency since administration of the drug.

[0048] The terms "subject" and "patient" are used interchangeably herein and refer to a vertebrate, preferably a mammal, including, but not limited to, a human.

[0049] As used herein, "composition" refers to a radiopharmaceutical composition, and vice versa. Thus, "composition" and "radiopharmaceutical composition" may be used interchangeably.

[0050] The term "effective amount" or "effective dose" refers to an amount of a therapy (e.g., radiation provided herein, or another active agent described herein, such as an anti-cancer therapy described herein) that is sufficient to achieve its stated purpose or otherwise achieve the effect for which it is administered. An effective dose can be sufficient to reduce and / or ameliorate the progression, occurrence, recurrence, severity, and / or duration of a given disease, disorder, or condition, and / or its associated symptoms. An effective dose can be a "therapeutically effective dose," which refers to an amount sufficient to provide a therapeutic benefit, such as reducing or ameliorating the advancement or progression of a given disease, disorder, or condition, reducing or ameliorating the recurrence, occurrence, or onset of a given disease, disorder, or condition, and / or improving or enhancing the prophylactic or therapeutic effect(s) of another therapy. A therapeutically effective amount of a composition described herein can also enhance the therapeutic effectiveness of another therapeutic agent.

[0051] The terms "therapies," "therapy," and / or "treatment" refer to any protocol(s), method(s), and / or agent(s) that can be used in the prevention, treatment, management, and / or amelioration of a disease, disorder, or condition, or one or more symptoms thereof. In certain cases, the term refers to radioligand therapy (RLT), as described herein. The term "therapy" may refer to antiviral therapy, antibacterial therapy, antifungal therapy, anticancer therapy, biological therapy, replacement therapy, and / or other therapies useful in the treatment, management, prevention, or amelioration of a disease, disorder, or condition, or one or more symptoms thereof, known to one of ordinary skill in the art, e.g., a medical professional such as a physician.

[0052] The term "cancer" refers to any physiological condition in a mammal characterized by uncontrolled cell growth. Cancers described herein include solid tumors and hematological (blood) cancers, including, but not limited to, mCRPC. "Hematological cancer" refers to any blood-based cancer, including, for example, myeloma, lymphoma, and leukemia. "Solid tumor" or "tumor" refers to all precancerous and cancerous cells and tissues that cause lesions and neoplastic cell growth and proliferation, and abnormal tissue growth, whether malignant or benign. As used herein, "neoplastic" refers to any form of dysregulated or unregulated cell growth that causes abnormal tissue growth, whether malignant or benign.

[0053] The term "treating" or "treatment" refers to any indication of success or improvement in the progression, severity, and / or duration of a disease, lesion, or condition, including any objective or subjective parameter, such as relief, remission, alleviation of symptoms, or making the injury, lesion, or condition more tolerable to the patient, slowing the rate of regression or decline, reducing wasting at the end of regression, or improving the patient's physical or mental well-being. When treating cancer or tumors, treatment can include slowing tumor growth, stopping tumor growth, reducing or shrinking the size of a tumor, preventing a tumor from changing shape or morphology, preventing the spread of a tumor (e.g., preventing metastasis), increasing survival rates, and / or decreasing mortality rates.

[0054] The term "enhance" refers to an increase or improvement in the function or activity of a protein or cell after administration of a "treatment" or "therapy" as described herein, as compared to the protein or cell prior to administration or contact with a "treatment" or "therapy" as described herein, or an improvement in the overall well-being of a patient.

[0055] The term "administering" refers to the act of delivering a pharmaceutical or radiopharmaceutical composition described herein to a subject by a parenteral route, including intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration. Administration generally occurs after the onset of a disease, disorder, or condition, or a symptom thereof, but in certain cases can occur before the onset of a disease, disorder, or condition, or a symptom thereof (e.g., administration to a patient predisposed to such a disease, disorder, or condition). In some embodiments, "intravenous infusion" is used interchangeably with "injection."

[0056] II. Introduction The present disclosure provides a method, comprising: 177 administering a radiopharmaceutical composition comprising Lu-PSMA I&T to a human patient in need thereof; 177The present invention relates to a method in which Lu has a low total absorbed radiation dose in the organs of a human patient. The low absorbed radiation dose (total, partial, or organ-specific) can be measured by one skilled in the art compared to other compositions of the prior art and objectively measured by SPECT imaging and / or two-dimensional imaging. For example, the compositions described herein 177 The method for administering Lu-PSMA I&T can, in some embodiments, be described as a mathematical formula to ensure that the total cumulative dose to a patient's kidneys after all treatments remains below 23 Gy. By providing improved safety and a reduced total absorbed radiation dose, the method of the present invention may allow for more treatment cycles for human patients (e.g., while remaining below the 23 Gy limit). Furthermore, this low absorbed dose prevents side effects associated with the use of radiopharmaceuticals when the radiopharmaceutical composition is absorbed by the human patient's organs rather than the composition's target, such as a malignant tumor. In some embodiments, the composition can be formulated as an injectable radiopharmaceutical solution. The present disclosure provides a method for administering Lu-PSMA I&T that functions as an antitumor agent for targeted radionuclide therapy. 177 The present invention further relates to high-energy, high-purity, and / or low-toxicity radiopharmaceutical compositions comprising Lu-PSMA I&T.

[0057] The present disclosure is also directed to methods of making the radiopharmaceutical compositions.

[0058] The present disclosure further relates to properties of radiopharmaceutical compositions and methods of using radiopharmaceutical compositions.

[0059] 177 Lu-PSMA I&T is also known by the following synonyms: 177 Lu]lutetium-PSMA I&T, 177 Lu-ITG-PSMA-1, PSMA-TUM3, 177 Lu-DOTAGA-(Iy)fk(Sub-KuE), or 177Lu-(3S,7S)-29-benzyl-32(3-iodo,4-hydroxy)-benzyl-5,12,20,28,31,34-hexaoxo-37-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)-4,6,12,21,27,30,33-heptaazaheptatriacontane-1,3,7,26,37-pentacarboxylic acid. The molecular formula of the unlabeled precursor is C 63 H 92 IN 11 O 23 ·4TFA·3H2O and has a relative molecular weight of 1498 g / mol.

[0060] Labeled substance 177 Lu-PSMA I&T is a non-carrier-doped lutetium-177 (T 1 / 2 =6.6d) can be labeled with solution. 177 Lu-PSMA I&T is a short-lived radiolabeled substance from which the product is formulated immediately after final synthesis. Control is performed on the labeled drug product. In another embodiment, 177 Lu-PSMA I&T can be labeled with carrier-loaded or non-carrier-loaded lutetium-177.

[0061] Synthesized 177 The Lu-PSMA I&T solution may be suitable for administration to a human patient in need thereof. 177The Lu-PSMA I&T solution may be formulated in an injection-grade aqueous solution containing a stabilizer such as ascorbic acid. The solution may be sterilized by aseptic filtration through a 0.22 μm filter before being dispensed into multi-dose vials. Administration of the formulated solution may be within 72 hours of completion of synthesis after quality control by a qualified person and release of the drug product. Administration of the formulated solution may be by injection into a human patient in need thereof within 72 hours of completion of synthesis after quality control by a qualified person and release of the drug product. Alternatively, administration of the formulated solution may be by injection into a human patient in need thereof within at least 1 week, at least 2 weeks, at least 3 weeks, at least 3.5 weeks, or at least 4 weeks after synthesis after quality control and release of the drug product by a qualified person. In this manner, the compositions described herein may be stable and suitable for administration to a human patient in need thereof for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 1 week, 1.5 weeks, 2 weeks, 2.5 weeks, 3 weeks, 3.5 weeks, and / or 4.0 weeks. Stable and suitable for administration to a human patient in need thereof may comprise a radiochemical purity of at least 95%, 95.5% or more, 96.5% or more, 97.0% or more, 97.5% or more, 98.0% or more, 98.5% or more, 99.0% or more, or 99.5% or more at the time of administration.

[0062] Ascorbic acid can be used to minimize radioactive degradation of radiolabeled preparations. In addition to ascorbic acid, a dosage formulation pH of 6.0, 5.5, or 5.0 or less can stabilize the labeled product against radioactive degradation and extend its shelf life. Thus, in another aspect, the present disclosure further provides dosage formulations containing ascorbic acid at a pH of 6, 5.5, or 5 or less, which improve the stability of radiopharmaceutical compositions against radioactive degradation and thus improve the shelf life of the compositions.

[0063] The stability-enhancing conditions can be applied as early as possible in the manufacturing process. For example, an ascorbic acid solution having a pH of 6.0, 5.5, or 5.0 or less (e.g., a pH of 6.0, 5.9, 5.8, 5.7, 5.6, 5.5, 5.4, 5.3, 5.2, 5.1, 5.0, 4.9, 4.8, 4.7, 4.6, 4.5, 4.4, 4.3, 4.2, 4.1, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.3, 3.2, 3.1, or 3.0) can be added to a labeled ascorbic acid solution. 177 It can be used in place of water in the purification steps of Lu-PSMA I&T to minimize radiolytic damage.

[0064] The compositions, when administered to a subject, can result in a low hematotoxicity, hepatotoxicity, and / or nephrotoxicity profile, providing better efficacy and fewer adverse effects than monoclonal antibody therapy and other comparable third-line therapies.

[0065] The composition is an improved composition in that it has a shelf life of more than 72 hours after formulation. In addition, the improved composition has a radiochemical purity of more than 95% at the time of administration. That is, the improved formulation maintains a high level of radiochemical purity for more than 72 hours after formulation. Thus, the improved formulation 177 It is suitable for administration for up to 24 hours or up to 72 hours longer than other compositions containing Lu-PSMA I&T.

[0066] III. Composition especially, 177 Disclosed herein is a composition comprising Lu, a PSMA I&T, and one or more optional agents, including a buffer and / or a solvent. In one embodiment, the composition is suitable for administration to a human patient in need thereof.

[0067] In one embodiment, the composition has a radiochemical purity (RCP) of 95% or greater at the time of administration. In another embodiment, the composition has a radiochemical purity (RCP) of 97% or greater at the time of administration. In another embodiment, the composition has a radiochemical purity (RCP) of 97.5% or greater at the time of administration. In another embodiment, the composition has a radiochemical purity (RCP) of 98.0% or greater, 98.5% or greater, 99.0% or greater, or 99.5% or greater at the time of administration.

[0068] In one embodiment, the composition has a radiochemical purity (RCP) of 95% or greater 72 hours after production. In another embodiment, the composition has a radiochemical purity (RCP) of 97% or greater 72 hours after production. In another embodiment, the composition has a radiochemical purity (RCP) of 97.5% or greater 72 hours after production. In another embodiment, the composition has a radiochemical purity (RCP) of 98.0% or greater, 98.5% or greater, 99.0% or greater, or 99.5% or greater 72 hours after production. In another embodiment, the composition has a radiochemical purity (RCP) of 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, or 95% or greater 7 days after production.

[0069] In one embodiment, the composition has a radiochemical purity (RCP) of 96.0% or greater, 96.5% or greater, 97.0% or greater, 97.5% or greater, 98.0% or greater, 98.5% or greater, 99.0% or greater, or 99.5% or greater after 7 days from production.

[0070] In one embodiment, the composition is produced as part of a 4 Ci to 10 Ci batch scale. In another embodiment, the composition is produced as part of a 4 Ci to 15 Ci batch scale. In another embodiment, the composition is produced as part of a 20 Ci to 32 Ci batch scale. In yet another embodiment, the composition is produced as part of a 32 Ci to 64 Ci batch scale.

[0071] A certain dose 177Further disclosed herein is a radiopharmaceutical composition or formulation comprising an Lu-PSMA I&T and at least one of a stabilizer, an antioxidant, a pH adjuster, a metal ion chelator, water, or a combination thereof.

[0072] In one specific embodiment, the stabilizer is ethanol. In another embodiment, the antioxidant may be ethanol, ascorbic acid, gentisic acid, or a combination thereof. In another embodiment, the pH adjuster includes, but is not limited to, sodium hydroxide, sodium bicarbonate, hydrochloric acid, or a combination thereof. In yet another embodiment, the chelating agent may be EDTA or DTPA. In another specific embodiment, the stabilizer is ethanol-free (i.e., 0% ethanol, less than 0.5% ethanol, or less than 1.0% ethanol (w / w) in the composition).

[0073] In one embodiment, the pharmaceutical product or radiopharmaceutical composition (or formulation) is dissolved in an aqueous solution of ascorbic acid containing ethanol. 177 The radiopharmaceutical solution may be a sterile-filtered solution containing a dose of Lu-PSMA I&T. For example, the total amount of ascorbic acid in the solution may be about 25 to about 65 mg / mL, and the total amount of ethanol in the solution may be about 3.8% (v / v) to about 7.5% (v / v). In some embodiments, the total amount of ascorbic acid in the solution is about 21 mg / mL to about 42.5 mg / mL. 177 Lu-PSMA I&T is present in sufficient amounts of radioactivity for its intended use. Experiments conducted with various dosage formulations contain approximately 31 mg / ml ascorbic acid at a pH of approximately 4.5, and radioactivity concentrations of approximately 640 MBq / ml or less. 177 These results suggest that the Lu-PSMA I&T formulation composition can provide sufficient radiochemical stability for 4 days. The sufficient radiochemical stability referred to herein is 177The radiopharmaceutical composition has a radiochemical purity of at least 95%, 95.5% or more, 96.5% or more, 97.0% or more, 97.5% or more, 98.0% or more, 98.5% or more, 99.0% or more, or 99.5% or more of Lu-PSMA I&T at the time of administration.

[0074] In one embodiment, the radiopharmaceutical composition comprises a dose of [ 177 In another embodiment, the radiopharmaceutical composition is a sterile-filtered radiopharmaceutical solution containing a dose of [Lu]Lu-PSMA I&T in an aqueous ascorbic acid solution without an ethanol solution. 177 For example, the radiopharmaceutical composition may be a microdose of [Lu]Lu-PSMA I&T in an acetate buffer solution (e.g., with or without ethanol) containing aqueous ascorbic acid and DTPA. 177 The product is diluted to a standard radioactivity concentration, and the final volume of the bulk product is then adjusted to the amount of radiopharmaceutical solution introduced. 177 Varies depending on the starting activity of Lu.

[0075] One aspect of the present disclosure provides a radiopharmaceutical composition having a pH of about 3 to about 9, about 4 to about 9, about 5 to about 9, about 3 to about 8, about 4 to about 8, about 3 to about 5, or about 5 to about 8. The pH of the radiopharmaceutical composition may be about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, about 4, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, It may be about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, about 8.0, about 8.1, about 8.2, about 8.3, about 8.4, about 8.5, or about 9.

[0076] Having a pH of 6.0 or less can stabilize the radiopharmaceutical composition against radiolysis and extend its shelf life.

[0077] In one embodiment, the pH of the radiopharmaceutical composition is from about 3 to about 5. This pH range can stabilize the radiopharmaceutical composition against radiolysis and extend its shelf life. In yet another embodiment, a radiopharmaceutical composition containing ascorbic acid and having a pH of from about 3 to about 5 can have a higher pH value and contain gentisic acid. 177 Lu-PSMA I&T has improved stability and extended shelf life compared to known radiopharmaceutical compositions. In other embodiments, the radiopharmaceutical composition may comprise the absence of gentisic acid (i.e., no gentisic acid).

[0078] The pH of the radiopharmaceutical composition is 3.0 to 6.0, 3.0 to 3.5, 3.0 to 3.05, 3.05 to 3.1, 3.0 to 3.1, 3.1 to 3.15, 3.1 to 3.2, 3.15 to 3.2, 3.2 to 3.25, 3.0 to 3.25, 3.2 to 3.3, 3.25 to 3.3, 3.3 to 3.35, 3.3 to 3.4, 3.35 to 3.4, 3.4 to 3.45, 3.4 to 3.5, 3.45 to 3.5, 3.25 to 3.5, 3.5 to 3.55, 3.5 to 3.6, 3.55 to 3.6, 3.6 to 3.65, 3.6 to 3.7, 3.65 to 3.7, 3.7 to 3.75 , 3.5~3.75, 3.7~3.8, 3.75~3.8, 3.8~3.85, 3.8~3.9, 3.85~3.9, 3.9~3.95, 3.9~4.0, 3.95~4.0, 3.5~4.0, 3.75~4.0, 4.0~4.05, 4.0~4.1, 4.05~4.1, 4.1~4.15, 4.1~4.2, 4.15~4.2, 3.5~4.2, 4.2~4.25, 4.0~4.25, 4.2~4.3, 4.25~4.3, 4.3~4.35, 4.3~4.4, 4.35~4.4, 4.4~4.45, 4.4~4.5, 4.4 5~4.5, 4.25~4.5, 4.0~4.5, 4.5~4.55, 4.5~4.6, 4.55~4.6, 4.6~4.65, 4.6~4.7, 4.65~4.7, 4.7~4.75, 4.7~4.8, 4.75~4.8, 4.8~4.85, 4.8~4.9, 4.85~4.9, 4.9~4.95, 4.9~5.0, 4.95~5.0, 4.5~5.0, 4.75~5.0, 5.0~5.1, 5.05~5.1, 5.1~5.15, 5.1~5.2, 5.15~5.2, 5.2~5.25, 5.0~5.25, 5.2~5. 5.3, 5.25-5.3, 5.3-5.35, 5.3-5.4, 5.35-5.4, 5.4-5.45, 5.4-5.5, 5.45-5.5, 5.25-5.5, 5.0-5.5, 5.5-5.55, 5.5-5.6, 5.55-5.6, 5.6-5.65, 5.6-5.7, 5.65-5.7, 5.7-5.75, 5.7-5.8, 5.75-5.8, 5.8-5.85, 5.8-5.9, 5.85-5.9, 5.9-5.95, 5.9-6.0, 5.95-6.0, 5.5-6.0, or 5.75-6.0.In some examples, the pH of the radiopharmaceutical composition may be adjusted to a final pH of 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, or 6.0. In some embodiments, including those pH numbers and ranges listed above, the pH value includes ±0.05, ±0.10, ±0.15, ±0.20, or ±0.25.

[0079] In another embodiment, the radiopharmaceutical composition or formulation has a radiochemical purity of at least about 90%, at least about 95%, or at least about 99%. In another embodiment, the radiopharmaceutical composition or formulation has a purity of about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.5%.

[0080] In another embodiment, the radiopharmaceutical composition or formulation has a radiochemical purity of at least about 90%, at least about 95%, or at least about 99% as measured by HPLC, TLC, or liquid chromatography. In another embodiment, the radiopharmaceutical composition or formulation has a purity of at least about 90.0%, at least about 91.0%, at least about 92.0%, at least about 93.0%, at least about 94.0%, at least about 95.0%, at least about 96.0%, at least about 97.0%, at least about 98.0%, at least about 99.0%, or at least about 99.5% as measured by HPLC, TLC, or liquid chromatography. In some examples, the radiopharmaceutical composition may have a radiochemical purity of 95.0% or greater, 95.5% or greater, 96.0% or greater, 96.5% or greater, 97.0% or greater, 97.5% or greater, 98.0% or greater, 98.5% or greater, 99.0% or greater, or 99.5% or greater upon administration. Figure 5 shows the radiochemical purity in different pH formulations.

[0081] In another embodiment, the radiochemical purity of the radiopharmaceutical composition or formulation is measured by HPLC, TLC, or liquid chromatography at any time after the end of synthesis (EOS). In one embodiment, the purity of the radiopharmaceutical composition or formulation is measured by HPLC, TLC, or liquid chromatography at about 0 hours, about 10 hours, about 20 hours, about 30 hours, about 40 hours, about 50 hours, about 50 hours, about 60 hours, about 70 hours, about 80 hours, about 90 hours, and about 100 hours after EOS.

[0082] In one specific embodiment, the radiopharmaceutical composition or formulation has a radiochemical purity of at least about 99% as measured by HPLC, TLC, or liquid chromatography at 0 hours after EOS. In another specific embodiment, the radiopharmaceutical composition or formulation has a purity of at least about 96.5% as measured by HPLC, TLC, or liquid chromatography at 24 hours after EOS, at least about 93% as measured by HPLC, TLC, or liquid chromatography at 46 hours after EOS, at least about 95% as measured by HPLC, TLC, or liquid chromatography at 67 hours after EOS, and at least about 96% as measured by HPLC, TLC, or liquid chromatography at 92 hours after EOS.

[0083] In another embodiment, the radioactivity is measured with a dose calibrator. 177 The amount of radioactivity in the [Lu]Lu-PSMA I&T is measured as the dose is dispensed.

[0084] In yet another embodiment, 177 The radiochemical purity of Lu-PSMA I&T is determined by liquid chromatography and thin layer chromatography with radioactivity detection.

[0085] In one embodiment, bacterial endotoxin content is measured for each batch prior to release using a PTS tester (Ph Eur method D) and sterility is determined according to Ph Eur.

[0086] In one embodiment, the radiopharmaceutical composition or formulation is stored at a temperature of about +5° C. to +40° C., about +10° C. to +35° C., or about +20° C. to +30° C. In a specific embodiment, the radiopharmaceutical composition or formulation is stored at a temperature of about +10° C., about +15° C., about +22° C., about +22.5° C., about +25° C., or at room temperature.

[0087] Another embodiment of the present disclosure provides a radioactive content of about 70% to 130% of the target administered dose. The radioactive content of the radiopharmaceutical composition may be about 70% to 125%, 70% to 120%, 70% to 115%, 70% to 110%, 80% to 130%, 85% to 130%, 90% to 130%, 95% to 130%, 75% to 125%, 75% to 120%, 75% to 115%, 75% to 110%, 80% to 125%, 80% to 120%, 80% to 115%, 80% to 110%, 85% to 125%, 85% to 120%, 85% to 115%, 85% to 110%, 90% to 125%, 90% to 120%, 90% to 115%, or 90% to 110%.

[0088] In a specific embodiment, the radioactive content of the formulation is about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 105%, about 110%, about 115%, about 120%, about 125%, or about 130% of the target administered dose.

[0089] Another aspect of the present disclosure provides a radiopharmaceutical composition having a mean whole-body effective dose of about 23±20 Gy (3.3 Gy / GBq), and mean absorbed organ doses of about 26±20 Gy (3.4 Gy / GBq), 24±16 Gy (3.2 Gy / GBq), 8.5±4.7 Gy (1.28 Gy / GBq), and 13±7.4 Gy (1.7 Gy / GBq) for bone metastases, lymph node metastases, liver metastases, and lung metastases, respectively.

[0090] In some embodiments, the radiopharmaceutical composition upon formulation may have a low radioactivity concentration ("low RAC") of about 563 MBq / ml to about 734 MBq / ml. For example, the radiopharmaceutical composition may have a low activity that may be about 11,580 MBq (313 mCi), about 11,770 MBq (318 mCi), or about 12,520 MBq (338 mCi) in a 15-20 ml volume of solution. In other embodiments, the radiopharmaceutical composition may have a low radioactivity concentration of at least about 550 MBq / ml, at least about 560 MBq / ml, at least about 570 MBq / ml, at least about 580 MBq / ml, at least about 590 MBq / ml, at least about 600 MBq / ml, at least about 610 MBq / ml, at least about 620 MBq / ml, at least about 630 MBq / ml, at least about 640 MBq / ml, at least about 650 MBq / ml, at least about 660 MBq / ml, at least about 670 MBq / ml, at least about 680 MBq / ml, at least about 690 MBq / ml, at least about 700 MBq / ml, at least about 710 MBq / ml, at least about 720 MBq / ml, at least about 730 MBq / ml, at least about 740 MBq / ml, or at least about 750 MBq / ml. In still other embodiments, the radiopharmaceutical composition may have a low radioactivity concentration of about 550 MBq / ml to about 575 MBq / ml, about 575 MBq / ml to about 600 MBq / ml, about 600 MBq / ml to about 625 MBq / ml, about 625 MBq / ml to about 650, about 650 MBq / ml to about 675 MBq / ml, about 675 MBq / ml to about 700 MBq / ml, about 700 MBq / ml to about 725 MBq / ml, or about 725 MBq / ml to about 750 MBq / ml.

[0091] In additional embodiments, the radiopharmaceutical composition upon formulation may have a high radioactivity concentration ("high RAC") of about 1,270 MBq / ml to about 1,311 MBq / ml. For example, the radiopharmaceutical composition may have a high activity that may be about 12,780 MBq (345 mCi), about 12,810 MBq (346 mCi), or about 13,110 MBq (354 mCi) in a 10 ml volume of solution. In other embodiments, the radiopharmaceutical composition is at least about 1,100 MBq / ml, at least about 1,110 MBq / ml, at least about 1,120 MBq / ml, at least about 1,130 MBq / ml, at least about 1,140 MBq / ml, at least about 1,150 MBq / ml, at least about 1,160 MBq / ml, at least about 1,170 MBq / ml, at least about 1,180 MBq / ml, at least about 1,190 MBq / ml, at least about 1,200 MBq / ml, at least about 1,210 MBq / ml, at least about 1,220 MBq / ml, at least about 1,230 MBq / ml, at least about 1,240 MBq / ml, at least about 1,250 MBq / ml, at least about 1,260 MBq / ml, at least about 1,270 MBq / ml, at least about 1,280 MBq / ml, at least about 1,300 MBq / ml, at least about 1,310 MBq / ml, at least about 1,320 MBq / ml, at least about 1,330 MBq / ml, at least about 1,340 MBq / ml, at least about 1,350 MBq / ml, at least about 1,360 MBq / ml, at least about 1,370 MBq / ml, at least about 1,380 MBq / ml, at least about 1,390 MBq / ml, at least about 1,400 MBq / ml, at least about 1,410 MBq / ml, at least about 1,420 MBq / ml, at least about 1,430 MBq / ml, at least about 1,440 MBq / ml, at least about 1,450 MBq / ml, at least about 1,46 The radioactive material may have a high radioactivity concentration of 20 MBq / ml, at least about 1,230 MBq / ml, at least about 1,240 MBq / ml, at least about 1,250 MBq / ml, at least about 1,260 MBq / ml, at least about 1,270 MBq / ml, at least about 1,280 MBq / ml, at least about 1,290 MBq / ml, at least about 1,300 MBq / ml, at least about 1,310 MBq / ml, at least about 1,320 MBq / ml, at least about 1,330 MBq / ml, at least about 1,340 MBq / ml, or at least about 1,350 MBq / ml. In still other embodiments, the radiopharmaceutical composition may have a high radioactivity concentration of about 1,000 MBq / ml to about 1,400 MBq / ml, about 1,050 MBq / ml to about 1,350 MBq / ml, about 1,100 MBq / ml to about 1,300 MBq / ml, about 1,150 MBq / ml to about 1,250 MBq / ml, about 1,200 MBq / ml to about 1,300 MBq / ml, about 1,250 MBq / ml to about 1,350 MBq / ml, or about 1,250 MBq / ml to about 1,300 MBq / ml.

[0092] (i) 177 Lu]Lu-PSMA I&T

[0023] present in the radiopharmaceutical composition177 The total amount of [Lu]Lu-PSMA I&T can be varied and will change. Figures 1A and 1B show the precursor PSMA I&T and 177 The chemical structure of Lu-PSMA I&T is shown.

[0093] In one embodiment, the radiopharmaceutical component ([ 177 In yet another embodiment, the mass of the radiopharmaceutical component ([Lu]Lu-PSMA I&T) in the drug product is less than about 40 μg, less than about 35 μg, less than about 30 μg, less than about 25 μg, less than about 20 μg, less than about 15 μg, or less than about 10 μg per vial. 177 The mass of [Lu]Lu-PSMA I&T) is about 1 μg, about 2 μg, about 3 μg, about 4 μg, about 5 μg, about 6 μg, about 7 μg, about 8 μg, about 9 μg, or about 10 μg, about 11 μg, about 12 μg, about 13 μg, about 14 μg, about 15 μg, about 16 μg, about 17 μg, about 18 μg, about 17.2 μg, about 18 μg, or about 19 μg per vial. About 19 μg, about 20 μg, about 21 μg, about 22 μg, about 23 μg, about 24 μg, about 25 μg, about 26 μg, about 27 μg, about 28 μg, about 29 μg, about 30 μg, about 31 μg, about 32 μg, about 33 μg, about 34 μg, about 35 μg, about 36 μg, about 37 μg, about 38 μg, about 39 μg, or about 40 μg 177 Lu]Lu-PSMA I&T.

[0094] In one embodiment, the pharmaceutical composition contains 177 The total amount of [Lu]Lu-PSMA I&T can be varied and will change. In the labeling process, the PSMA I&T ligand may be labeled with a trace metal present to form a chelated trace metal-PSMA I&T complex (i.e., "M-PSMA I&T"). Excess PSMA I&T present in the labeling process may be 177 The amount of M-PSMA I&T and unlabeled PSMA I&T in the composition is hereinafter referred to as "related substances" or "RS." The composition is then 177The formulation may contain both [Lu]Lu-PSMA I&T, M-PSMA I&T, and unlabeled PSMA I&T. In one embodiment, the PSMA content, including PSMA I&T and related substances (RS), is 250 μg / dose ±15%, ±10%, or ±5%. In another embodiment, the PSMA I&T content is 120 μg / dose ±15%, ±10%, or ±5% to about 250 μg / dose ±15%, ±10%, or ±5%. In another embodiment, the PSMA I&T content is 120 μg / dose ±15%, ±10%, or ±5% to about 200 μg / dose ±15%, ±10%, or ±5%. In another embodiment, the PSMA I&T content is about 100 μg / dose ±15%, ±10%, or ±5% to about 120 μg / dose ±15%, ±10%, or ±5%. In yet another embodiment, the PSMA I&T content is about 40 μg / dose ±15%, ±10%, or ±5% to about 100 μg / dose ±15%, ±10%, or ±5%, 50 μg / dose ±15%, ±10%, or ±5% to about 100 μg / dose ±15%, ±10%, or ±5%, 60 μg / dose ±15%, ±10%, or ±5% to about 100 μg / dose ±15%, ±10%, or ±5%, or 70 μg / dose ±15%, ±10%, or ±5% to about 100 μg / dose ±15%, ±10%, or ±5%. In yet another embodiment, the PSMA I&T content is about 40 μg / dose ±15%, ±10%, or ±5% to about 90 μg / dose ±15%, ±10%, or ±5%, 50 μg / dose ±15%, ±10%, or ±5% to about 90 μg / dose ±15%, ±10%, or ±5%, 60 μg / dose ±15%, ±10%, or ±5% to about 90 μg / dose ±15%, ±10%, or ±5%, or 70 μg / dose ±15%, ±10%, or ±5% to about 90 μg / dose ±15%, ±10%, or ±5%.In yet another embodiment, the PSMA I&T content is about 40 μg / dose ±15%, ±10%, or ±5% to about 80 μg / dose ±15%, ±10%, or ±5%, 50 μg / dose ±15%, ±10%, or ±5% to about 80 μg / dose ±15%, ±10%, or ±5%, 60 μg / dose ±15%, ±10%, or ±5% to about 80 μg / dose ±15%, ±10%, or ±5%, or 70 μg / dose ±15%, ±10%, or ±5% to about 80 μg / dose ±15%, ±10%, or ±5%.

[0095] In another embodiment, the compound of formula (I) described herein 177 Lu]Lu-PSMA Compositions containing I&T may include about 120 μg / dose to about 250 μg / dose, about 130 μg / dose to about 250 μg / dose, about 140 μg / dose to about 250 μg / dose Amount, about 150μg / dose to about 250μg / dose, about 160μg / dose to about 250μg / dose, about 170μg / dose to about 250μg / dose, about 180μg / dose Amount ~ approx. 250 μg / dose, approx. 190 μg / dose ~ approx. 250 μg / dose, approx. 200 μg / dose ~ approx. 250 μg / dose, approx. 210 μg / dose ~ approx. 250 μg / dose PSMA in an amount of about 220 μg / dose to about 250 μg / dose, about 230 μg / dose to about 250 μg / dose, or about 240 μg / dose to about 250 μg / dose In another embodiment, the composition may contain the I&T content described herein. 177 A composition comprising [Lu]Lu-PSMA I&T may comprise a PSMA I&T content of about 100 μg / dose to about 120 μg / dose, about 105 μg / dose to about 120 μg / dose, about 110 μg / dose to about 120 μg / dose, or about 115 μg / dose to about 120 μg / dose. 177Lu]Lu-PSMA Compositions comprising I&T may include about 30 μg / dose to about 100 μg / dose, about 35 μg / dose to about 100 μg / dose, about 40 μg / dose to about 100 μg / dose, about 45 μg / dose to about 100 μg / dose, μg / dose ~ approx. 100 μg / dose, approx. 50 μg / dose ~ approx. 100 μg / dose, approx. 55 μg / dose ~ approx. 100 μg / dose, approx. 60 μg / dose ~ approx. 100 μg / dose In another embodiment, the PSMA I&T content may be about 65 μg / dose to about 100 μg / dose, about 70 μg / dose to about 100 μg / dose, about 75 μg / dose to about 100 μg / dose, about 80 μg / dose to about 100 μg / dose, about 85 μg / dose to about 100 μg / dose, about 90 μg / dose to about 100 μg / dose, or about 95 μg / dose to about 100 μg / dose. 177 Compositions comprising [Lu]Lu-PSMA I&T may comprise a PSMA I&T content of about 45 μg / dose to about 95 μg / dose, 50 μg / dose to about 100 μg / dose, 55 μg / dose to about 95 μg / dose, 60 μg / dose to about 95 μg / dose, 65 μg / dose to about 95 μg / dose, 70 μg / dose to about 95 μg / dose, 75 μg / dose to about 95 μg / dose, 80 μg / dose to about 95 μg / dose, 85 μg / dose to about 95 μg / dose, or about 90 μg / dose to about 95 μg / dose. 177 Compositions comprising [Lu]Lu-PSMA I&T may comprise a PSMA I&T content of about 40 μg / dose to about 90 μg / dose, about 45 μg / dose to about 90 μg / dose, about 50 μg / dose to about 90 μg / dose, about 55 μg / dose to about 90 μg / dose, about 60 μg / dose to about 90 μg / dose, about 65 μg / dose to about 90 μg / dose, about 70 μg / dose to about 90 μg / dose, about 75 μg / dose to about 90 μg / dose, about 80 μg / dose to about 90 μg / dose, or about 85 μg / dose to about 90 μg / dose. 177Compositions comprising [Lu]Lu-PSMA I&T may comprise a PSMA I&T content of about 40 μg / dose to about 85 μg / dose, about 45 μg / dose to about 85 μg / dose, about 50 μg / dose to about 85 μg / dose, about 55 μg / dose to about 85 μg / dose, about 60 μg / dose to about 85 μg / dose, about 65 μg / dose to about 85 μg / dose, about 70 μg / dose to about 85 μg / dose, about 75 μg / dose to about 85 μg / dose, or about 80 μg / dose to about 85 μg / dose. In another embodiment, the compositions comprising [Lu]Lu-PSMA I&T described herein may comprise a PSMA I&T content of about 40 μg / dose to about 85 μg / dose, about 45 μg / dose to about 85 μg / dose, about 50 μg / dose to about 85 μg / dose, about 55 μg / dose to about 85 μg / dose, about 60 μg / dose to about 85 μg / dose, about 65 μg / dose to about 85 μg / dose, about 70 μg / dose to about 85 μg / dose, about 75 μg / dose to about 85 μg / dose, or about 80 μg / dose to about 85 μg / dose. 177 Compositions comprising [Lu]Lu-PSMA I&T may comprise a PSMA I&T content of about 40 μg / dose to about 80 μg / dose, about 45 μg / dose to about 80 μg / dose, about 50 μg / dose to about 80 μg / dose, about 55 μg / dose to about 80 μg / dose, about 60 μg / dose to about 80 μg / dose, about 65 μg / dose to about 80 μg / dose, about 70 μg / dose to about 80 μg / dose, or about 75 μg / dose to about 80 μg / dose. 177 Lu]Lu-PSMA Compositions comprising I&T may include about 40 μg / dose to about 75 μg / dose, about 45 μg / dose to about 75 μg / dose, about 50 μg / dose to about 75 μg / dose, about 55 μg / dose PSMA that is a dose ~ about 75μg / dose, about 60μg / dose ~ about 75μg / dose, about 65μg / dose ~ about 75μg / dose, about 70μg / dose ~ about 75μg / dose May contain I&T content.

[0096] In one embodiment, the pharmaceutical composition contains 177The [Lu]Lu-PSMA I&T amount is approximately 30μg-120μg per vial, 35μg-120μg per vial, 40μg-120μg per vial, 45μg-120μg per vial, 50μg-120μg per vial, 55μg-120μg per vial, 60μg-120μg per vial, 65μg-120μg per vial, 70μg per vial g to 120 μg per vial, 75 μg to 120 μg per vial, 85 μg to 120 μg per vial, 90 μg to 120 μg per vial, 95 μg to 120 μg per vial, 100 μg to 120 μg per vial, 105 μg to 120 μg per vial, 110 μg to 120 μg per vial, or 115 μg to 120 μg per vial. In one embodiment, the amount of PSMA I&T present in the pharmaceutical composition is about 30 μg to 100 μg per vial, 35 μg to 100 μg per vial, 40 μg to 100 μg per vial, 45 μg to 100 μg per vial, 50 μg to 100 μg per vial, 55 μg to 100 μg per vial, 60 μg to 100 μg per vial, 65 μg to 100 μg per vial, 70 μg to 100 μg per vial, 75 μg to 100 μg per vial, 85 μg to 100 μg per vial, or 90 μg to 100 μg per vial. In another embodiment, the amount of PSMA I&T present in the pharmaceutical composition is about 30 μg-90 μg per vial, 35 μg-90 μg per vial, 40 μg-90 μg per vial, 45 μg-90 μg per vial, 50 μg-90 μg per vial, 55 μg-90 μg per vial, 60 μg-90 μg per vial, 65 μg-90 μg per vial, 70 μg-90 μg per vial, 75 μg-90 μg per vial, or 85 μg-90 μg per vial.In another embodiment, the amount of PSMA I&T present in the pharmaceutical composition is about 30 μg to 80 μg per vial, 35 μg to 80 μg per vial, 40 μg to 80 μg per vial, 45 μg to 80 μg per vial, 50 μg to 80 μg per vial, 55 μg to 80 μg per vial, 60 μg to 80 μg per vial, 65 μg to 80 μg per vial, 70 μg to 80 μg per vial, or 75 μg to 80 μg per vial. In yet another embodiment, the amount of PSMA I&T present in the pharmaceutical composition is about 30 μg-70 μg per vial, 35 μg-70 μg per vial, 40 μg-70 μg per vial, 45 μg-70 μg per vial, 50 μg-70 μg per vial, 55 μg-70 μg per vial, 60 μg-70 μg per vial, or 65 μg-70 μg per vial.

[0097] In one embodiment, the pharmaceutical composition contains 177 The amount of [Lu]Lu-PSMA I&T and related substances (RS) is approximately 30 μg to 120 μg per vial, 35 μg to 120 μg per vial, 40 μg to 120 μg per vial, 45 μg to 120 μg per vial, 50 μg to 120 μg per vial, 55 μg to 120 μg per vial, 60 μg to 120 μg per vial, 65 μg to 120 μg per vial, In one embodiment, the amount of [ 177The amount of [Lu]Lu-PSMA I&T and related substances (RS) is about 30 μg-100 μg per vial, 35 μg-100 μg per vial, 40 μg-100 μg per vial, 45 μg-100 μg per vial, 50 μg-100 μg per vial, 55 μg-100 μg per vial, 60 μg-100 μg per vial, 65 μg-100 μg per vial, 70 μg-100 μg per vial, 75 μg-100 μg per vial, 85 μg-100 μg per vial, or 90 μg-100 μg per vial. 177 The amount of [Lu]Lu-PSMA I&T and related substances (RS) is about 30 μg-90 μg per vial, 35 μg-90 μg per vial, 40 μg-90 μg per vial, 45 μg-90 μg per vial, 50 μg-90 μg per vial, 55 μg-90 μg per vial, 60 μg-90 μg per vial, 65 μg-90 μg per vial, 70 μg-90 μg per vial, 75 μg-90 μg per vial, or 85 μg-90 μg per vial. In another embodiment, the amount of [Lu]Lu-PSMA I&T and related substances (RS) present in the pharmaceutical composition is about 30 μg-90 μg per vial, 35 μg-90 μg per vial, 40 μg-90 μg per vial, 45 μg-90 μg per vial, 50 μg-90 μg per vial, 55 μg-90 μg per vial, 60 μg-90 μg per vial, 65 μg-90 μg per vial, 70 μg-90 μg per vial, 75 μg-90 μg per vial, or 85 μg-90 μg per vial. 177 The amount of [Lu]Lu-PSMA I&T and related substances (RS) is about 30 μg-80 μg per vial, 35 μg-80 μg per vial, 40 μg-80 μg per vial, 45 μg-80 μg per vial, 50 μg-80 μg per vial, 55 μg-80 μg per vial, 60 μg-80 μg per vial, 65 μg-80 μg per vial, 70 μg-80 μg per vial, or 75 μg-80 μg per vial. 177 The amount of [Lu]Lu-PSMA I&T and related substances (RS) is about 30 μg-70 μg per vial, 35 μg-70 μg per vial, 40 μg-70 μg per vial, 45 μg-70 μg per vial, 50 μg-70 μg per vial, 55 μg-70 μg per vial, 60 μg-70 μg per vial, or 65 μg-70 μg per vial.

[0098] In another embodiment, the pharmaceutical composition contains 177 In another embodiment, the amount of [Lu]Lu-PSMA I&T and related substances (RS) present in the pharmaceutical composition is about 55 μg to 110 μg per vial. 177 The amount of [Lu]Lu-PSMA I&T and related substances (RS) is approximately 75 μg to 100 μg per vial.

[0099] In one embodiment, the pharmaceutical composition contains 177 In another embodiment, the amount of [Lu]Lu-PSMA I&T and related substances (RS) present in the pharmaceutical composition is about 80 μg to 110 μg per vial. 177 In another embodiment, the amount of [Lu]Lu-PSMA I&T and related substances (RS) present in the pharmaceutical composition is about 70 μg to 85 μg per vial. 177 In another embodiment, the amount of [Lu]Lu-PSMA I&T and related substances (RS) present in the pharmaceutical composition is about 73 μg to 85 μg per vial. 177 In another embodiment, the amount of [Lu]Lu-PSMA I&T and related substances (RS) present in the pharmaceutical composition is about 90 μg to 115 μg per vial. 177 The amount of [Lu]Lu-PSMA I&T and related substances (RS) is approximately 100 μg to 80 μg per vial.

[0100] In one embodiment, the pharmaceutical composition contains 177 In another embodiment, the amount of [Lu]Lu-PSMA I&T and related substances (RS) present in the pharmaceutical composition is about 110 μg to 80 μg per vial. 177 The amount of [Lu]Lu-PSMA I&T and related substances (RS) is about 115 μg to 125 μg per vial. In another embodiment, the amount of PSMA I&T and related substances (RS) present in the pharmaceutical composition is about 115 μg to 130 μg per vial.

[0101] In one embodiment, the pharmaceutical composition contains 177The amount of [Lu]Lu-PSMA I&T and related substances (RS) is about 45 μg, 50 μg, 57 μg, 60 μg, 70 μg, 75 μg, 80 μg, 85 μg, 99 μg, 100 μg, 115 μg, 80 μg, 125 μg, 130 μg per vial. In another embodiment, the amount of PSMA I&T and related substances (RS) present in the pharmaceutical composition is about 80 μg.

[0102] In one embodiment, the pharmaceutical composition contains 177 In one embodiment, the amount of PSMA I&T and related substances (RS) present in the pharmaceutical composition is about 99 μg.

[0103] In one embodiment, 177 In another embodiment, the total volume of the vial containing [Lu]Lu-PSMA I&T and related substances (RS) is about 5 to 30 mL. 177 In another embodiment, the total volume of the vial containing [Lu]Lu-PSMA I&T and related substances (RS) is about 10-20 mL. 177 In another embodiment, the total volume of the vial containing [Lu]Lu-PSMA I&T and related substances (RS) is about 15-20 mL. 177 In another embodiment, the total volume of the vial containing [Lu]Lu-PSMA I&T and related substances (RS) is about 15-17 mL. 177 The total volume of the vial containing the [Lu]Lu-PSMA I&T and related substances (RS) is approximately 15 mL.

[0104] In one embodiment, [ 177 In another embodiment, the concentration of [Lu]Lu-PSMA I&T and related substances (RS) is 3-8 μg / mL. 177 In another embodiment, the concentration of [Lu]Lu-PSMA I&T and related substances (RS) is 4-7 μg / mL. 177 In another embodiment, the concentration of [Lu]Lu-PSMA I&T and related substances (RS) is 4.5-6.5 μg / mL.177 The concentrations of [Lu]Lu-PSMA I&T and related substances (RS) are 4.8–6 μg / mL.

[0105] In one embodiment, [ 177 In another embodiment, the concentration of [Lu]Lu-PSMA I&T and related substances (RS) is 4 μg / mL. 177 In another embodiment, the concentration of [Lu]Lu-PSMA I&T and related substances (RS) is 5 μg / mL. 177 In another embodiment, the concentration of [Lu]Lu-PSMA I&T and related substances (RS) is 6 μg / mL. 177 In another embodiment, the concentration of [Lu]Lu-PSMA I&T and related substances (RS) is 7 μg / mL. 177 The concentration of [Lu]Lu-PSMA I&T and related substances (RS) is 8 μg / mL.

[0106] In one embodiment, the PSMA I&T in the composition 177 In another embodiment, the molar ratio of PSMA I&T to Lu in the composition is 4.0:1.0 to 12.0:1.0. 177 The molar ratio to Lu is 4.0:1.0 to 12.0:1.0, 4.0:1.0 to 11.5:1.0, 4.0:1.0 to 11.0:1.0, 4.0:1.0 to 10.5:1.0, 4.0:1.0 to 10.0:1.0, 4.0:1.0 to 9.5:1.0, 4.0:1.0 to 9.0:1.0, 4.0:1.0 to 8.5:1.0, 4.0:1.0 to 8.0:1.0, 4.0:1.0 to 7.5:1.0, 4.0:1.0 to 7.0:1.0, 4.0:1.0 to 6.5:1.0, or 4.0:1.0 to 6.0:1.0.

[0107] In one embodiment, the PSMA I&T in the composition 177In another embodiment, the molar ratio of PSMA I&T to Lu in the composition is 11.0:1.0 to 12.0:1.0, 11.1:1.0 to 11.9:1.0, 11.2:1.0 to 11.8:1.0, 11.3:1.0 to 11.7:1.0, or 11.4:1.0 to 11.6:1.0. 177 The molar ratio to Lu is 10.0:1.0 to 11.0:1.0, 10.1:1.0 to 10.9:1.0, 10.2:1.0 to 10.8:1.0, 10.3:1.0 to 10.7:1.0, or 10.4:1.0 to 10.6:1.0.

[0108] In one embodiment, the PSMA I&T in the composition 177 In another embodiment, the molar ratio of PSMA I&T to Lu in the composition is 9.0:1.0 to 10.0:1.0, 9.1:1.0 to 9.9:1.0, 9.2:1.0 to 9.8:1.0, 9.3:1.0 to 9.7:1.0, or 9.4:1.0 to 9.6:1.0. 177 In another embodiment, the molar ratio of PSMA I&T to Lu in the composition is 8.0:1.0 to 9.0:1.0, 8.1:1.0 to 8.9:1.0, 8.2:1.0 to 8.8:1.0, 8.3:1.0 to 8.7:1.0, or 8.4:1.0 to 8.6:1.0. 177 In another embodiment, the molar ratio of PSMA I&T to Lu in the composition is 7.0:1.0 to 8.0:1.0, 7.1:1.0 to 7.9:1.0, 7.2:1.0 to 7.8:1.0, 7.3:1.0 to 7.7:1.0, or 7.4:1.0 to 7.6:1.0. 177 In another embodiment, the molar ratio of PSMA I&T to Lu in the composition is 6.0:1.0 to 7.0:1.0, 6.1:1.0 to 6.9:1.0, 6.2:1.0 to 7.8:1.0, 7.3:1.0 to 7.7:1.0, or 7.4:1.0 to 6.6:1.0. 177 The molar ratio to Lu is 5.0:1.0 to 6.0:1.0, 5.1:1.0 to 5.9:1.0, 5.2:1.0 to 5.8:1.0, 5.3:1.0 to 5.7.0:1.0, or 5.4:1.0 to 5.6:1.0.

[0109] In one embodiment, the PSMA I&T in the composition 177 The molar ratio to Lu is about 4.0:1.0 to about 4.5:1.0, about 4.5:1.0 to about 5.0:1.0, about 5.0:1.0 to about 5.5:1.0, about 5.5:1.0 to about 6.0:1.0, about 6.0:1.0 to about 6.5:1.0, about 6.5:1.0 to about 7.0:1.0, about 7.0:1.0 to about 7.5:1.0, about 7.5:1.0 to about 8.0:1.0, about The ratio is 8.0:1.0 to about 8.5:1.0, about 8.5:1.0 to about 9.0:1.0, about 9.0:1.0 to about 9.5:1.0, about 9.5:1.0 to about 10.0:1.0, about 10.0:1.0 to about 10.5:1.0, about 10.5:1.0 to about 11.0:1.0, about 11.0:1.0 to about 11.5:1.0, or about 11.5:1.0 to about 12.0:1.0.

[0110] In one embodiment, the PSMA I&T in the composition 177 The molar ratio to Lu is about 4.0:1.0 to about 4.5:1.0, about 4.0:1.0 to about 5.0:1.0, about 4.0:1.0 to about 5.5:1.0, about 4.0:1.0 to about 6.0:1.0, about 4.0:1.0 to about 6.5:1.0, about 4.0:1.0 to about 7.0:1.0, about 4.0:1.0 to about 7.5:1.0, about 4.0:1.0 to about 8.0:1.0 .0, about 4.5:1.0 to about 8.0:1.0, about 5.0:1.0 to about 8.0:1.0, about 5.0:1.0 to about 8.0:1.0, about 5.5:1.0 to about 8.0:1.0, about 6.0:1.0 to about 8.0:1.0, about 6.5:1.0 to about 8.0:1.0, about 7.0:1.0 to about 8.0:1.0, or about 7.5:1.0 to about 8.0:1.0.

[0111] In some embodiments, the [ 177 The total amount of [Lu]Lu-PSMA I&T can range from about 1.0 μg / ml to about 3 μg / ml, from about 1 μg / ml to about 2 μg / ml, from about 1.1 μg / ml to about 2 μg / ml, from about 1.1 μg / ml to about 1.5 μg / ml, from about 1.1 μg / ml to about 1.4 μg / ml, or from about 1.1 μg / ml to about 1.3 μg / ml. In another embodiment, the total amount of [Lu]Lu-PSMA I&T in the radiopharmaceutical composition can range from about 1.0 μg / ml to about 3 μg / ml, from about 1 μg / ml to about 2 μg / ml, from about 1.1 μg / ml to about 1.5 μg / ml, from about 1.1 μg / ml to about 1.4 μg / ml, or from about 1.1 μg / ml to about 1.3 μg / ml. 177The total amount of [Lu]Lu-PSMA I&T can range from about 0.5 μg / ml to about 1.5 μg / ml. In various embodiments, the total amount of [Lu]Lu-PSMA I&T present in the radiopharmaceutical composition can range from about 0.5 μg / ml to about 1.5 μg / ml. 177 The total amount of [Lu]Lu-PSMA I&T can be about 0.5 μg / ml, about 0.6 μg / ml, about 0.7 μg / ml, about 0.8 μg / ml, about 0.9 μg / ml, about 1.0 μg / ml, about 1.1 μg / ml, about 1.2 μg / ml, about 1.3 μg / ml, about 1.4 μg / ml, about 1.5 μg / ml, about 1.6 μg / ml, about 1.7 μg / ml, or about 1.8 μg / ml.

[0112] In some embodiments, the [ 177 The total amount of [Lu]Lu-PSMA I&T can range from about 3.0 μg / ml to about 9.0 μg / ml, from about 3.5 μg / ml to about 8.5 μg / ml, from about 4.0 μg / ml to about 8.0 μg / ml, from about 4.5 μg / ml to about 7.5 μg / ml, from about 5.0 μg / ml to about 7.0 μg / ml, or from about 5.5 μg / ml to about 6.5 μg / ml. In another embodiment, the total amount of [Lu]Lu-PSMA I&T in the radiopharmaceutical composition can range from about 3.0 μg / ml to about 9.0 μg / ml, from about 3.5 μg / ml to about 8.5 μg / ml, from about 4.0 μg / ml to about 8.0 μg / ml, from about 4.5 μg / ml to about 7.5 μg / ml, from about 5.0 μg / ml to about 7.0 μg / ml, or from about 5.5 μg / ml to about 6.5 μg / ml. 177 The total amount of [Lu]Lu-PSMA I&T can range from about 0.5 μg / ml to about 1.5 μg / ml.

[0113] In some embodiments, the [ 177 The total amount of [Lu]Lu-PSMA I&T may be less than 3.0 μg / ml. In other embodiments, the total amount of [Lu]Lu-PSMA I&T present in the radiopharmaceutical composition may be less than 3.0 μg / ml. 177 The total amount of [Lu]Lu-PSMA I&T may be less than 4.0 μg / ml. In other embodiments, the total amount of [Lu]Lu-PSMA I&T present in the radiopharmaceutical composition may be less than 4.0 μg / ml. 177 The total amount of [Lu]Lu-PSMA I&T may be less than 5.0 μg / ml. In other embodiments, the total amount of [Lu]Lu-PSMA I&T present in the radiopharmaceutical composition may be less than 5.0 μg / ml. 177 The total amount of [Lu]Lu-PSMA I&T can be less than 6.0 μg / ml.

[0114] In some embodiments, the [ 177The total amount of [Lu]Lu-PSMA I&T can be in the range of about 9 μg / ml to 20 μg / ml, 10 μg / ml to 20 μg / ml, 11 μg / ml to 20 μg / ml, 11 μg / ml to 15 μg / ml, 11 μg / ml to 14 μg / ml, or 11 μg / ml to 13 μg / ml. 177 The total amount of [Lu]Lu-PSMA I&T can range from about 5 μg / ml to about 15 μg / ml. In various embodiments, the total amount of [Lu]Lu-PSMA I&T present in the radiopharmaceutical composition can range from about 5 μg / ml to about 15 μg / ml. 177 The total amount of Lu]Lu-PSMA I&T can be about 5 μg / ml, 6 μg / ml, 7 μg / ml, 8 μg / ml, 9 μg / ml, 10 μg / ml, 11 μg / ml, 12 μg / ml, 13 μg / ml, 14 μg / ml, 15 μg / ml, 16 μg / ml, 17 μg / ml, or 18 μg / ml. The composition can have less than 12 μg / ml, or less than 6 μg / ml of Lu-PSMA I&T.

[0115] [ in the composition 177 The activity / volume of the [Lu]Lu-PSMA I&T can be adjusted according to the dose intensity. In one embodiment, the composition contains 0.5 GBq (13.5 mCi) of [Lu]Lu in 1 ml of solution. 177 In other words, the composition may contain 10 GBq (270 mCi) of [Lu]Lu-PSMA I&T in a 20 ml solution. 177 In another embodiment, the composition may comprise 1 GBq (27 mCi) of [Lu]Lu-PSMA I&T in 1 ml of solution. 177 In other words, the composition may contain 10 GBq (270 mCi) of Lu-PSMA I&T in a 10 ml solution. 177 Lu-PSMA I&T may be included.

[0116] In one embodiment, the [ 177 The radioactivity concentration of the [Lu]Lu-PSMA I&T is less than about 50 mCi / ml, less than about 45 mCi / ml, less than about 40 mCi / ml, less than about 35 mCi / ml, less than about 30 mCi / ml, less than about 25 mCi / ml, less than about 20 mCi / ml, or less than about 15 mCi / ml.177 The radioactivity concentration of Lu-PSMA I&T is about 5 mCi / ml to about 30 mCi / ml, about 10 mCi / ml to about 20 mCi / ml, or about 13 mCi / ml to about 30 mCi / ml. 177 The radioactivity concentration of Lu-PSMA I&T is about 5 mCi / ml, about 10 mCi / ml, about 13.5 mCi / ml, about 15 mCi / ml, about 20 mCi / ml, about 27 mCi / ml, about 30 mCi / ml, about 30 mCi / ml, about 35 mCi / ml or about 40 mCi / ml.

[0117] In one embodiment, the [ 177 The radioactivity of the [Lu]Lu-PSMA I&T is less than about 500 mCi, less than about 450 mCi, less than about 400 mCi, less than about 350 mCi, less than about 300 mCi, less than about 250 mCi, or less than about 200 mCi per vial. 177 The radioactivity of Lu-PSMA I&T is about 10 mCi to about 750 mCi, about 200 mCi to about 600 mCi, or about 300 mCi to about 400 mCi per vial. 177 The radioactivity of the Lu]Lu-PSMA I&T is about 27 mCi, 150 mCi, about 160 mCi, about 170 mCi, about 180 mCi, about 190 mCi, about 200 mCi, about 250 mCi, about 270 mCi, about 300 mCi, about 313 mCi, about 318 mCi, about 338 mCi, about 345 mCi, about 346 mCi, about 354 mCi, about 360 mCi, about 370 mCi, about 380 mCi, about 390 mCi, about 400 mCi, about 450 mCi, about 500 mCi, about 550 mCi, about 600 mCi, or about 700 mCi per vial.

[0118] In yet another embodiment, 177 The [Lu]Lu-PSMA I&T drug product has a standard radioactivity concentration of about 12 mCi / ml or about 32 mCi / ml at the end of production. 177The Lu-PSMA I&T drug product has a standard radioactivity concentration of about 13.5 mCi / ml or about 27 mCi / ml at the end of production.

[0119] (ii) antioxidants The antioxidant may act as a buffering agent and / or stabilizer. The total amount of antioxidant in the radiopharmaceutical composition can vary and will vary. Examples of suitable antioxidants include, but are not limited to, ascorbic acid or gentisic acid. The amount of antioxidant in the composition can range from about 10 mg / ml to 90 mg / ml, about 15 mg / ml to 85 mg / ml, about 20 mg / ml to 80 mg / ml, about 25 mg / ml to 75 mg / ml, about 30 mg / ml to 70 mg / ml, about 35 mg / ml to 65 mg / ml, about 40 mg / ml to 60 mg / ml, or about 45 mg / ml to 55 mg / ml. Alternatively stated, the amount of antioxidant in the composition can range from about 10 mg to 90 mg, about 15 mg to 85 mg, about 20 mg to 80 mg, about 25 mg to 75 mg, about 30 mg to 70 mg, about 35 mg to 65 mg, about 40 mg to 60 mg, or about 45 mg to 55 mg per ml.

[0120] In some embodiments, antioxidants may be present at 10 mg / ml or less, 9.5 mg / ml or less, 9 mg / ml or less, 8.5 mg / ml or less, 8 mg / ml or less, 7.5 mg / ml or less, 7 mg / ml or less, 6.5 mg / ml or less, 6 mg / ml or less, 5.5 mg / ml or less, 5 mg / ml, 4.5 mg / ml or less, 4 mg / ml or less, 3.5 mg / ml or less, 3 mg / ml or less, 2.5 mg / ml or less, 2 mg / ml or less, 1.5 mg / ml or less, 1 mg / ml or less, or 0.5 mg / ml or less.

[0121] In certain embodiments, the antioxidant may be ascorbic acid and / or ascorbate, which may minimize or reduce radiodegradation of the radiolabeled composition.

[0122] In some embodiments, the ascorbic acid present in the radiopharmaceutical composition may be in the range of about 10 to about 50 mg per ml, about 20 to about 50 mg per ml, about 30 to about 50 mg per ml, or about 35 to about 45 mg per ml. In other embodiments, the ascorbic acid present in the radiopharmaceutical composition may be in the range of about 5 mg to about 50 mg per ml. In other embodiments, the ascorbic acid or ascorbate may be present at up to 10 mg / ml, up to 9.5 mg / ml, up to 9 mg / ml, up to 8.5 mg / ml, up to 8 mg / ml, up to 7.5 mg / ml, up to 7 mg / ml, up to 6.5 mg / ml, up to 6 mg / ml, up to 5.5 mg / ml, up to 5 mg / ml, up to 4.5 mg / ml, up to 4 mg / ml, up to 3.5 mg / ml, up to 3 mg / ml, up to 2.5 mg / ml, up to 2 mg / ml, up to 1.5 mg / ml, up to 1 mg / ml, or up to 0.5 mg / ml.

[0123] In various embodiments, the ascorbic acid present in the radiopharmaceutical composition may be about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 31 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 40.5 mg, about 41 mg, about 41.5 mg, about 42 mg, about 42.5 mg, about 43 mg, about 43.5 mg, about 44 mg, about 44.5 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, or about 90 mg per ml. For example, the amount of ascorbic acid in 1 ml of the composition can be about 25 mg to 30 mg, about 30 mg to 35 mg, about 35 mg to 40 mg, or about 40 mg to 45 mg per ml.

[0124] In yet another embodiment, the concentration of ascorbic acid in the radiopharmaceutical composition can be from about 10 mg / ml to about 80 mg / ml, from about 10 mg / ml to about 75 mg / ml, from about 10 mg / ml to about 70 mg / ml, from about 15 mg / ml to about 80 mg / ml, from about 15 mg / ml to about 75 mg / ml, from about 15 mg / ml to about 70 mg / ml, from about 20 mg / ml to about 80 mg / ml, from about 20 mg / ml to about 75 mg / ml, from about 20 mg / ml to about 70 mg / ml, or from about 20 mg / ml to about 40 mg / mL.

[0125] In a specific embodiment, the concentration of ascorbic acid in the radiopharmaceutical composition is about 10 mg / ml, about 15 mg / ml, about 20 mg / ml, about 25 mg / ml, about 21 mg / ml, about 25 mg / ml, about 30 mg / ml, about 31 mg / ml, about 35 mg / ml, about 40 mg / ml, about 42.5 mg / ml, about 45 mg / ml, about 50 mg / ml, about 55 mg / ml, about 60 mg / ml, about 65 mg / ml, about 70 mg / ml, about 75 mg / ml, about 80 mg / ml, about 85 mg / ml, about 90 mg / ml, about 95 mg / ml, or about 100 mg / ml.

[0126] In at least one embodiment, the total amount of ascorbic acid in the radiopharmaceutical composition may be about 31 mg / ml. In another embodiment, the total amount of ascorbic acid in the radiopharmaceutical composition may be about 33 mg / ml. In further embodiments, the total amount of ascorbic acid in the radiopharmaceutical composition may be about 15 mg / ml, about 21 mg / ml, about 25 mg / ml, about 31 mg / ml, 33 mg / ml, 35 mg / ml, or about 42.5 mg / ml.

[0127] (iii) stabilizers The stabilizer may be separate from the antioxidant. The total amount of stabilizer present in the radiopharmaceutical composition can and will vary. Stabilizers may also be used to limit or reduce radiolysis. The stabilizer may also function as a vehicle for the composition.

[0128] Stabilizers may include, but are not limited to, ethanol, para-aminobenzoic acid (PABA), dihydroxybenzoic acid (gentisic acid compound), gentisic acid, cysteine, selenomethionine, ascorbic acid / sodium ascorbate, methionine, and / or combinations thereof.

[0129] In some embodiments, the stabilizer is ethanol. Ethanol may be present in the pharmaceutical composition at a concentration of about 0.01% (v / v) to about 10% (v / v), 0.01% (v / v) to 3% (v / v), about 0.5% (v / v) to 1% (v / v), about 1% (v / v) to 2% (v / v), about 2% (v / v) to about 3% (v / v), about 3% (v / v) to 4% (v / v), or about 3.5% to 4.5% (v / v). ethanol may be present at about 4% to 5% (v / v), about 4.5% to 5.5% (v / v), about 5% to 6% (v / v), about 5.5% to 6.5% (v / v), about 6% to 7% (v / v), about 6.5% to 7.5% (v / v), or about 7% to 8% (v / v). In some embodiments, the pharmaceutical composition comprises zero (0.00% v / v) ethanol (i.e., ethanol may be absent from the pharmaceutical composition).

[0130] In one embodiment, the total amount of ethanol present in the radiopharmaceutical composition is from about 3% (v / v) to about 8% (v / v), or from 2% (v / v) to about 4% (v / v), or from about 7% (v / v) to about 8% (v / v). In various embodiments, the total amount of ethanol present in the radiopharmaceutical composition can be about 1% (v / v), about 2% (v / v), about 3% (v / v), about 3.5% (v / v), about 3.8% (v / v), about 4% (v / v), about 4.5% (v / v), about 5% (v / v), about 5.5% (v / v), about 6% (v / v), about 6.5% (v / v), about 7% (v / v), about 7.5% (v / v), about 8% (v / v), about 8.5% (v / v), about 9% (v / v), about 9.5% (v / v), or about 10% (v / v).

[0131] In other embodiments, there may be less than 10 mg / ml, less than 9.5 mg / ml, less than 9 mg / ml, less than 8.5 mg / ml, less than 8 mg / ml, less than 7.5 mg / ml, less than 7 mg / ml, less than 6.5 mg / ml, less than 6 mg / ml, less than 5.5 mg / ml, less than 5 mg / ml, less than 4.5 mg / ml, less than 4 mg / ml, less than 3.5 mg / ml, less than 3 mg / ml, less than 2.5 mg / ml, less than 2 mg / ml, less than 1.5 mg / ml, less than 1 mg / ml, or less than 0.5 mg / ml of gentisic acid or gentisate.

[0132] In at least one example, the radiopharmaceutical composition comprises 3.8% (v / v) ethanol, hi another example, the radiopharmaceutical composition comprises 7.5% (v / v).

[0133] Alternatively stated, the total amount of ethanol present in the radiopharmaceutical composition can be about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, or about 80 mg per ml.

[0134] In some embodiments, the total amount of ethanol present in the radiopharmaceutical composition may range from about 20 mg to about 35 mg per ml, hi other embodiments, the total amount of ethanol in the radiopharmaceutical composition may range from about 43 mg to about 63 mg per ml.

[0135] In some embodiments, the total amount of ethanol present in the radiopharmaceutical composition may range from about 25 mg to about 80 mg, about 30 mg to about 40 mg, about 40 mg to about 50 mg, about 50 mg to about 60 mg, about 60 mg to about 70 mg, or about 70 mg to about 80 mg per ml. In other embodiments, the total amount of ethanol in the radiopharmaceutical composition may range from about 30 mg to about 60 mg per ml.

[0136] In further embodiments, the proportion of ethanol in the radiopharmaceutical composition may be about 300 mg per 10 ml, or about 30 mg / ml. In another embodiment, the proportion of ethanol in the radiopharmaceutical composition may be about 200 mg per 10 ml. In yet another embodiment, the proportion of ethanol in the radiopharmaceutical composition may be about 350 mg per 10 ml.

[0137] Alternatively, the amount of ethanol in the composition can range from about 35 μl / ml to about 75 μl / ml. For example, the amount of ethanol in 1 ml of the composition can be about 35 μl to 40 μl, about 40 μl to 45 μl, about 45 μl to 50 μl, about 50 μl to 55 μl, about 55 μl to 60 μl, about 60 μl to 65 μl, about 65 μl to 70 μl, or about 70 μl to 75 μl. In at least one example, 1 ml of the composition contains 37.5 μl (29.5 mg) of ethanol. In another example, 1 ml of the composition contains 75 μl (58.9 mg) of ethanol.

[0138] (iv) Metal ion chelating agents (chelating agents) In some embodiments, the present disclosure provides a dose of 177A radiopharmaceutical composition is provided comprising an Lu-PSMA I&T solution and at least one metal ion chelating agent, including ethylenediaminetetraacetic acid (EDTA) and its salts, N-(hydroxyethyl)ethylenediaminetriacetic acid, nitrilotriacetic acid (NTA), ethylene-bis(oxyethylene-nitrilo)tetraacetic acid, 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid, 1,4,7,10-tetraazacyclododecane-N,N',N''-triacetic acid, 1,4,7,10-tetraazacyclododecane-N,N',N''-triacetic acid, 1,4,7-tris(carboxymethyl)-10-(2'-hydroxypropyl)-1,4,7-tris(carboxymethyl ... )-1,4,7,10-tetraazocyclodecane, 1,4,7-triazacyclonane-N,N',N''-triacetic acid, 1,4,8,11-tetraazacyclotetra-decane-N,N',N'',N'''-tetraacetic acid, diethylenetriamine-pentaacetic acid (DTPA), ethylenedicysteine, bis(aminoethanethiol)carboxylic acid, triethylenetetramine-hexaacetic acid, 1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid, or a combination thereof. In one embodiment, the chelating agent can be the sodium salt of EDTA. In one embodiment, the chelating agent can include DTPA and be free of EDTA.

[0139] In some embodiments, the metal ion chelator is selected from the group consisting of ethylenediaminetetraacetic acid (EDTA) and its salts, N-(hydroxy-ethyl)ethylenediaminetriacetic acid, nitrilotriacetic acid (NTA), ethylene-bis(oxyethylene-nitrilo)tetraacetic acid, 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid, 1,4,7,10-tetraaza-cyclododecane-N,N',N''-triacetic acid, 1,4,7,10-tetraaza-cyclododecane-N,N',N''-triacetic acid, 1,4,7,10-tris(carboxymethyl)-10-( 2'-hydroxypropyl)-1,4,7,10-tetraazocyclodecane, 1,4,7-triazacyclonane-N,N',N"-triacetic acid, 1,4,8,11-tetraazacyclotetra-decane-N,N',N'',N'"-tetraacetic acid, diethylenetriamine-pentaacetic acid (DTPA), ethylenedicysteine, bis(aminoethanethiol)carboxylic acid, triethylenetetramine-hexaacetic acid, and 1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid. In one embodiment, the metal ion chelator can be disodium EDTA. In one embodiment, the metal ion chelator can be DPTA.

[0140] In one embodiment, the amount of chelating agent present in the radiopharmaceutical composition may range from about 5 μg to 500 μg, hi some embodiments, the amount of metal ion chelating agent present in the radiopharmaceutical composition may range from about 5 μg to 50 μg.

[0141] In some embodiments, the amount of chelating agent present is about 5 μg, about 6 μg, about 7 μg, about 8 μg, about 9 μg, about 10.5 μg, about 11 μg, about 12 μg, about 13 μg, about 14 μg, about 15 μg, about 16 μg, about 17 μg, about 18 μg, about 19 μg, about 20 μg, about 21 μg, about 22 μg, about 23 μg, about 24 μg , about 25μg, about 26μg, about 27μg, about 28μg, about 29μg, about 30μg, about 31μg, about 32μg, about 33μg, about 34μg, about 35μg, about 36μ g, about 37μg, about 38μg, about 39μg, about 40μg, about 45μg, about 50μg, about 60μg, about 70μg, about 80μg, about 90μg, about 100μg, about 1 10μg, about 80μg, about 130μg, about 140μg, about 150μg, about 160μg, about 170μg, about 180μg, about 190μg, about 200μg, about 210 μg, approx. 220 μg, approx. 230 μg, approx. 240 μg, approx. 250 μg, approx. 260 μg, approx. 270 μg, approx. 280 μg, approx. 290 μg, approx. 300 μg, approx. 310 μg g, about 320 μg, about 330 μg, about 340 μg, about 350 μg, about 360 μg, about 370 μg, about 380 μg, about 390 μg, about 400 μg, about 410 μg, about 420 μg, about 430 μg, about 440 μg, about 450 μg, about 460 μg, about 470 μg, about 480 μg, about 490 μg, or about 500 μg.

[0142] The concentration of the metal ion chelating agent in the composition may range from about 5 μg / ml to about 500 μg / ml. In another embodiment, the concentration of the chelating agent present in the radiopharmaceutical composition may range from about 5 μg / ml to about 200 μg / ml, about 5 μg / ml to about 75 μg / ml, 10 μg / ml to about 25 μg / ml, about 25 μg / ml to about 50 μg / ml, about 50 μg / ml to about 75 μg / ml, or about 75 μg / ml to about 100 μg / ml, about 100 μg / ml to about 125 μg / ml, about 125 μg / ml to about 150 μg / ml, or about 150 μg / ml to about 200 μg / ml. In some embodiments, the concentration of chelating agent present is about 5 μg / ml, about 6 μg / ml, about 7 μg / ml, about 8 μg / ml, about 9 μg / ml, about 10.5 μg / ml, about 11 μg / ml, about 12 μg / ml, about 13 μg / ml, about 14 μg / ml, about 15 μg / ml, about 16 μg / ml, about 17 μg / ml, about 18 μg / ml, about 19 μg / ml, about 20 μg / ml, about 21 μg / ml, about 22 μg / ml, about It can be 23 μg / ml, about 24 μg / ml, about 25 μg / ml, about 26 μg / ml, about 27 μg / ml, about 28 μg / ml, about 29 μg / ml, about 30 μg / ml, about 31 μg / ml, about 32 μg / ml, about 33 μg / ml, about 34 μg / ml, about 35 μg / ml, about 36 μg / ml, about 37 μg / ml, about 38 μg / ml, about 39 μg / ml, about 40 μg / ml, about 45 μg / ml, or about 50 μg / ml.

[0143] In other embodiments, the concentration of chelating agent present is about 80 μg / ml, about 90 μg / ml, about 91 μg / ml, about 92 μg / ml, about 93 μg / ml, about 94 μg / ml, about 95 μg / ml, about 96 μg / ml, about 97 μg / ml, about 98 μg / ml, about 99 μg / ml, about 100 μg / ml, about 101 μg / ml, about 102 μg / ml, about 103 μg / ml, about 104 μg / ml, about 105 μg / ml, about 106 μg / ml ml, about 107 μg / ml, about 108 μg / ml, about 109 μg / ml, about 110 μg / ml, about 115 μg / ml, about 120 μg / ml, about 125 μg / ml, about 130 μg / ml, about 135 μg / ml, about 140 μg / ml, about 145 μg / ml, about 150 μg / ml, about 155 μg / ml, about 160 μg / ml, about 170 μg / ml, about 180 μg / ml, about 190 μg / ml, or about 200 μg / ml.

[0144] In alternative embodiments, the amount of metal ion chelator in a radiopharmaceutical composition may be from about 0.001% to about 0.20% (w / w), from about 0.20% to about 0.40% (w / w), from about 0.40% to about 0.60% (w / w), from about 0.60% to about 0.80% (w / w), or from about 0.80% to about 1.00% (w / w) of such radiopharmaceutical composition. In some embodiments, the amount of metal ion chelator present in the radiopharmaceutical composition may be about 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, or 0.15% (w / w) of the total weight of the radiopharmaceutical composition.

[0145] For example, the amount of disodium EDTA, diethylenetriaminepentaacetic acid (DTPA), or a combination thereof in 1 ml of the composition can be about 10 μg to 15 μg, about 13 μg to 18 μg, about 15 μg to 20 μg, about 20 μg to 25 μg, about 25 μg to 50 μg, about 50 μg to 75 μg, or about 75 μg to 150 μg. In some embodiments, the amount of disodium EDTA present can be about 5 μg, about 6 μg, about 7 μg, about 8 μg, about 9 μg, about 10.5 μg, about 11 μg, about 12 μg, about 13 μg, about 14 μg, about 15 μg, about 16 μg, about 17 μg, about 18 μg, about 19 μg, about 20 μg, about 21 μg, about 22 μg, about 23 μg, about 24 μg, about 25 μg, about 26 μg, about 27 μg, about 28 μg, about 29 μg, about 30 μg, about 31 μg, about 32 μg, about 33 μg, about 34 μg, about 35 μg, about 36 μg, about 37 μg, about 38 μg, about 39 μg, about 40 μg, about 45 μg, or about 50 μg.

[0146] In at least one example, 1 ml of the composition contains 15.5 μg of disodium EDTA. In another example, 1 ml of the composition contains 21 μg of disodium EDTA.

[0147] In one embodiment, the trace metal content in the composition is undetectable. In another embodiment, the Fe metal content in the composition is 0.05 μg / GBq or less, 0.03 μg / GBq or less, 0.01 μg / GBq or less, or below the detectable limit. In another embodiment, the Cu metal content in the composition is 0.05 μg / GBq or less, 0.03 μg / GBq or less, 0.01 μg / GBq or less, or below the detectable limit. In another embodiment, the Zn metal content in the composition is 0.05 μg / GBq or less, 0.03 μg / GBq or less, 0.01 μg / GBq or less, or below the detectable limit. In another embodiment, the Pb metal content in the composition is 0.05 μg / GBq or less, 0.03 μg / GBq or less, 0.01 μg / GBq or less, or below the detectable limit.

[0148] (v) pH adjuster Suitable pH adjusters include, but are not limited to, any one of hydrochloric acid, sodium hydroxide, sodium bicarbonate, or combinations thereof.

[0149] In some embodiments, hydrochloric acid may be used to adjust the pH of the radiopharmaceutical composition. In certain embodiments, the amount of hydrochloric acid in the composition may range from 0 mg / ml to about 2 mg / ml. In some embodiments, the amount of HCl may range from 1.6 ml of 0.05 M HCl to 2 ml of 0.04 M HCl. The amount of HCl in the composition may be varied in production batches to adjust the final formulation pH. In one embodiment, the batch has an activity of about 10 to 20 Ci. In another embodiment, the batch has an activity of about 16 Ci. In various embodiments, the final formulation pH ranges from pH 3.0 to 5.0. In at least one example, HCl is added to the composition to reach a final pH of 3.5±0.1 to 4.5±0.1.

[0150] In some embodiments, the amount of sodium bicarbonate in the composition may be sufficient to control the pH of the composition between 5.5 and 7.0 prior to the addition of HCl.

[0151] In some embodiments, the amount of NaOH in the composition may be sufficient to control the pH of the composition between 5.5 and 7.0 prior to the addition of HCl.

[0152] (vi) Water The composition may further comprise a sufficient amount of water to produce the desired final volume of the injectable solution. For example, water may be added to produce a final volume of 1 ml, 10 ml, or 20 ml. The 10 ml or 20 ml solution may be stored in a vial and divided into smaller volumes for administration.

[0153] IV. PROCESSES FOR MAKING RADIOPHARMACEUTICAL COMPOSITIONS The entire manufacturing process is a one-step radiolabeling process using PSMA I&T precursors. Successful labeling depends on temperature, time, and pH. The reaction is carried out in a reactor vial at elevated temperature. For example, the reactor may be heated to a setpoint of 110°C, with the maximum temperature reached in the reaction solution being approximately 95°C. The radiolabeled product is isolated on a C18 cartridge and formulated into the final composition after elution into bulk vials. The final product is dispensed in a Grade A controlled environment.

[0154] 177 The Lu-PSMA I&T composition solution may be prepared using the following method 100, for example, as shown in Figure 2. The order of steps may vary, including the order in which the various solutions are prepared.

[0155] In certain embodiments, step 102 may include preparing four solutions for synthesis. The four solutions may include 0.04 M hydrochloric acid, 0.4 M sodium acetate, 20% (w / w) L-ascorbic acid, and about 460 to about 500 μg / ml of PSMA I&T in water. The PSMA I&T precursor may be dissolved in sterile water for injection. For example, depending on the number of doses to be produced, 80 μg to 600 μg of precursor may be used in the reaction. In at least one example, 463 μl / ml of PSMA I&T precursor may be used to produce the composition.

[0156] In some embodiments, step 104 may include preparing an ascorbic acid solution (dilution buffer). In some examples, the ascorbic acid solution may be a 50 mg / ml ascorbic acid solution. The solution pH may be adjusted to 4.5±0.25, 4.5±0.30, 4.5±0.35, 4.5±0.40, 4.5±0.45, or 4.5±0.50. For example, a 50 mg / ml ascorbic acid solution may be prepared and the pH of the solution adjusted to 4.5 using 30% hydrochloric acid. In another example, the ascorbic acid solution may include 33 mg / ml ascorbic acid / sodium ascorbate and 0.1 mg / ml DTPA at a pH of 4.25±0.25.

[0157] In some embodiments, optional step 106 may include preparing a formulation solution / buffer. The formulation solution is prepared from an injection-grade solution containing ascorbic acid, absolute ethanol, and injection-grade water. In one example, the formulation solution is prepared by adding sufficient amounts of the following solutions to a bulk vial: approximately 50 mg / ml ascorbic acid pH 4.5 solution (prepared in step 104), 30% ethanol solution, and water. The formulation solution may contain 31 mg / ml to 42.5 mg / ml ascorbic acid and 3.8% to 7.5% ethanol (v / v%). In some embodiments, the formulation buffer may be adjusted to enable the final composition to have an extended shelf life. In at least one example, the formulation solution contains 31 mg / ml ascorbic acid, 3.8% (v / v) ethanol, and pH 4.5. The formulation buffer is temporarily prepared as part of the synthesis preparation, and a predetermined amount is added to the bulk vial as part of the synthesis preparation.

[0158] In some embodiments, step 108 may include preparing a reaction solution. The reaction solution may include sodium acetate, HCl, and L-ascorbic acid. Alternatively, the reaction solution may include sodium ascorbate. The reaction solution may be prepared in a reactor using the solution prepared in step 102. In one example, the reaction solution may include 4 ml of 0.4 M sodium acetate, a volume of approximately 463 μg / ml PSMA I&T solution, and 150 μl of 20% (w / w) L-ascorbic acid. In another example, the reaction solution may include 0.33 M sodium ascorbate (reaction buffer) and PSMA I&T in a reaction buffer. In some examples, the reaction solution may include 1.6 ml of 0.05 M HCl or 2 ml of 0.04 M HCl (0.08 mmol HCl). The ascorbic acid concentration in the reaction solution may range from 3.75 mg / ml to 5.00 mg / ml.

[0159] In one embodiment, step 110 includes: 177 In some embodiments, the method may include preparing Lu by 177Lu can be provided in HCl. 177 Lu]LuCl3 can be provided in 0.04M or 0.05M HCl. For example, 40-44 GBq / ml 177 Lu can be provided in 0.04 M HCl. In another example, less than 61 GBq 177 Lu can be provided in 0.05M HCl. 177 Lu]LuCl3 may be transferred to a reactor and 177 The [Lu]LuCl vial may be rinsed with an additional required volume of 0.04 M hydrochloric acid (prepared in step 102), which is then also transferred to the reactor.

[0160] The reaction volume can range from 6 ml to 8 ml. The volume can depend on the amount of precursor used.

[0161] In one embodiment, step 112 includes 177 The method may include radiolabeling with Lu. The reaction mixture may be heated to a maximum of about 75°C, a maximum of about 80°C, a maximum of about 85°C, a maximum of about 90°C, or a maximum of about 95°C. In one example, the set point for heating is 110°C, and the actual maximum temperature reached is about 95°C. The reaction volume may be heated for a maximum of 5 minutes, a maximum of 10 minutes, a maximum of 15 minutes, or a maximum of 20 minutes. In at least one example, the reaction mixture is heated at a set point of 110°C for 15 minutes. In at least one additional example, the reaction mixture is heated at a set point of 75°C for 10 minutes.

[0162] In certain embodiments, optional step 114 can include purifying the reaction mixture. For example, the solution can be run through a cassette / cartridge containing a hydrophobic, reversed-phase, silica-based bonded phase. Sep-Pak C18 can be used to purify the composition. In at least one example, the reaction mixture can be passed through a C18 Sep-Pak cartridge, and the cartridge can be rinsed with water. 177 The Lu-PSMA I&T product is retained within the cartridge. In some embodiments, the reaction mixture may not be purified.

[0163] In some embodiments, step 116 may include eluting or diluting the final product. 177 The Lu-PSMA I&T is diluted to the desired radioactivity concentration with the dilution buffer prepared in step 104. The composition may be eluted using 1.5 ml of ethanol-water in a 1:1 ratio. The cassette may then be flushed with 8.5 ml of ascorbic acid 50 mg / ml. A formulation solution may then be added to form the final composition. In at least one example, 177 The Lu-PSMA I&T is eluted from the C18 cartridge into a bulk vial using 1.5 ml of 50% (v / v) ethanol, followed by 8.5 ml of the 50 mg / ml pH 4.5 ascorbic acid solution (prepared in step 104), which is then diluted with the formulation solution / buffer (prepared in step 106 and already in the bulk vial). The resulting solution may have a pH of 3.5-4.5. In some embodiments, the pH may be adjusted. In one example, the pH of the 50 mg / ml ascorbic acid solution is adjusted to 3.5-4.5. In another example, the pH is adjusted to 5.0 or below.

[0164] Stability-enhancing conditions, such as an ascorbic acid solution at a pH of about 5 or less, should preferably be applied as early in the process as possible. For example, an ascorbic acid solution at a pH of 5 or less may be used in place of water in step 114 to minimize radiolytic damage.

[0165] In some embodiments, in step 118, the final composition may be sterile filtered. The sterile filter may be a 0.22 μm sterile filter. The final product may be passed through a 0.22 μm sterile filter and dispensed into single-dose vials containing the appropriate volume and activity referenced to a predetermined calibration time. For example, the final composition may be passed through a 0.22 μm sterile filter in a Class A environment and dispensed into doses containing the appropriate volume and activity for the calibration time.

[0166] In other embodiments, the reactor may be heated at a set point of 110° C., and the maximum temperature reached in the reaction solution is about 90° C., about 85° C., about 80° C., about 75° C., or about 70° C. The final composition may be formulated as a solution suitable for injection. The product is diluted to a standard radioactivity concentration, and thus the final volume of the bulk composition is determined by the amount of the introduced 177 Varies depending on the starting radioactivity of Lu. This solution meets the sterility and bacterial endotoxin requirements according to the European Pharmacopoeia, which confirms an acceptable manufacturing process from a microbiological point of view.

[0167] Figure 3A provides an example of a process for making a radiopharmaceutical composition by purifying the reaction mixture and formulation solution with ethanol, and Figure 3B provides an example of a process for making a radiopharmaceutical composition without purification and without ethanol.

[0168] 177 Provided herein are methods for increasing the shelf life of a radiopharmaceutical product comprising Lu-PSMA I&T. The methods may include adjusting the pH of the composition to 3.5, 3.75, 4.0, 4.25, or 4.5, adjusting the amount of ascorbic acid in the composition, and / or adjusting the radioactivity to extend the shelf life of the composition by 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.25, 2.5, 2.75, or 3 days. For example, a radiopharmaceutical composition may have a shelf life of 1, 1.5, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, or 5 days. In certain embodiments, adjusting the pH, radioactivity, and / or ascorbic acid may increase the radiochemical purity of the composition to at least 99%, at least 98.5%, at least 98%, at least 97.5%, at least 97%, at least 96.5%, at least 96%, at least 95.5%, or at least 95% for up to 1, 1.5, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, or 5 days.

[0169] Targeted pharmaceutical formulations according to the present disclosure are as provided in Table 1A. [Table 1A]

[0170] In another embodiment, the preparation of composition 4 disclosed in Table 1A above may be carried out using a one-step radiolabeling process carried out in the following steps:

[0171] Successful labeling is dependent on temperature, time, and pH. The reaction is carried out in a reactor vial at elevated temperature. For example, the reactor may be preheated to a setpoint of 100°C for 5 minutes, then reduced to 85°C to achieve a reaction temperature of approximately 75°C for 10 minutes. The radiolabeled product is formulated into the final composition, sterile filtered, and dispensed in a Grade A controlled environment.

[0172] 177 The Lu-PSMA I&T composition solution may be prepared as shown in Figure 2b (201, 202, 203). The order of steps may vary, including the order in which the various solutions are prepared.

[0173] In some embodiments, step 201 may include preparing a reaction buffer for synthesis. The solution may include 82 mg / mL sodium ascorbate in water at pH > 5. The PSMA-I&T precursor may be dissolved in the reaction buffer, as shown in step 202. For example, depending on the batch size, 1000 μg to 5000 μg of precursor may be used in the reaction.

[0174] In one embodiment, the [ 177 The amount of [Lu]LuCl3 can range from 50 mCi up to 15,200 mCi. The corresponding amount of PSMA I&T used during radiolabeling can range from 0.1 to 0.9 μg / mCi. For example, 15,000 mCi of [ 177 Lu]LuCl3 and 4200 μg of PSMA I&T are added to the reaction vessel during radiolabeling.

[0175] In some embodiments, step 203 can include preparing an ascorbic acid solution (dilution buffer). In some examples, the ascorbic acid solution can be a 33 mg / ml ascorbic acid solution. The solution pH can be adjusted to 4.25±0.05, 4.25±0.10, 4.25±0.15, 4.25±0.20, or 4.25±0.25. For example, the ascorbic acid solution can include 33 mg / ml ascorbic acid / sodium ascorbate and 0.1 mg / ml DTPA at a pH of 4.25±0.25.

[0176] In one embodiment, step 204 includes: 177 In some embodiments, the method may include preparing Lu by 177 Lu can be provided in HCl. 177 Lu]LuCl3 can be provided in 0.05 M HCl. For example, 2 Ci / ml 177 Lu can be provided in 0.05M HCl. 177 Lu]LuCl3 may be transferred to a reactor and 177 The [Lu]LuCl vial may be rinsed with an additional required volume of 82 mg / mL sodium ascorbate (prepared in step 201), which is then also transferred to the reactor.

[0177] The reaction volume can range from 8 ml to 15 ml. The volume used for the radiolabeling reaction is 177 Lu] LuCl3.

[0178] In one embodiment, step 204 includes using PSMA-I&T. 177The method may include radiolabeling with Lu. The reaction mixture may be heated to a temperature of up to about 70°C, up to about 75°C, up to about 80°C, up to about 85°C, up to about 90°C, or up to about 95°C. In one example, the set point for heating is 85°C, and the actual maximum temperature reached is about 75°C. The reaction volume may be heated for up to 5 minutes, up to 10 minutes, up to 15 minutes, up to 20 minutes, up to 25 minutes, up to 30 minutes, up to 35 minutes, up to 40 minutes, or up to 45 minutes. In at least one example, the reaction mixture is heated at a set point of 80°C for 10 minutes. In at least one additional example, the reaction mixture is heated at a set point of 70°C for 10 minutes.

[0179] Stability-enhancing conditions, such as an ascorbic acid solution at a pH of about 5 or less, should preferably be applied as early in the process as possible. For example, an ascorbic acid solution at a pH of 5 or less may be used in place of water in step 205 to minimize radiolytic damage.

[0180] The final composition can be formulated as a solution suitable for injection. The product is diluted to a standard radioactivity concentration, and thus the final volume of the bulk composition is the amount of the introduced 177 Varies depending on the starting activity of Lu.

[0181] In some embodiments, in step 206, the final composition may be sterile filtered. The sterile filter may be a 0.22 μm sterile filter. The final product may be passed through a 0.22 μm sterile filter and dispensed into single-dose vials containing the appropriate volume and activity referenced to a predetermined calibration time. For example, the final composition may be passed through a 0.22 μm sterile filter in a Class A environment and dispensed into doses containing the appropriate volume and activity for the calibration time.

[0182] FIG. 3B provides an example of a process for making a radiopharmaceutical composition without purification and without the inclusion of ethanol.

[0183] 177Provided herein are methods for increasing the shelf life of radiopharmaceutical products containing Lu-PSMA I&T. The methods may include adjusting the pH of the composition to 4.0, 4.25, 4.5, or 4.75 by adjusting the amount of ascorbic acid in the composition, and / or adjusting the radioactivity to extend the shelf life of the composition by 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.25, 2.5, 2.75, or 3 days. For example, a radiopharmaceutical composition may have a shelf life of 1, 1.5, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, or 4 days. In certain embodiments, adjusting the pH, radioactivity, and / or ascorbic acid may increase the radiochemical purity of the composition to at least 99%, at least 98.5%, at least 98%, at least 97.5%, at least 97%, at least 96.5%, at least 96%, at least 95.5%, or at least 95% for up to 1, 1.5, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4 days.

[0184] V. Stability A stable, non-radiolabeled standard can be used to identify the product peak in HPLC analysis. The formulation can be prepared from an injection-grade solution containing ascorbic acid, a chelating agent (EDTA, DTPA, or a combination thereof), optionally absolute ethanol, and injection-grade water. The formulation matrix can be temporarily prepared as part of the synthetic preparation, and a predetermined amount is added to a bulk vial as part of the synthetic preparation.

[0185] Without being limited to any one theory, the radioactivity, the amount of ascorbic acid, and / or the pH of the solution may affect the shelf life of the composition. Surprisingly, a lower concentration of ascorbic acid in the composition (e.g., 31 mg / ml versus 42.5 mg / ml), a pH of 4.5 or less, a low RAC, and / or a combination thereof may result in a higher stability profile and a longer shelf life of the composition compared to a composition having a pH of 5 or more, a high RAC, and / or a combination thereof. For example, this can be seen in Figure 5. The shelf life can generally be determined based on the radiochemical purity of the composition after formulation or at the end of the expiration date of the composition. The radiochemical purity may be confirmed by HPLC.

[0186] In one or more embodiments, a 177Lu-PSMA I&T formulation composition with a radioactivity concentration of 640 MBq / ml or less, 31 mg / ml ascorbic acid in the dosage formulation, and a pH of about 4.5 can provide sufficient stability for 4 days.

[0187] A composition having a low radioactivity concentration (e.g., 588.5 MBq / ml), pH 4.5, and 31 mg / ml ascorbic acid has a radiochemical purity of 99.1% at 0 hours after EOS, 98.7% at 20 hours after EOS, 98.0% at 44 hours after EOS, 97.4% at 69 hours after EOS, and 97.0% at 93 hours after EOS. A composition having a low radioactivity concentration (e.g., 626 MBq / ml), pH 5.0, and 31 mg / ml ascorbic acid has a radiochemical purity of 99.2% at 0 hours after EOS, 98.4% at 25 hours after EOS, 97.3% at 47 hours after EOS, and 96.5% at 71 hours after EOS. A composition having a low radioactivity concentration (e.g., 579 MBq / ml), pH 4.5, and 21 mg / ml ascorbic acid has a radiochemical purity of 99.4% at 0 hours after EOS, 98.3% at 19 hours after EOS, 97.5% at 46 hours after EOS, 96.8% at 71 hours after EOS, and 96.0% at 92 hours after EOS. A composition having a high radioactivity concentration (e.g., 1,278 MBq / ml), pH 4.5, and 42.5 mg / ml ascorbic acid has a radiochemical purity of 99.4% at 0 hours after EOS, 98.0% at 24 hours after EOS, 96.7% at 46 hours after EOS, 95.3% at 67 hours after EOS, and 95.2% at 71 hours after EOS.

[0188] The radiopharmaceutical composition may be stored at a temperature ranging from 2°C to 40°C, about 2°C to 5°C, about 5°C to 10°C, about 10°C to 15°C, about 15°C to 20°C, about 20°C to 25°C, about 25°C to 30°C, about 30°C to 35°C, or about 35°C to 40°C.

[0189] In certain embodiments, the radiopharmaceutical composition is stored at a temperature of about 5° C. to 40° C., about 10° C. to 35° C., or about 20° C. to 30° C. In a specific embodiment, the radiopharmaceutical composition is stored at a temperature of about 10° C., about 15° C., about 22° C., about 22.5° C., about 25° C., or at room temperature.

[0190] In one embodiment, the radiopharmaceutical composition is stored at about 22.5° C. In another embodiment, the radiopharmaceutical composition is stored at room temperature.

[0191] VI. Specific Radiopharmaceutical Compositions In some embodiments, the pharmaceutical product is administered at a dose of 42.5 mg / ml of ascorbic acid in water containing 7.5% (v / v) or 59 mg / ml of ethanol. 177 The sterile filtered radiopharmaceutical solution contains Lu-PSMA I&T solution. The product is diluted to a standard radioactivity concentration, and therefore the final volume of the bulk product varies depending on the starting radioactivity introduced. The composition of the final product is listed in Table 1B ( 177 Lu-PSMA I&T composition 1): [Table 1B]

[0192] In yet another embodiment, the pharmaceutical product is a dose of 31 mg / ml of ascorbic acid in water containing 3.8% (v / v) or 30 mg / ml of ethanol at a pH of about 4.5. 177 A sterile filtered radiopharmaceutical solution containing Lu-PSMA I&T solution. The product is diluted to a standard radioactivity concentration, and therefore the final volume of the bulk product varies depending on the starting radioactivity introduced. The composition is described in Table 1C below ( 177 Lu-PSMA I&T composition 3): [Table 1C]

[0193] In yet another embodiment, the pharmaceutical product is a dose of 33 mg / ml of ascorbic acid in water at a pH of about 4.25. 177 A sterile filtered radiopharmaceutical solution containing Lu-PSMA I&T solution. The product is diluted to a standard radioactivity concentration, and therefore the final volume of the bulk product varies depending on the starting radioactivity introduced. The composition is described in Table 1D below ( 177 Lu-PSMA I&T composition 4): [Table 1D]

[0194] VII. Formulating a Pharmaceutical Product The pharmaceutical product may be delivered in a Type 1 glass sterile pyrogen-free glass vial with a fluorine-coated bromobutyl rubber septum. The septum is sealed with a crimped aluminum capsule. The glass vial containing the radiopharmaceutical is maintained in a lead-shielded container during transport. The shipping container, including the lead shielding and outer packaging, complies with Type A requirements (IAEA standards). Figure 4 depicts a drawing of a product vial that may be used in this embodiment.

[0195] In one embodiment, the volume of the solution containing the formulation or radiopharmaceutical composition is about 10 ml to about 20 ml, about 20 ml to about 30 ml, about 30 ml to about 40 ml, about 40 ml to about 50 ml, about 50 ml to about 60 ml, about 60 ml to about 70 ml, about 70 ml to about 80 ml, about 80 ml to about 90 ml, or about 90 ml to about 100 ml. In a specific embodiment, the volume of the solution containing the formulation or radiopharmaceutical composition is about 1 ml, about 5 ml, about 7 ml, about 8 ml, about 9 ml, about 10 ml, about 11 ml, about 12 ml, about 13 ml, about 14 ml, about 15 ml, about 16 ml, about 17 ml, about 18 ml, about 19 ml, about 20 ml, about 25 ml, or about 30 ml.

[0196] In one embodiment, the volume of the solution containing the formulation or radiopharmaceutical composition is about 100 ml to about 200 ml, about 200 ml to about 300 ml, about 300 ml to about 400 ml, about 400 ml to about 500 ml, about 500 ml to about 600 ml, about 600 ml to about 700 ml, about 700 ml to about 800 ml, about 800 ml to about 900 ml, or about 900 ml to about 1000 ml. In a specific embodiment, the volume of the solution containing the formulation or radiopharmaceutical composition is about 200 ml, about 225 ml, about 250 ml, about 275 ml, about 300 ml, about 325 ml, about 350 ml, about 375 ml, about 400 ml, about 425 ml, about 450 ml, about 475 ml, about 500 ml, about 525 ml, about 550 ml, about 575 ml, about 600 ml, about 625 ml, about 650 ml, about 675 ml, about 700 ml, about 725 ml or about 750 ml.

[0197] In a specific embodiment, the final volume in the dose vial is adjusted to 7 ml to 10 ml, 10 ml to 15 ml, or 15 ml to 20 ml to provide the amount of radioactivity required for the day and time of injection.

[0198] In another embodiment, 177 Lu-PSMA I&T injection is supplied as a single-dose vial. For example, 177 Provided herein is a radiopharmaceutical kit comprising a vial containing the Lu-PSMA I&T injection product composition. In one embodiment, 177 The strength of the Lu-PSMA I&T injection product composition is about 0.1 GBq / ml, about 0.2 GBq / ml, about 0.3 GBq / ml, about 0.4 GBq / ml, about 0.5 GBq / ml, about 0.6 GBq / ml, about 0.7 GBq / ml, about 0.8 GBq / ml, about 0.9 GBq / ml, about 1.0 GBq / ml, about 1.1 GBq / ml, about 1.2 GBq / ml, about 1.3 GBq / ml, about 1.4 GBq / ml, about 1.5 GBq / ml, about 1.6 GBq / ml, about 1.7 GBq / ml, about 1.8 GBq / ml, about 1.9 GBq / ml, or about 2.0 GBq / ml. 177The strength of the Lu-PSMA I&T injection product composition is less than about 2.0 GBq / ml, less than about 1.5 GBq / ml, less than about 1.0 GBq / ml, or less than about 0.5 GBq / ml.

[0199] In yet another embodiment, 177 The shelf life of the Lu-PSMA I&T injection product composition is about 30 hours to about 90 hours, about 40 hours to about 80 hours, or about 48 hours to about 72 hours. 177 The shelf life of the Lu-PSMA I&T injection product composition is about 30 hours, about 35 hours, about 40 hours, about 45 hours, about 48 hours, about 50 hours, about 55 hours, about 60 hours, about 65 hours, about 70 hours, about 72 hours, about 75 hours, about 80 hours, about 85 hours, or about 90 hours.

[0200] In some embodiments, the radiopharmaceutical composition is prepared in a manner sufficient for administration to a patient. 177 The radiopharmaceutical composition should have a radiochemical purity of 95% or greater for Lu-PSMA I&T. The combined radiochemical impurities in the composition may be 5% or less. In various embodiments, the radiopharmaceutical composition may have a chemical purity such that Lu-PSMA I&T is present in the composition at a concentration of less than about 12 μg / ml, less than about 11 μg / ml, less than about 10 μg / ml, less than about 9 μg / ml, less than about 8 μg / ml, less than about 7 μg / ml, less than about 6 μg / ml, less than about 5 μg / ml, less than about 4 μg / ml, less than about 3 μg / ml, less than about 2 μg / ml, or less than about 1 μg / ml.

[0201] In some embodiments, the radiopharmaceutical composition comprises a colloid in an amount of less than about 5% radioactivity, less than about 4.5% radioactivity, less than about 4% radioactivity, less than about 3.5% radioactivity, less than about 3% radioactivity, less than about 2.5% radioactivity, less than about 2% radioactivity, less than about 1.5% radioactivity, less than about 1% radioactivity, less than about 0.5% radioactivity, less than about 0.3% radioactivity, less than about 0.2% radioactivity, or less than about 0.1% radioactivity. 177In one embodiment, the radiopharmaceutical composition administered to a human patient in need thereof may have less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, or less than 0.1% colloidal Lu. 177 Contains Lu.

[0202] In some embodiments, the radiopharmaceutical composition is less than about 17.5 EU / ml, less than about 17 EU / ml, less than about 16.5 EU / ml, less than about 16 EU / ml, less than about 15.5 EU / ml, less than about 15 EU / ml, less than about 14.5 EU / ml, less than about 14 EU / ml. The bacterial endotoxin may be less than about 13.5 EU / ml, less than about 13 EU / ml, less than about 12.5 EU / ml, less than about 12 EU / ml, less than about 11.5 EU / ml, less than about 11 EU / ml, less than about 10.5 EU / ml, less than about 10 EU / ml, less than about 9.5 EU / ml, less than about 9 EU / ml, less than about 8.5 EU / ml, less than about 8 EU / ml, less than about 7.5 EU / ml, less than about 7 EU / ml, less than about 6.5 EU / ml, less than about 6 EU / ml, less than about 5.5 EU / ml, less than about 5 EU / ml, less than about 4.5 EU / ml, less than about 4 EU / ml, less than about 3.5 EU / ml, less than about 3 EU / ml, less than about 2.5 EU / ml, less than about 2 EU / ml, less than about 1.5 EU / ml, less than about 1 EU / ml, less than about 0.5 EU / ml, or may be free of bacterial endotoxin.

[0203] In certain embodiments, the radiochemical purity of the composition is 95% or greater 1 day, up to 2 days, up to 3 days, up to 4 days, or up to 5 days after formulation. In additional embodiments, the radiochemical purity of the composition is 95% or greater 24 hours, up to 36 hours, up to 48 hours, up to 72 hours, or up to 96 hours after formulation. In further embodiments, the radiochemical purity of the composition is suitable for injection or administration to a patient in need thereof more than 72 hours after formulation, more than 96 hours after formulation, or more than 100 hours after formulation. The radiopharmaceutical composition may have a radiochemical purity of at least 95%, at least 95.5%, at least 96%, at least 96.5%, at least 97%, at least 97.5%, at least 98%, at least 98.5%, or at least 99% 24 hours, 48 ​​hours, 72 hours, and / or 96 hours after formulation. In some examples, the radiopharmaceutical composition may have a radiochemical purity of 95.0% or greater, 95.5% or greater, 96.0% or greater, 96.5% or greater, 97.0% or greater, 97.5% or greater, 98.0% or greater, 98.5% or greater, 99.0% or greater, or 99.5% or greater upon administration. For example, a radiopharmaceutical composition may have a radiochemical purity of greater than 95% after 46-48 hours from formulation, greater than 96% after 46-48 hours from formulation, greater than 97% after 46-48 hours from formulation, greater than 95% after 69-72 hours from formulation, greater than 96% after 69-72 hours from formulation, greater than 97% after 69-72 hours from formulation, greater than 95% after 90-93 hours from formulation, greater than 96% after 90-93 hours from formulation, and / or greater than 97% after 90-93 hours from formulation.

[0204] In some examples, the radiochemical purity of the composition may range from about 99.0% to about 99.4% at 0 hours after EOS. In various embodiments, the radiochemical purity of the composition may range from about 96.5% to about 98.7% at 19 to 25 hours after EOS. In other examples, the radiochemical purity of the composition may range from about 93.3% to about 98.0% at 44 to 47 hours after EOS. In additional examples, the radiochemical purity of the composition may range from about 91.2% to about 97.4% at 69 to 71 hours after EOS. In some examples, the radiochemical purity of the composition may range from about 94.5% to about 97.0% at 90 to 93 hours after EOS.

[0205] In another embodiment, 177 Lu-PSMA I&T Injection is supplied as a single-dose vial.

[0206] In yet another embodiment, patients requiring radioligand therapy during treatment receive a single intravenous radioactive dose at the beginning of a treatment cycle. A treatment cycle is 1 to 10 weeks long. In one embodiment, treatment includes 1 to 6 treatment cycles. In another embodiment, dose reductions or dose escalations are introduced during treatment.

[0207] In one embodiment, the patient dose volume is calculated according to the administered radioactive dose.

[0208] In another embodiment, 177 Lu-PSMA I&T is injected slowly over approximately 10 minutes via intravenous (IV) route, followed by 500-1000 mL of Ringer's solution or normal saline. If the total blood volume exceeds 5000 mL, an additional 7 mL injection will have no effect. This dose is administered every 6 weeks for 4 cycles.

[0209] In yet another embodiment, patients requiring radioligand therapy during treatment receive a single intravenous radioactive dose at the beginning of a treatment cycle. A treatment cycle is 1 to 10 weeks long. In one embodiment, treatment includes 1 to 6 treatment cycles. In another embodiment, dose reductions or dose escalations are introduced during treatment.

[0210] In one embodiment, the patient dose volume is calculated according to the administered radioactive dose.

[0211] IX. Administration Further provided herein are methods of administering the radiopharmaceutical composition.The radiopharmaceutical composition may be administered by injection to a human patient in need thereof.

[0212] There can be about six main modes of administration.

[0213] First, it cools the salivary glands, reducing the risk of salivary gland radiation damage to the patient. 177 Ice packs are placed on the parotid and submandibular glands 30 minutes before and up to four hours after administration of Lu-PSMA I&T. There is no scientific evidence that cooling the salivary glands is an effective therapy for sparing these glands from radiation, however, it is well tolerated and not harmful to patients.

[0214] Second, use a urinary catheter in incontinent patients within the first 48 hours to avoid any contamination.

[0215] Third, 6.5–7.5 GBq (range: 6.0–8.0 GBq) 177 Lu-PSMA I&T activity. The dose can be reduced to 4.0-5.0 GBq in cases of renal dysfunction (e.g., creatinine within 1.0-1.5 UNL). Preliminary results suggest that 7.4 GBq of activity can be safely administered; however, more data are needed to determine whether the dose should be increased.

[0216] Fourth, the active ingredient is infused intravenously as a slow bolus (over approximately 1 to 15 minutes) followed by 500 to 1000 ml of Ringer's solution or NaCl solution. Patients should be encouraged to urinate as frequently as possible and to drink approximately 2 liters of water per day. In patients with extensive non-obstructive renal disease, the administration of a diuretic may be beneficial.

[0217] Fifth, with an average of 3 to 5 cycles of RLT every 5 to 8 weeks, up to 11 cycles have been reported. If PSA continues to increase or if performance status worsens after the first two cycles, the indication for further RLT should be reevaluated. If PSA falls below 1.0 μg / L during a therapy cycle, or if post-injection SPECT studies are not sufficiently informative, PSMA imaging can be used to assess the presence of small PSMA-positive metastases after completion of RLT. In the event of a significant decline in platelets or white blood cells, the time interval between two cycles can be extended.

[0218] Sixth, at least one whole-body scan (preferably SPECT( / CT)) should be performed 24–48 hours after injection. Concomitant corticosteroid therapy (e.g., prednisolone 20 mg / day) during the first 2 weeks after administration is recommended for patients with diffuse bone and bone marrow metastases, as well as for patients with brain metastases.

[0219] In some embodiments, the method may include injecting the radiopharmaceutical composition into a patient in need thereof more than 48 hours after formulation. In some examples, the radiopharmaceutical composition comprises: 177 The Lu-PSMA I&T and ascorbic acid may be contained in a solution having a pH of 3.5-4.5, and the solution may have a radiochemical purity of greater than 96% when administered. In one embodiment, the pH of the solution is about 3.5-4.2. The composition may contain less than 6 μg / ml of Lu-PSMA I&T. 177The composition may include Lu-PSMA I&T, about 7 μg / ml to about 18 μg / ml disodium EDTA, about 25 μl / ml to about 45 μl / ml ethanol, and / or about 15 to about 35 mg / ml ascorbic acid. 177 The composition may comprise Lu-PSMA I&T, about 0.1 mg / ml DTPA, and about 30 to about 35 mg / ml ascorbic acid. The composition may have a radioactivity of about 0.5 GBq / ml or about 13.3 mCi / mL, and may have a radiochemical purity of at least 98% after 44 hours from formulation, at least 97% after 69 hours from formulation, and / or at least 97% after 93 hours from formulation.

[0220] The pharmaceutical composition may be administered every 5 to 8 weeks for 2 to 11 cycles / treatments. In some embodiments, a patient may receive up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 treatments, with treatments administered every 4, 5, 6, 7, or 8 weeks. In some examples, a patient may receive up to 4 treatments, with each treatment administered every 6 weeks.

[0221] In various embodiments, patients receive a dose of 0.5 GBq to 10 GBq per dose per cycle. 177Lu-PSMA I&T may be administered. For example, the radiopharmaceutical composition may contain a standard radioactivity concentration of about 27 mCi / mL at the end of production and a standard radioactivity of about 200 mCi at the end of expiration, and therefore the final volume of the dose vial may be adjusted to 7-10 mL to provide the amount of radioactivity required for the day and time of injection. In some embodiments, the dose vial contains 10-20 mL. In some embodiments, the dose vial contains 7-15 mL. In at least one example, a patient may receive a dose of about 200 mCi (7.4 GBq ± 0.1 GBq) for each treatment. In one aspect, a patient may receive a dose of about 200 mCi (7.4 GBq ± 0.1 GBq) for each of four, five, six, seven, or more treatments. In another embodiment, the patient may receive a dose of about 200 mCi (7.4 GBq±0.1 GBq) for each of four or more treatments, five or more, six or more, seven or more, or eight or more treatments. In yet another embodiment, the patient may receive a dose of about 200 mCi (≧7.1 GBq) for each of four, five, six, seven, eight, or more treatments. In another example, the patient may receive a dose of about 6.8 GBq±0.3 GBq for each treatment. In one embodiment, the patient may receive a dose of about 6.8 GBq±0.3 GBq for each of four, five, six, seven, eight, or more treatments.

[0222] In various embodiments, the patient receives a dose of about 0.5 GBq to about 10 GBq, about 1.0 GBq to about 9.0 GBq, about 1.5 GBq to about 8.5 GBq, about 2.0 GBq to about 8.0 GBq, about 2.5 GBq to about 7.5 GBq, or about 3.0 GBq to about 7.0 GBq. 177Lu-PSMA I&T may be administered, wherein the patient's total cumulative dose to the kidney per administration is 3.9 Gy or less, 3.8 Gy or less, 3.7 Gy or less, 3.6 Gy or less, 3.5 Gy or less, 3.4 Gy or less, 3.3 Gy or less, 3.2 Gy or less, 3.1 Gy or less, 3.0 Gy or less, 2.9 Gy or less, 2.8 Gy or less, 2.7 Gy or less, 2.6 Gy or less, 2.5 Gy or less, or 2.4 Gy or less, and the patient may receive 1, 2, 3, 4, 5, 6, 7, 8, or more treatments (i.e., treatment cycles), or a dose for each treatment of 4, 5, 6, 7, 8, or more treatments (i.e., treatment cycles). In various embodiments, the patient receives about 0.5 GBq to about 10.0 GBq, about 0.5 GBq to about 9.5 GBq, about 0.5 GBq to about 9.0 GBq, about 0.5 GBq to about 8.5 GBq, about 0.5 GBq to about 8.0 GBq, about 0.5 GBq to about 7.5 GBq, about 1.0 GBq to about 10.0 GBq, about 1.0 GBq to about 9.5 GBq, about 1.0 GBq to about 9.0 GBq, about 1.0 GBq to about 8.5 GBq, about 1.0 GBq to about 10 ... GBq to approximately 1.0 GBq, approximately 1.0 GBq to approximately 7.5 GBq, approximately 1.5 GBq to approximately 10.0 GBq, approximately 1.5 GBq to approximately 9.5 GBq, approximately 1.5 GBq to approximately 9.0 GBq, approximately 1.5 GBq to approximately 8.5 GBq, approximately 1.5 GBq to approximately 8.0 GBq, approximately 1.5 GBq to approximately 7.5 GBq, approximately 2.0 GBq to approximately 10.0 GBq, approximately 2.0 GBq to approximately 9.5 GBq, approximately 2.0 GBq to approximately 9.0 GBq, approximately 2.0 GBq q to approximately 8.5GBq, approximately 2.0GBq to approximately 8.0GBq, approximately 2.5GBq to approximately 10.0GBq, approximately 2.5GBq to approximately 2.5GBq, approximately 2.5GBq to approximately 9.0GBq, approximately 2.5GBq to approximately 8.5GBq, approximately 2.5GBq to approximately 8.0GBq, approximately 2.5GBq to approximately 7.5GBq, approximately 3.0GBq to approximately 10.0GBq, approximately 3.0GBq to approximately 9.5GBq, approximately 3.0GBq to approximately 9.0GBq, approximately 3.0GBq Approximately 8.5 GBq, approximately 3.0 GBq to approximately 8.0 GBq, approximately 3.0 GBq to approximately 7.5 GBq, approximately 3.5 GBq to approximately 10.0 GBq, approximately 3.5 GBq to approximately 9.5 GBq, approximately 3.5 GBq to approximately 9.0 GBq, approximately 3.5 GBq to approximately 8.5 GBq, approximately 3.5 GBq to approximately 8.0 GBq, approximately 3.5 GBq to approximately 7.5 GBq, approximately 0.5 GBq to approximately 7.5 GBq, approximately 0.5 GBq to approximately 7.4 GBq, approximately 1.0 GBq to approximately 7.4GBq, approximately 1.5GBq to approximately 7.4GBq, approximately 2.0GBq to approximately 7.4GBq, approximately 2.5GBq to approximately 7.4GBq, approximately 3.0GBq to approximately 7.4GBq, approximately 3.5GBq to approximately 7.4GBq, approximately 4.0GBq to approximately 7.4GBq, approximately 4.5GBq to approximately 7.4GBq, approximately 5.0GBq to approximately 7.4GBq, approximately 5.5GBq to approximately 7.4GBq, approximately 6.0GBq At a dose of about 7.4 GBq, about 6.5 GBq to about 7.4 GBq, about 6.6 GBq to about 7.4 GBq, about 6.7 GBq to about 7.4 GBq, about 6.8 GBq to about 7.4 GBq, about 6.9 GBq to about 7.4 GBq, about 7.0 GBq to about 7.4 GBq, about 7.1 GBq to about 7.4 GBq, about 7.2 GBq to about 7.4 GBq, or about 7.3 GBq to about 7.4 GBq. 177 Lu-PSMA I&T may be administered, wherein the patient's total cumulative dose to the kidney per administration is 3.9 Gy or less, 3.8 Gy or less, 3.7 Gy or less, 3.6 Gy or less, 3.5 Gy or less, 3.4 Gy or less, 3.3 Gy or less, 3.2 Gy or less, 3.1 Gy or less, 3.0 Gy or less, 2.9 Gy or less, 2.8 Gy or less, 2.7 Gy or less, 2.6 Gy or less, 2.5 Gy or less, or 2.4 Gy or less, and the patient may receive a dose for each treatment of 1, 2, 3, 4, 5, 6, 7, 8, or more treatments (i.e., treatment cycles). In various other embodiments, the patient receives between about 0.5 GBq and about 6.8 GBq, between about 1.0 GBq and about 6.8 GBq, between about 1.5 GBq and about 6.8 GBq, between about 2.0 GBq and about 6.8 GBq, between about 2.5 GBq and about 6.8 GBq, between about 3.0 GBq and about 6.8 GBq, between about 3.5 GBq and about 6.8 GBq, between about 4.0 GBq and about 6.8 GBq, between about 4.5 GBq and about 6.8 GBq, between about 5 GBq and about 6.8 GBq, between about 6 GBq and about 6.8 GBq, between about 7 GBq and about 7.8 GBq, between about 8 GBq and about 8.8 GBq, between about 9 GBq and about 9.8 GBq, between about 10 GBq and about 10.8 GBq, between about 11 GBq and about 11.8 GBq, between about 12 GBq and about 12.8 GBq, between about 13 GBq and about 13.8 GBq, between about 14 GBq and about 14.8 GBq, between about 15 GBq and about 15.8 GBq, between about 16 GBq and about 16.8 GBq, between about 17 GBq and about 17.8 GBq, between about 18 GBq and about 18.8 GBq, between about 19 GBq and about 20 GBq, between about 21 GBq and about 22.8 GBq, between about 23 GBq and about 24.8 GBq, between about 25 GBq and about 26.8 GBq, between about 26 GBq and about 28.8 GBq, between about 29 GBq and about 30.8 GBq, between about 31 GBq and about 32.8 GBq, between about 32 at a dose of about 0.0 GBq to about 6.8 GBq, about 5.5 GBq to about 6.8 GBq, about 6.0 GBq to about 6.8 GBq, about 6.1 GBq to about 6.8 GBq, about 6.2 GBq to about 6.8 GBq, about 6.3 GBq to about 6.8 GBq, about 6.4 GBq to about 6.8 GBq, about 6.5 GBq to about 6.8 GBq, about 6.6 GBq to about 6.8 GBq, or about 6.7 GBq to about 7.4 GBq 177Lu-PSMA I&T may be administered, wherein the patient's total cumulative dose to the kidney per administration is 3.9 Gy or less, 3.8 Gy or less, 3.7 Gy or less, 3.6 Gy or less, 3.5 Gy or less, 3.4 Gy or less, 3.3 Gy or less, 3.2 Gy or less, 3.1 Gy or less, 3.0 Gy or less, 2.9 Gy or less, 2.8 Gy or less, 2.7 Gy or less, 2.6 Gy or less, 2.5 Gy or less, or 2.4 Gy or less, and the patient may receive a dose for each treatment of 1, 2, 3, 4, 5, 6, 7, 8, or more treatments (i.e., treatment cycles).

[0223] In various embodiments, a patient may receive more than 10 treatments, and treatments may be administered every 4, 5, 6, 7, or 8 weeks, so long as the patient's total cumulative dose to the kidneys after all treatments remains less than 23 Gray (Gy). For example, a patient may receive more than 10, more than 15, more than 20, more than 25, more than 30, more than 35, more than 40, more than 45, more than 50, more than 55, more than 60, more than 65, more than 70, or more than 75 treatments, and treatments may be administered every 4, 5, 6, 7, or 8 weeks, so long as the patient's total cumulative dose to the kidneys after all treatments remains less than 23 Gray (Gy).

[0224] In various embodiments, 177 The administration of Lu-PSMA I&T to the patient's kidneys ranged from 0.2 Gy / GBq to approximately 0.6 Gy / GBq (i.e., administered 177 In some additional embodiments, the Lu-PSMA I&T provides an absorbed dose per gram of tissue of about 0.2 to about 0.6 Gy per GBq per gram of tissue. 177 Administration of Lu-PSMA I&T results in an absorbed dose to the patient's kidney of 0.43 Gy / GBq or less.

[0225] In some embodiments, administration of 177Lu-PSMA I&T results in an absorbed dose to the patient's kidneys of 0.46 Gy / GBq±0.23 Gy / GBq (i.e., 0.46 Gy per GBq of administered 177Lu-PSMA I&T). In some additional embodiments, administration of 177Lu-PSMA I&T results in an absorbed dose to the patient's kidneys of 0.46 Gy / GBq or less.

[0226] In various embodiments, administration of 177Lu-PSMA I&T results in an absorbed dose to the patient's kidneys of 0.43 Gy / GBq±0.18 Gy / GBq (i.e., 0.43 Gy per GBq of administered 177Lu-PSMA I&T). In some additional embodiments, administration of 177Lu-PSMA I&T results in an absorbed dose to the patient's kidneys of 0.43 Gy / GBq or less.

[0227] In other embodiments, administration of 177Lu-PSMA I&T results in an absorbed dose to the patient's kidneys of 0.41 Gy / GBq±0.15 Gy / GBq (i.e., 0.41 Gy per GBq of administered 177Lu-PSMA I&T). In some additional embodiments, administration of 177Lu-PSMA I&T results in an absorbed dose to the patient's kidneys of 0.41 Gy / GBq or less.

[0228] In various embodiments, administration of 177Lu-PSMA I&T results in an absorbed dose to the patient's lacrimal glands of 0.67 Gy / GBq±0.33 Gy / GBq (i.e., 0.67 Gy per GBq of administered 177Lu-PSMA I&T). In some additional embodiments, administration of 177Lu-PSMA I&T results in an absorbed dose to the patient's lacrimal glands of 0.67 Gy / GBq or less.

[0229] In other embodiments, administration of 177Lu-PSMA I&T results in an absorbed dose to the patient's lacrimal glands of 0.40 Gy / GBq±0.37 Gy / GBq (i.e., 0.40 Gy per GBq of administered 177Lu-PSMA I&T). In some additional embodiments, administration of 177Lu-PSMA I&T results in an absorbed dose to the patient's lacrimal glands of 0.40 Gy / GBq or less.

[0230] In other embodiments, administration of 177Lu-PSMA I&T results in an absorbed dose to the patient's salivary glands of 0.10 Gy / GBq±0.06 Gy / GBq (i.e., 0.10 Gy per GBq of administered 177Lu-PSMA I&T). In some additional embodiments, administration of 177Lu-PSMA I&T results in an absorbed dose to the patient's salivary glands of 0.10 Gy / GBq or less.

[0231] In various embodiments, administration of 177Lu-PSMA I&T results in an absorbed dose to the patient's salivary glands of 0.13 Gy / GBq±0.08 Gy / GBq (i.e., 0.13 Gy per GBq of administered 177Lu-PSMA I&T). In some additional embodiments, administration of 177Lu-PSMA I&T results in an absorbed dose to the patient's salivary glands of 0.13 Gy / GBq or less.

[0232] In other embodiments, administration of 177Lu-PSMA I&T results in an absorbed dose to the patient's salivary glands of 0.18 Gy / GBq±0.16 Gy / GBq (i.e., 0.18 Gy per GBq of administered 177Lu-PSMA I&T). In some additional embodiments, administration of 177Lu-PSMA I&T results in an absorbed dose to the patient's salivary glands of 0.18 Gy / GBq or less.

[0233] In various embodiments, administration of 177Lu-PSMA I&T results in an absorbed dose to the patient's liver of 0.03 Gy / GBq±0.02 Gy / GBq (i.e., 0.03 Gy per GBq of administered 177Lu-PSMA I&T). In some additional embodiments, administration of 177Lu-PSMA I&T results in an absorbed dose to the patient's liver of 0.03 Gy / GBq or less.

[0234] In other embodiments, administration of 177Lu-PSMA I&T results in an absorbed dose to the patient's liver of 0.04 Gy / GBq±0.02 Gy / GBq (i.e., 0.04 Gy per GBq of administered 177Lu-PSMA I&T). In some additional embodiments, administration of 177Lu-PSMA I&T results in an absorbed dose to the patient's liver of 0.04 Gy / GBq or less.

[0235] 177 The administration of Lu-PSMA I&T can be described as a mathematical formula to ensure that the patient's total cumulative dose to the kidneys after all treatments remains below 23 Gy. An exemplary formula for determining the acceptable number of cycles is shown below.

number

[0236] In various embodiments, patients receive 1 GBq of IV iodine for 53 treatments. 177 Lu-PSMA I&T, 2GBq for 26 treatments 177 Lu-PSMA I&T, 3 GBq for 17 treatments 177 Lu-PSMA I&T, 4 GBq for 13 treatments 177Lu-PSMA I&T, 5GBq for 10 treatments 177 Lu-PSMA I&T, 6 GBq for 8 treatments 177 Lu-PSMA I&T, 7 GBq for 7 treatments 177 Lu-PSMA I&T, 8 GBq for 6 treatments 177 Lu-PSMA I&T, 9GBq for 5 treatments 177 Lu-PSMA I&T, 10 GBq for 5 treatments 177 Lu-PSMA I&T, etc. may also be administered.

[0237] In various embodiments, the present disclosure provides a radiopharmaceutical kit for injection into a human patient in need thereof. 177 a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a dose of 6.5 GBq±0.10 GBq, a dose of 6.5 GBq±0.15 GBq, a dose of 6.5 GBq±0.20 GBq, a dose of 6.5 GBq±0.25 GBq, or a dose of 6.5 GBq±0.30 GBq, and 1, 2, 3, 4, 5, 6, or 7 cycles at that dose; 177 Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, or 7 cycles 177 Further relates to a radiopharmaceutical kit, wherein the Lu-PSMA I&T treatment provides a mean predicted dose that is less than a cumulative absorbed dose to the kidney of 23 Gy, and / or the predicted or actual cumulative absorbed dose to the kidney over 1, 2, 3, 4, 5, 6, or 7 cycles is less than 23 Gy, and no nephrotoxicity is observed.

[0238] In various embodiments, the present disclosure provides a radiopharmaceutical kit for injection into a human patient in need thereof. 177 a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a dose of 6.6 GBq±0.10 GBq, a dose of 6.6 GBq±0.15 GBq, a dose of 6.6 GBq±0.20 GBq, a dose of 6.6 GBq±0.25 GBq, or a dose of 6.6 GBq±0.30 GBq, and 1, 2, 3, 4, 5, 6, or 7 cycles at that dose;177 Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, or 7 cycles 177 Further relates to a radiopharmaceutical kit, wherein the Lu-PSMA I&T treatment provides a mean predicted dose that is less than a cumulative absorbed dose to the kidney of 23 Gy, and / or the predicted or actual cumulative absorbed dose to the kidney over 1, 2, 3, 4, 5, 6, or 7 cycles is less than 23 Gy, and no nephrotoxicity is observed.

[0239] In various embodiments, the present disclosure provides a radiopharmaceutical kit for injection into a human patient in need thereof. 177 a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a dose of 6.7 GBq±0.10 GBq, a dose of 6.7 GBq±0.15 GBq, a dose of 6.7 GBq±0.20 GBq, a dose of 6.7 GBq±0.25 GBq, or a dose of 6.7 GBq±0.30 GBq, and 1, 2, 3, 4, 5, 6, or 7 cycles of the dose; 177 Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, or 7 cycles 177 Further relates to a radiopharmaceutical kit, wherein the Lu-PSMA I&T treatment provides a mean predicted dose that is less than a cumulative absorbed dose to the kidney of 23 Gy, and / or the predicted or actual cumulative absorbed dose to the kidney over 1, 2, 3, 4, 5, 6, or 7 cycles is less than 23 Gy, and no nephrotoxicity is observed.

[0240] In various embodiments, the present disclosure provides a radiopharmaceutical kit for injection into a human patient in need thereof. 177 a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a dose of 6.8 GBq±0.10 GBq, a dose of 6.8 GBq±0.15 GBq, a dose of 6.8 GBq±0.20 GBq, a dose of 6.8 GBq±0.25 GBq, or a dose of 6.8 GBq±0.30 GBq, and 1, 2, 3, 4, 5, 6, or 7 cycles at that dose; 177Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, or 7 cycles 177 Further relates to a radiopharmaceutical kit, wherein the Lu-PSMA I&T treatment provides a mean predicted dose that is less than a cumulative absorbed dose to the kidney of 23 Gy, and / or the predicted or actual cumulative absorbed dose to the kidney over 1, 2, 3, 4, 5, 6, or 7 cycles is less than 23 Gy, and no nephrotoxicity is observed.

[0241] In various embodiments, the present disclosure provides a radiopharmaceutical kit for injection into a human patient in need thereof. 177 a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a dose of 6.9 GBq±0.10 GBq, a dose of 6.9 GBq±0.15 GBq, a dose of 6.9 GBq±0.20 GBq, a dose of 6.9 GBq±0.25 GBq, or a dose of 6.9 GBq±0.30 GBq, and 1, 2, 3, 4, 5, 6, or 7 cycles at that dose; 177 Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, or 7 cycles 177 Further relates to a radiopharmaceutical kit, wherein the Lu-PSMA I&T treatment provides a mean predicted dose that is less than a cumulative absorbed dose to the kidney of 23 Gy, and / or the predicted or actual cumulative absorbed dose to the kidney over 1, 2, 3, 4, 5, 6, or 7 cycles is less than 23 Gy, and no nephrotoxicity is observed.

[0242] In various embodiments, the present disclosure provides a radiopharmaceutical kit for injection into a human patient in need thereof. 177 a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a dose of 7.0 GBq±0.10 GBq, a dose of 7.0 GBq±0.15 GBq, a dose of 7.0 GBq±0.20 GBq, a dose of 7.0 GBq±0.25 GBq, or a dose of 7.0 GBq±0.30 GBq, and 1, 2, 3, 4, 5, 6, or 7 cycles at that dose; 177Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, or 7 cycles 177 Further relates to a radiopharmaceutical kit, wherein the Lu-PSMA I&T treatment provides a mean predicted dose that is less than a cumulative absorbed dose to the kidney of 23 Gy, and / or the predicted or actual cumulative absorbed dose to the kidney over 1, 2, 3, 4, 5, 6, or 7 cycles is less than 23 Gy, and no nephrotoxicity is observed.

[0243] In various embodiments, the present disclosure provides a radiopharmaceutical kit for injection into a human patient in need thereof. 177 a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a dose of 7.1 GBq±0.10 GBq, a dose of 7.1 GBq±0.15 GBq, a dose of 7.1 GBq±0.20 GBq, a dose of 7.1 GBq±0.25 GBq, or a dose of 7.1 GBq±0.30 GBq, and 1, 2, 3, 4, 5, 6, or 7 cycles of the dose; 177 Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, or 7 cycles 177 Further relates to a radiopharmaceutical kit, wherein the Lu-PSMA I&T treatment provides a mean predicted dose that is less than a cumulative absorbed dose to the kidney of 23 Gy, and / or the predicted or actual cumulative absorbed dose to the kidney over 1, 2, 3, 4, 5, 6, or 7 cycles is less than 23 Gy, and no nephrotoxicity is observed.

[0244] In various embodiments, the present disclosure provides a radiopharmaceutical kit for injection into a human patient in need thereof. 177 a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a dose of 7.2 GBq±0.10 GBq, a dose of 7.2 GBq±0.15 GBq, a dose of 7.2 GBq±0.20 GBq, a dose of 7.2 GBq±0.25 GBq, or a dose of 7.2 GBq±0.30 GBq, and 1, 2, 3, 4, 5, 6, or 7 cycles of the dose; 177Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, or 7 cycles 177 Further relates to a radiopharmaceutical kit, wherein the Lu-PSMA I&T treatment provides a mean predicted dose that is less than a cumulative absorbed dose to the kidney of 23 Gy, and / or the predicted or actual cumulative absorbed dose to the kidney over 1, 2, 3, 4, 5, 6, or 7 cycles is less than 23 Gy, and no nephrotoxicity is observed.

[0245] In various embodiments, the present disclosure provides a radiopharmaceutical kit for injection into a human patient in need thereof. 177 a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a dose of 7.3 GBq±0.10 GBq, a dose of 7.3 GBq±0.15 GBq, a dose of 7.3 GBq±0.20 GBq, a dose of 7.3 GBq±0.25 GBq, or a dose of 7.3 GBq±0.30 GBq, and 1, 2, 3, 4, 5, 6, or 7 cycles of the dose; 177 Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, or 7 cycles 177 Further relates to a radiopharmaceutical kit, wherein the Lu-PSMA I&T treatment provides a mean predicted dose that is less than a cumulative absorbed dose to the kidney of 23 Gy, and / or the predicted or actual cumulative absorbed dose to the kidney over 1, 2, 3, 4, 5, 6, or 7 cycles is less than 23 Gy, and no nephrotoxicity is observed.

[0246] In various embodiments, the present disclosure provides a radiopharmaceutical kit for injection into a human patient in need thereof. 177 a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a dose of 7.4 GBq ± 0.10 GBq, a dose of 7.4 GBq ± 0.15 GBq, a dose of 7.4 GBq ± 0.20 GBq, a dose of 7.4 GBq ± 0.25 GBq, or a dose of 7.4 GBq ± 0.30 GBq, and six cycles of the dose. 177 Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, or 7 cycles177 Further relates to a radiopharmaceutical kit, wherein the Lu-PSMA I&T treatment provides a mean predicted dose that is less than a cumulative absorbed dose to the kidney of 23 Gy, and / or the predicted or actual cumulative absorbed dose to the kidney over 1, 2, 3, 4, 5, 6, or 7 cycles is less than 23 Gy, and no nephrotoxicity is observed.

[0247] In various embodiments, the present disclosure provides a radiopharmaceutical kit for injection into a human patient in need thereof. 177 a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a dose of 7.5 GBq±0.10 GBq, a dose of 7.5 GBq±0.15 GBq, a dose of 7.5 GBq±0.20 GBq, a dose of 7.5 GBq±0.25 GBq, or a dose of 7.5 GBq±0.30 GBq, and 1, 2, 3, 4, 5, 6, or 7 cycles of the dose; 177 Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, or 7 cycles 177 Further relates to a radiopharmaceutical kit, wherein the Lu-PSMA I&T treatment provides a mean predicted dose that is less than a cumulative absorbed dose to the kidney of 23 Gy, and / or the predicted or actual cumulative absorbed dose to the kidney over 6 cycles is less than 23 Gy, and no nephrotoxicity is observed.

[0248] In various embodiments, the present disclosure provides a radiopharmaceutical kit for injection into a human patient in need thereof. 177 and a vial containing at least a single dose of Lu-PSMA I&T solution, the injection of which is to deliver a dose of 7.4 GBq (mean 7.52 ± 0.16 GBq). 177 Lu-PSMA I&T and 6 cycles at that dose 177 Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, or 7 cycles 177The present disclosure further relates to a radiopharmaceutical kit, wherein the Lu-PSMA I&T treatment provides a mean predicted dose that is less than a cumulative absorbed dose to the kidney of 23 Gy, and / or the predicted or actual cumulative absorbed dose to the kidney for 1, 2, 3, 4, 5, 6, or 7 cycles is less than 23 Gy, and no nephrotoxicity is observed. 177 and a vial containing at least a single dose of Lu-PSMA I&T solution, the injection of which is to deliver a dose of 7.4 GBq (mean 7.52 ± 0.16 GBq). 177 Lu-PSMA I&T, 1, 2, 3, 4, 5, 6, or 7 cycles 177 Further relates to a radiopharmaceutical kit, wherein the Lu-PSMA I&T treatment provides a mean predicted dose that is less than a cumulative absorbed dose to the kidney of 23 Gy, and / or the predicted or actual cumulative absorbed dose to the kidney over 1, 2, 3, 4, 5, 6, or 7 cycles is less than 23 Gy, and no nephrotoxicity is observed.

[0249] The present disclosure also provides a radiopharmaceutical kit for injection into a human patient in need thereof. 177 a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection is administered at a dose of 6.5 GBq + / - 10% GBq, a dose of 6.5 GBq + / - 5% GBq, or a dose of 6.5 GBq + / - 3% GBq; 177 1, 2, 3, 4, 5, 6, or 7 cycles of Lu-PSMA-I&T at that dose 177 Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, or 7 cycles 177 Further relates to a radiopharmaceutical kit, wherein the Lu-PSMA I&T treatment provides a mean predicted dose that is less than a cumulative absorbed dose to the kidney of 23 Gy, and / or the predicted or actual cumulative absorbed dose to the kidney over 1, 2, 3, 4, 5, 6, or 7 cycles is less than 23 Gy, and no nephrotoxicity is observed.

[0250] The present disclosure also provides a radiopharmaceutical kit for injection into a human patient in need thereof. 177a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection is administered at a dose of 6.8 GBq + / - 10% GBq, a dose of 6.8 GBq + / - 5% GBq, or a dose of 6.8 GBq + / - 3% GBq; 177 1, 2, 3, 4, 5, 6, or 7 cycles of Lu-PSMA-I&T at that dose 177 Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, or 7 cycles 177 Further relates to a radiopharmaceutical kit, wherein the Lu-PSMA I&T treatment provides a mean predicted dose that is less than a cumulative absorbed dose to the kidney of 23 Gy, and / or the predicted or actual cumulative absorbed dose to the kidney over 1, 2, 3, 4, 5, 6, or 7 cycles is less than 23 Gy, and no nephrotoxicity is observed.

[0251] The present disclosure also provides a radiopharmaceutical kit for injection into a human patient in need thereof. 177 a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection is administered at a dose of 7.4 GBq + / - 10% GBq, a dose of 7.4 GBq + / - 5% GBq, or a dose of 7.4 GBq + / - 3% GBq; 177 1, 2, 3, 4, 5, 6, or 7 cycles of Lu-PSMA-I&T at that dose 177 Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 1, 2, 3, 4, 5, 6, or 7 cycles 177 Further relates to a radiopharmaceutical kit, wherein the Lu-PSMA I&T treatment provides a mean predicted dose that is less than a cumulative absorbed dose to the kidney of 23 Gy, and / or the predicted or actual cumulative absorbed dose to the kidney over 1, 2, 3, 4, 5, 6, or 7 cycles is less than 23 Gy, and no nephrotoxicity is observed.

[0252] The present disclosure also provides a radiopharmaceutical kit for injection into a human patient in need thereof. 177 a vial containing at least a single dose of Lu-PSMA I&T solution, the injection of which is to deliver a dose of 7.4 (+ / - 10%) GBq; 177Lu-PSMA I&T and 6 cycles at that dose 177 Lu-PSMA I&T treatment is possible without risk of nephrotoxicity and / or 6 cycles 177 Further relates to a radiopharmaceutical kit, wherein the Lu-PSMA I&T treatment provides a mean predicted dose that is less than a cumulative absorbed dose to the kidney of 23 Gy, and / or the predicted or actual cumulative absorbed dose to the kidney over 6 cycles is less than 23 Gy, and no nephrotoxicity is observed.

[0253] The present disclosure relates to a radiopharmaceutical kit for injection into a human patient in need thereof. 177 The present disclosure further relates to a radiopharmaceutical kit comprising a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a dose of 7.4 GBq±0.10 GBq, a dose of 7.4 GBq±0.15 GBq, a dose of 7.4 GBq±0.20 GBq, a dose of 7.4 GBq±0.25 GBq, or a dose of 7.4 GBq±0.30 GBq, and wherein the predicted cumulative absorbed dose to the kidney over six cycles would be 20.4±10.2 Gy. 177 Further relates to a radiopharmaceutical kit comprising a vial containing at least a single dose of Lu-PSMA I&T solution, wherein the injection comprises a dose of 7.5 GBq±0.10 GBq, a dose of 7.5 GBq±0.15 GBq, a dose of 7.5 GBq±0.20 GBq, a dose of 7.5 GBq±0.25 GBq, or a dose of 7.5 GBq±0.30 GBq, and wherein the predicted cumulative absorbed dose to the kidney over six cycles would be 20.4±10.2 Gy.

[0254] In some embodiments, the present disclosure provides: 177 In another embodiment, the kit comprises a predetermined amount of a composition comprising Lu-PSMA I&T. 177 The molar ratio to Lu is from 5.0:1.0 to 12.0:1.0. In another embodiment, the composition is suitable for administration to a human patient in need thereof.

[0255] Upon administration of the radiopharmaceutical composition to a patient, the patient may maintain low levels of hematotoxicity and nephrotoxicity, hi some embodiments, the reduction in prostate specific antigen (PSA) is greater than about 40%, greater than about 45%, greater than about 50%, greater than about 55%, greater than about 60%, greater than about 65%, greater than about 70%, greater than about 75%, or greater than about 80%.

[0256] 177 Further provided herein is a method of treating a patient with mCRPC by administering a radiopharmaceutical composition comprising Lu-PSMA I&T. The method may further include imaging the patient using PSMA-PET prior to administering the radiopharmaceutical composition to document and confirm that the patient is mCRPC positive. For example, the patient may have a PSMA-PET scan (e.g., [ 68 Ga]Ga-PSMA-11 or [ 18 F]DCFPyL) positive.

[0257] In one embodiment, provided herein is a method of imaging cancer in a human patient. In another embodiment, the method comprises: 177 In another embodiment, the method further comprises administering to a human patient a composition comprising the Lu-PSMA I&T. 177 The molar ratio to Lu is 5.0:1.0 to 12.0:1.0.

[0258] The absorbed radiation dose from administration of the composition can be measured by SPECT / CT imaging, two-dimensional imaging, or a combination thereof, or via other techniques known to those skilled in the art. The anatomical coverage of the imaging can extend from the salivary glands to the pelvis of a human patient.

[0259] After administration of one of the compositions provided herein, the absorbed radiation dose per gram of tissue in the kidney of a human patient can be about 0.2 Gy / GBq to about 0.6 Gy / GBq, about 0.25 Gy / GBq to about 0.55 Gy / GBq, about 0.3 Gy / GBq to about 0.5 Gy / GBq, or about 0.35 Gy / GBq to about 0.45 Gy / GBq. In some embodiments, the absorbed radiation dose per gram of tissue in the kidney of a human patient can be 0.60 Gy / GBq or less, 0.55 Gy / GBq or less, 0.50 Gy / GBq or less, 0.45 Gy / GBq or less, 0.40 Gy / GBq or less, 0.35 Gy / GBq or less, 0.30 Gy / GBq or less, 0.25 Gy / GBq or less, 0.20 Gy / GBq or less, or 0.15 Gy / GBq or less.

[0260] PSMA I&T in composition 177 The molar ratio of Lu to Lu can be about 4.0:1 to about 8.0:1, e.g., about 4.5:1 to about 5.5:1, or about 5.0:1 to about 6.0:1. In some embodiments, the composition can be about 4.0:1, about 4.1:1, about 4.2:1, about 4.3:1, about 4.4:1, about 4.5:1, about 4.6:1, about 4.7:1, about 4.8:1, about 4.9:1, about 5.0:1, about 5.1:1, about 5.2:1, about 5.3:1, about 5.4:1, about 5.5:1, about 5.6:1, about 5.7:1, about 5.8:1, about 5.9:1 , about 6.0:1, about 6.1:1, about 6.2:1, about 6.3:1, about 6.4:1, about 6.5:1, about 6.6:1, about 6.7:1, about 6.8:1, about 6.9:1, about 7.0:1, about 7.1:1, about 7.2:1, about 7.3:1, about 7.4:1, about 7.5:1, about 7.6:1, about 7.7:1, about 7.8:1, about 7.9:1, or about 8.0:1 of PSMA I&T. 177 In some embodiments, the composition has a molar ratio of PSMA I&T to Lu of about 5.1:1.0 to about 5.9:1.0, about 5.2:1.0 to about 5.8:1.0, about 5.3:1.0 to about 5.7:1.0, or about 5.4:1.0 to about 5.6:1.0. 177 The molar ratio of Zn to Lu is:

[0261] The composition contains about 7.1 GBq to about 7.6 GBq 177For example, the composition can contain about 7.1 GBq, about 7.2 GBq, about 7.3 GBq, about 7.4 GBq, about 7.5 GBq, or about 7.6 GBq of Lu-PSMA I&T. 177 In some specific embodiments, the composition may comprise 7.4±15% GBq of Lu-PSMA I&T. 177 Lu-PSMA I&T, 7.4±10% GBq 177 Lu-PSMA I&T, or 7.4±5%GBq 177 Lu-PSMA I&T may be included.

[0262] In some embodiments, the average absorbed radiation dose per gram of tissue in the kidney of a human patient can be about 0.39±0.15 Gy / GBq, about 0.40±0.15 Gy / GBq, about 0.41±0.15 Gy / GBq, about 0.42±0.15 Gy / GBq, about 0.43±0.15 Gy / GBq, or about 0.45±0.15 Gy / GBq. In some additional embodiments, the average absorbed radiation dose per gram of tissue in the kidney of a human patient can be 0.39 Gy / GBq or less, 0.40 Gy / GBq or less, 0.41 Gy / GBq or less, or 0.42 Gy / GBq or less.

[0263] In some aspects, the standard deviation of the mean absorbed radiation dose per gram of tissue in the kidney of a human patient can be 0.19 Gy / GBq or less, 0.18 Gy / GBq or less, 0.17 Gy / GBq or less, 0.16 Gy / GBq or less, or 0.15 Gy / GBq or less.

[0264] The absorbed radiation dose per gram of tissue in the lacrimal gland of a human patient can be about 0.01 Gy / GBq to about 1.5 Gy / GBq, for example, about 0.1 Gy / GBq to about 0.8 Gy / GBq. In some embodiments, the absorbed radiation dose per gram of tissue in the lacrimal gland of a human patient can be 1.5 Gy / GBq or less, 1.4 Gy / GBq or less, 1.3 Gy / GBq or less, 1.2 Gy / GBq or less, 1.1 Gy / GBq or less, 1.0 Gy / GBq or less, 0.9 Gy / GBq or less, 0.8 Gy / GBq or less, 0.7 Gy / GBq or less, 0.6 Gy / GBq or less, 0.5 Gy / GBq or less, 0.4 Gy / GBq or less, 0.3 Gy / GBq or less, 0.2 Gy / GBq or less, or 0.1 Gy / GBq or less. The absorbed radiation dose can be measured by SPECT / CT imaging, two-dimensional imaging, or a combination thereof, or through other techniques known to those skilled in the art.

[0265] In some embodiments, the absorbed radiation dose per gram of tissue in the lacrimal gland of a human patient can be about 0.01, about 0.05, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, or about 1.5 Gy / GBq.

[0266] In some embodiments, the average absorbed radiation dose per gram of tissue in the lacrimal gland of a human patient can be 0.37±0.36 Gy / GBq, 0.38±0.36 Gy / GBq, 0.39±0.36 Gy / GBq, or 0.40±0.36 Gy / GBq. In some embodiments, the average absorbed radiation dose per gram of tissue in the lacrimal gland of a human patient can be 1.5 Gy / GBq or less, 1.4 Gy / GBq or less, 1.3 Gy / GBq or less, 1.2 Gy / GBq or less, 1.1 Gy / GBq or less, 1.0 Gy / GBq or less, 0.9 Gy / GBq or less, 0.8 Gy / GBq or less, 0.7 Gy / GBq or less, 0.6 Gy / GBq or less, 0.5 Gy / GBq or less, 0.4 Gy / GBq or less, 0.3 Gy / GBq or less, 0.2 Gy / GBq or less, or 0.1 Gy / GBq or less. In some additional embodiments, the standard deviation of the mean absorbed radiation dose per gram of tissue in the lacrimal gland of a human patient can be 0.40 Gy / GBq or less, 0.39 Gy / GBq or less, 0.38 Gy / GBq or less, 0.37 Gy / GBq or less, 0.36 Gy / GBq or less, 0.35 Gy / GBq or less, 0.34 Gy / GBq or less, 0.33 Gy / GBq or less, 0.32 Gy / GBq or less, 0.31 Gy / GBq or less, or 0.30 Gy / GBq or less.

[0267] After administration of the composition, the absorbed radiation dose per gram of tissue in the salivary gland of the human patient can be about 0.01 Gy / GBq to about 1.0 Gy / GBq, e.g., about 0.1 Gy / GBq to about 0.5 Gy / GBq. In some embodiments, the absorbed radiation dose per gram of tissue in the salivary gland of the human patient can be 1.0 Gy / GBq or less, 0.9 Gy / GBq or less, 0.8 Gy / GBq or less, 0.7 Gy / GBq or less, 0.6 Gy / GBq or less, 0.5 Gy / GBq or less, 0.4 Gy / GBq or less, 0.3 Gy / GBq or less, 0.2 Gy / GBq or less, or 0.1 Gy / GBq or less.

[0268] In some embodiments, the absorbed radiation dose per gram of tissue in the salivary gland of a human patient can be about 0.01, about 0.05, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, or about 1.0 Gy / GBq.

[0269] In some embodiments, the average absorbed radiation dose per gram of tissue in the salivary gland of a human patient can be about 0.17±0.16 Gy / GBq, about 0.18±0.16 Gy / GBq, about 0.19±0.16 Gy / GBq, or about 0.20±0.16 Gy / GBq. In some additional embodiments, the average absorbed radiation dose per gram of tissue in the salivary glands of a human patient can be 0.18 Gy / GBq or less, 0.19 Gy / GBq or less, 0.20 Gy / GBq or less, 0.21 Gy / GBq or less, 0.22 Gy / GBq or less, 0.23 Gy / GBq or less, 0.24 Gy / GBq or less, 0.25 Gy / GBq or less, 0.26 Gy / GBq or less, 0.27 Gy / GBq or less, 0.28 Gy / GBq or less, 0.29 Gy / GBq or less, or 0.30 Gy / GBq or less.

[0270] In some embodiments, the standard deviation of the mean absorbed radiation dose per gram of tissue in the salivary glands of a human patient can be 0.25 Gy / GBq or less, 0.24 Gy / GBq or less, 0.23 Gy / GBq or less, 0.22 Gy / GBq or less, 0.21 Gy / GBq or less, 0.20 Gy / GBq or less, 0.19 Gy / GBq or less, 0.18 Gy / GBq or less, 0.17 Gy / GBq or less, or 0.16 Gy / GBq or less.

[0271] After administration of the composition, the absorbed radiation dose per gram of tissue in the left colon of a human patient can be from about 0.01 Gy / GBq to about 1.6 Gy / GBq, for example, from about 0.1 Gy / GBq to about 0.8 Gy / GBq. In some aspects, the absorbed radiation dose per gram of tissue in the left colon of a human patient can be 1.6 Gy / GBq or less, 1.5 Gy / GBq or less, 1.4 Gy / GBq or less, 1.3 Gy / GBq or less, 1.2 Gy / GBq or less, 1.1 Gy / GBq or less, 1.0 Gy / GBq or less, 0.9 Gy / GBq or less, 0.8 Gy / GBq or less, 0.7 Gy / GBq or less, 0.6 Gy / GBq or less, 0.5 Gy / GBq or less, 0.4 Gy / GBq or less, 0.3 Gy / GBq or less, 0.2 Gy / GBq or less, or 0.1 Gy / GBq or less.

[0272] In some embodiments, the absorbed radiation dose per gram of tissue in the left colon of a human patient can be about 0.01, about 0.05, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, or about 1.6 Gy / GBq.

[0273] In some embodiments, the average absorbed radiation dose per gram of tissue in the left colon of a human patient can be 0.45±0.31 Gy / GBq, 0.46±0.31 Gy / GBq, or 0.47±0.31 Gy / GBq. In some aspects, the average absorbed radiation dose per gram of tissue in the left colon of a human patient can be 0.50 Gy / GBq or less, 0.49 Gy / GBq or less, 0.48 Gy / GBq or less, 0.47 Gy / GBq or less, 0.46 Gy / GBq or less, 0.45 Gy / GBq or less, 0.44 Gy / GBq or less, 0.43 Gy / GBq or less, 0.42 Gy / GBq or less, 0.41 Gy / GBq or less, or 0.40 Gy / GBq or less.

[0274] After administration of the composition, the absorbed radiation dose per gram of tissue in the rectum of a human patient can be about 0.01 Gy / GBq to about 1.5 Gy / GBq, e.g., about 0.1 Gy / GBq to about 0.8 Gy / GBq. In some embodiments, the absorbed radiation dose per gram of tissue in the rectum of a human patient can be 1.5 Gy / GBq or less, 1.4 Gy / GBq or less, 1.3 Gy / GBq or less, 1.2 Gy / GBq or less, 1.1 Gy / GBq or less, 1.0 Gy / GBq or less, 0.9 Gy / GBq or less, 0.8 Gy / GBq or less, 0.7 Gy / GBq or less, 0.6 Gy / GBq or less, 0.5 Gy / GBq or less, 0.4 Gy / GBq or less, 0.3 Gy / GBq or less, 0.2 Gy / GBq or less, or 0.1 Gy / GBq or less.

[0275] In some embodiments, the absorbed radiation dose per gram of tissue in the rectum of a human patient can be about 0.01, about 0.05, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, or about 1.5 Gy / GBq.

[0276] In some embodiments, the average absorbed radiation dose per gram of tissue in the rectum of a human patient can be 0.50±0.30 Gy / GBq, 0.49±0.30 Gy / GBq, 0.48±0.30 Gy / GBq, 0.47±0.30 Gy / GBq, 0.46±0.30 Gy / GBq, 0.45±0.30 Gy / GBq, 0.44±0.30 Gy / GBq, 0.43±0.30 Gy / GBq, 0.42±0.30 Gy / GBq, 0.41±0.30 Gy / GBq, or 0.40±0.30 Gy / GBq.

[0277] After administration of the composition, the systemic 177 The ratio of activity of the Lu-PSMA I&T can be about 0.5 or less within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. In some embodiments, the ratio of activity of the Lu-PSMA I&T can be about 0.5 or less within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. 177 The percent activity of Lu-PSMA I&T may be 0.5 or less, 0.4 or less, 0.3 or less, 0.2 or less, or 0.1 or less within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. Activity from administration of the composition may be measured by SPECT / CT imaging, two-dimensional imaging, or a combination thereof, or via other techniques known to those skilled in the art. The anatomical coverage of the imaging may extend from the salivary glands to the pelvis of a human patient.

[0278] In some embodiments, the systemic 177 The percent activity of the Lu-PSMA I&T can be about 0.5, about 0.4, about 0.3, about 0.2, about 0.1, or less than about 0.1 within 24 hours, 48 ​​hours, or 168 hours after administration of the composition.

[0279] In some embodiments, systemically in a human patient 177 The ratio of activity of the Lu-PSMA I&T can be about 0.4 or less within 48 hours or 168 hours after administration of the composition. For example, in a human patient, 177The ratio of activity of the Lu-PSMA I&T can be less than about 0.4, about 0.3, about 0.2, about 0.1, or 0.1 within 48 hours or 168 hours after administration of the composition. In some embodiments, the ratio of activity of the Lu-PSMA I&T can be less than about 0.4, about 0.3, about 0.2, about 0.1, or 0.1 within 48 hours or 168 hours after administration of the composition. 177 The percent activity of the Lu-PSMA I&T can be 0.4 or less, 0.3 or less, 0.2 or less, or 0.1 or less within 48 hours or 168 hours after administration of the composition.

[0280] In some embodiments, systemically in a human patient 177 The ratio of activity of the Lu-PSMA I&T is about 0.2 or less within 168 hours after administration of the composition.

[0281] in the kidneys of human patients after administration of the composition 177 The percent activity of Lu-PSMA I&T can be about 0.05 or less, e.g., about 0.04, about 0.03, about 0.02, about 0.01, or less than about 0.01, within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. In some embodiments, the percent activity of Lu-PSMA I&T in the kidney of a human patient can be about 0.05 or less, e.g., about 0.04, about 0.03, about 0.02, about 0.01, or less than about 0.01, within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. 177 The percent activity of Lu-PSMA I&T can be 0.05 or less, 0.04 or less, 0.03 or less, 0.02 or less, 0.01 or less, or less within 24 hours, 48 ​​hours, or 168 hours after administration of the composition.

[0282] In some embodiments, in the kidney of a human patient 177 The percent activity of Lu-PSMA I&T can be 0.040 or less, 0.03 or less, 0.02 or less, or 0.01 or less within 48 hours or 168 hours after administration of the composition. In some embodiments, the percent activity of Lu-PSMA I&T in the kidney of a human patient 177 The percent activity of the Lu-PSMA I&T can be about 0.040, about 0.03, about 0.02, about 0.01, or less than about 0.01 within 48 hours or 168 hours after administration of the composition.

[0283] In some embodiments, in the kidney of a human patient 177The percent activity of the Lu-PSMA I&T is about 0.03 or less, e.g., about 0.03, about 0.02, about 0.01, or less than about 0.01, within 168 hours after administration of the composition.

[0284] in the red bone marrow of a human patient after administration of the composition 177 The percent activity of the Lu-PSMA I&T can be about 0.08 or less within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. In some embodiments, the percent activity of the Lu-PSMA I&T in the red bone marrow of a human patient can be about 0.08 or less within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. 177 The percent activity of the Lu-PSMA I&T can be 0.08 or less, 0.07 or less, 0.06 or less, 0.05 or less, 0.04 or less, 0.03 or less, 0.02 or less, 0.01 or less, or less within 24 hours, 48 ​​hours, or 168 hours after administration of the composition.

[0285] In some embodiments, in the red bone marrow of a human patient 177 The percent activity of the Lu-PSMA I&T can be about 0.08, about 0.07, about 0.06, about 0.05, about 0.04, about 0.03, about 0.02, about 0.01, or less than about 0.01 within 24 hours, 48 ​​hours, or 168 hours after administration of the composition.

[0286] In some embodiments, in the red bone marrow of a human patient 177 The ratio of activity of the Lu-PSMA I&T can be about 0.06 or less within 48 hours or 168 hours after administration of the composition. In some embodiments, the ratio of activity of the Lu-PSMA I&T in the red bone marrow of a human patient can be about 0.06 or less within 48 hours or 168 hours after administration of the composition. 177 The percent activity of Lu-PSMA I&T can be less than about 0.06, about 0.05, about 0.04, about 0.03, about 0.02, about 0.01, or about 0.01 within 48 hours or 168 hours after administration of the composition. In some embodiments, the percent activity of Lu-PSMA I&T in red bone marrow of a human patient can be less than about 0.06, about 0.05, about 0.04, about 0.03, about 0.02, about 0.01, or about 0.01 within 48 hours or 168 hours after administration of the composition. 177 The percent activity of Lu-PSMA I&T can be 0.06 or less, 0.05 or less, 0.04 or less, 0.03 or less, 0.02 or less, 0.01 or less, or less within 48 hours or 168 hours after administration of the composition.

[0287] In some embodiments, in the red bone marrow of a human patient 177 The ratio of activity of the Lu-PSMA I&T can be about 0.04 or less within 168 hours after administration of the composition. In some embodiments, the ratio of activity of the Lu-PSMA I&T in the red bone marrow of a human patient can be about 0.04 or less within 168 hours after administration of the composition. 177 The percent activity of Lu-PSMA I&T can be about 0.04, about 0.03, about 0.02, about 0.01, or less than 0.01 within 168 hours after administration of the composition. In some embodiments, the percent activity of Lu-PSMA I&T in red bone marrow of a human patient can be about 0.04, about 0.03, about 0.02, about 0.01, or less than 0.01 within 168 hours after administration of the composition. 177 The percent activity of the Lu-PSMA I&T can be 0.04 or less, 0.03 or less, 0.02 or less, 0.01 or less, or less within 168 hours after administration of the composition.

[0288] in the salivary glands of human patients after administration of the composition 177 The ratio of activity of Lu-PSMA I&T can be about 0.015 or less within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. In some embodiments, the ratio of activity of Lu-PSMA I&T in the salivary glands of a human patient can be about 0.015 or less within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. 177 The percent activity of Lu-PSMA I&T can be 0.015 or less, 0.014 or less, 0.013 or less, 0.012 or less, 0.011 or less, 0.010 or less, 0.009 or less, 0.008 or less, 0.007 or less, 0.006 or less, 0.005 or less, 0.004 or less, 0.003 or less, 0.002 or less, 0.001 or less, or less within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. In some embodiments, the percent activity of Lu-PSMA I&T in the salivary glands of a human patient can be 0.015 or less, 0.014 or less, 0.013 or less, 0.012 or less, 0.011 or less, 0.010 or less, 0.009 or less, 0.008 or less, 0.007 or less, 0.006 or less, 0.005 or less, 0.004 or less, 0.003 or less, 0.002 or less, 0.001 or less, or less, or less, within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. 177 The percent activity of the Lu-PSMA I&T can be about 0.015, about 0.014, about 0.013, about 0.012, about 0.011, about 0.010, about 0.009, about 0.008, about 0.007, about 0.006, about 0.005, about 0.004, about 0.003, about 0.002, about 0.001, or less than about 0.001 within 24 hours, 48 ​​hours, or 168 hours after administration of the composition.

[0289] In some embodiments, in the salivary glands of a human patient 177The ratio of activity of Lu-PSMA I&T can be about 0.007 or less within 48 hours or 168 hours after administration of the composition. In some embodiments, the ratio of activity of Lu-PSMA I&T in the salivary glands of a human patient can be about 0.007 or less within 48 hours or 168 hours after administration of the composition. 177 The percent activity of Lu-PSMA I&T can be less than about 0.007, about 0.006, about 0.005, about 0.004, about 0.003, about 0.002, about 0.001, or about 0.001 within 48 hours or 168 hours after administration of the composition. In some embodiments, the percent activity of Lu-PSMA I&T in the salivary glands of a human patient can be less than about 0.007, about 0.006, about 0.005, about 0.004, about 0.003, about 0.002, about 0.001, or about 0.001 within 48 hours or 168 hours after administration of the composition. 177 The percent activity of Lu-PSMA I&T can be 0.007 or less, 0.006 or less, 0.005 or less, 0.004 or less, 0.003 or less, 0.002 or less, 0.001 or less, or less within 48 hours or 168 hours after administration of the composition.

[0290] In some embodiments, in the salivary glands of a human patient 177 The ratio of activity of Lu-PSMA I&T can be about 0.004 or less within 168 hours after administration of the composition. In some embodiments, the ratio of activity of Lu-PSMA I&T in the salivary glands of a human patient can be about 0.004 or less within 168 hours after administration of the composition. 177 The percent activity of Lu-PSMA I&T can be less than about 0.004, about 0.003, about 0.002, about 0.001, or about 0.001 within 168 hours after administration of the composition. In some embodiments, the percent activity of Lu-PSMA I&T in the salivary glands of a human patient 177 The percent activity of Lu-PSMA I&T can be 0.004 or less, 0.003 or less, 0.002 or less, 0.001 or less, or less within 168 hours after administration of the composition.

[0291] in the gastrointestinal tract of a human patient after administration of the composition 177 The ratio of activity of the Lu-PSMA I&T can be about 0.10 or less within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. 177The percent activity of the Lu-PSMA I&T can be about 0.10, about 0.09, about 0.08, about 0.07, about 0.06, about 0.05, about 0.04, about 0.03, about 0.02, about 0.01, or less than about 0.01 within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. In some embodiments, the percent activity of the Lu-PSMA I&T in the gastrointestinal tract of a human patient can be about 0.10, about 0.09, about 0.08, about 0.07, about 0.06, about 0.05, about 0.04, about 0.03, about 0.02, about 0.01, or less than about 0.01 within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. 177 The percent activity of the Lu-PSMA I&T can be 0.10 or less, 0.09 or less, 0.08 or less, 0.07 or less, 0.06 or less, 0.05 or less, 0.04 or less, 0.03 or less, 0.02 or less, 0.01 or less, or less within 24 hours, 48 ​​hours, or 168 hours after administration of the composition.

[0292] In some embodiments, in the gastrointestinal tract of a human patient 177 The ratio of activity of the Lu-PSMA I&T can be about 0.10 or less within 48 hours or 168 hours after administration of the composition. In some embodiments, the ratio of activity of the Lu-PSMA I&T in the gastrointestinal tract of a human patient can be about 0.10 or less within 48 hours or 168 hours after administration of the composition. 177 The percent activity of the Lu-PSMA I&T can be about 0.10, about 0.09, about 0.08, about 0.07, about 0.06, about 0.05, about 0.04, about 0.03, about 0.02, about 0.01, or less than about 0.01 within 48 hours or 168 hours after administration of the composition. In some embodiments, the percent activity of the Lu-PSMA I&T in the gastrointestinal tract of a human patient can be about 0.10, about 0.09, about 0.08, about 0.07, about 0.06, about 0.05, about 0.04, about 0.03, about 0.02, about 0.01, or less than about 0.01 within 48 hours or 168 hours after administration of the composition. 177 The percent activity of the Lu-PSMA I&T can be 0.10 or less, 0.09 or less, 0.08 or less, 0.07 or less, 0.06 or less, 0.05 or less, 0.04 or less, 0.03 or less, 0.02 or less, 0.01 or less, or less within 48 hours or 168 hours after administration of the composition.

[0293] In some embodiments, in the gastrointestinal tract of a human patient 177 The ratio of activity of the Lu-PSMA I&T can be about 0.05 or less within 168 hours after administration of the composition. In some embodiments, the ratio of activity of the Lu-PSMA I&T in the gastrointestinal tract of a human patient can be about 0.05 or less within 168 hours after administration of the composition. 177 The percent activity of the Lu-PSMA I&T can be about 0.05, about 0.04, about 0.03, about 0.02, about 0.01, or less than about 0.01 within 168 hours after administration of the composition. In some embodiments, the percent activity of the Lu-PSMA I&T in the gastrointestinal tract of a human patient can be about 0.05, about 0.04, about 0.03, about 0.02, about 0.01, or less than about 0.01 within 168 hours after administration of the composition. 177The percent activity of Lu-PSMA I&T can be 0.05 or less, 0.04 or less, 0.03 or less, 0.02 or less, 0.01 or less, or less within 168 hours after administration of the composition.

[0294] in the liver of a human patient after administration of the composition 177 The ratio of activity of Lu-PSMA I&T can be about 0.04 or less within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. In some embodiments, the ratio of activity of Lu-PSMA I&T in the liver of a human patient can be about 0.04 or less within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. 177 The percent activity of Lu-PSMA I&T can be less than about 0.04, about 0.03, about 0.02, about 0.01, or about 0.01 within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. In some embodiments, the percent activity of Lu-PSMA I&T in the liver of a human patient is less than about 0.04, about 0.03, about 0.02, about 0.01, or about 0.01 within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. 177 The percent activity of the Lu-PSMA I&T can be 0.04 or less, 0.03 or less, 0.02 or less, 0.01 or less, or less within 24 hours, 48 ​​hours, or 168 hours after administration of the composition.

[0295] In some embodiments, in the liver of a human patient 177 The ratio of activity of Lu-PSMA I&T can be about 0.02, about 0.01, or less than 0.01 within 48 hours or 168 hours after administration of the composition. In some embodiments, the ratio of activity of Lu-PSMA I&T in the liver of a human patient can be about 0.02, about 0.01, or less than 0.01 within 48 hours or 168 hours after administration of the composition. 177 The percent activity of the Lu-PSMA I&T is 0.02 or less, 0.01 or less, or less within 48 hours or 168 hours after administration of the composition.

[0296] In some embodiments, in the liver of a human patient 177 The percent activity of the Lu-PSMA I&T can be about 0.01 or less within 168 hours after administration of the composition.

[0297] in the spleen of a human patient after administration of the composition 177 The percent activity of Lu-PSMA I&T can be about 0.004 or less within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. In some embodiments, the percent activity of Lu-PSMA I&T in the spleen of a human patient 177The percent activity of Lu-PSMA I&T can be less than about 0.004, about 0.003, about 0.002, about 0.001, or about 0.001 within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. In some embodiments, the percent activity of Lu-PSMA I&T in the spleen of a human patient is less than about 0.004, about 0.003, about 0.002, about 0.001, or about 0.001 within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. 177 The percent activity of the Lu-PSMA I&T can be 0.004 or less, 0.003 or less, 0.002 or less, 0.001 or less, or less within 24 hours, 48 ​​hours, or 168 hours after administration of the composition.

[0298] In some embodiments, in the spleen of a human patient 177 The percent activity of Lu-PSMA I&T can be about 0.002 or less within 48 hours or 168 hours after administration of the composition. In some embodiments, the percent activity of Lu-PSMA I&T in the spleen of a human patient 177 The percent activity of Lu-PSMA I&T can be less than about 0.002, about 0.001, or about 0.001 within 48 hours or 168 hours after administration of the composition. In some embodiments, the percent activity of Lu-PSMA I&T in the spleen of a human patient is less than about 0.002, about 0.001, or about 0.001 within 48 hours or 168 hours after administration of the composition. 177 The percent activity of the Lu-PSMA I&T can be 0.002 or less, 0.001 or less, or less within 48 hours or 168 hours after administration of the composition.

[0299] In some embodiments, in the spleen of a human patient 177 The percent activity of the Lu-PSMA I&T is about 0.001 or less within 168 hours after administration of the composition.

[0300] in the lacrimal glands of human patients after administration of the composition 177 The percent activity of Lu-PSMA I&T can be about 0.0004 or less within 24 hours, 48 ​​hours, or 168 hours after injection of the composition. In some embodiments, the percent activity of Lu-PSMA I&T in the spleen of a human patient 177 The percent activity of Lu-PSMA I&T can be less than about 0.0004, about 0.0003, about 0.0002, about 0.0001, or about 0.0001 within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. In some embodiments, the percent activity of Lu-PSMA I&T in the lacrimal gland of a human patient is less than about 0.0004, about 0.0003, about 0.0002, about 0.0001, or about 0.0001 within 24 hours, 48 ​​hours, or 168 hours after administration of the composition. 177The percent activity of the Lu-PSMA I&T can be 0.0004 or less, 0.0003 or less, 0.0002 or less, 0.0001 or less, or less within 24 hours, 48 ​​hours, or 168 hours after injection of the composition.

[0301] In some embodiments, in the spleen of a human patient 177 The percent activity of Lu-PSMA I&T can be about 0.0002 or less within 48 hours or 168 hours after administration of the composition. In some embodiments, the percent activity of Lu-PSMA I&T in the spleen of a human patient 177 The percent activity of Lu-PSMA I&T can be less than about 0.0002, about 0.0001, or about 0.0001 within 48 hours or 168 hours after administration of the composition. In some embodiments, the percent activity of Lu-PSMA I&T in the spleen of a human patient is less than about 0.0002, about 0.0001, or about 0.0001 within 48 hours or 168 hours after administration of the composition. 177 The percent activity of the Lu-PSMA I&T can be 0.0002 or less, 0.0001 or less, or less within 48 hours or 168 hours after administration of the composition.

[0302] In some embodiments, in the spleen of a human patient 177 The percent activity of the Lu-PSMA I&T can be less than about 0.0001 within 168 hours after administration of the composition.

[0303] Indications and contraindications RLT with 177Lu-PSMA I&T may be indicated for the treatment of patients with mCRPC who do not have any other approved therapeutic options as planned by a multidisciplinary team.

[0304] In another embodiment, the method comprises: 177 In another embodiment, the method further comprises administering to a human patient a composition comprising Lu-PSMA I&T. 177 In another embodiment, the molar ratio of PSMA I&T to Lu is 1.0:1.0 to 12.0:1.0, 3.0:1.0 to 12.0:1.0, or 5.0:1.0 to 12.0:1.0. 177The molar ratio of PSMA I&T to Lu is 1.0:1.0 to 8.0:1.0, 1.5:1.0 to 8.0:1.0, 2.0:1.0 to 8.0:1.0, 2.5:1.0 to 8.0:1.0, 3.0:1.0 to 8.0:1.0, 3.5:1.0 to 8.0:1.0, or 4.0:1.0 to 8.0:1.0. 177 The molar ratio of PSMA I&T to Lu is 4.1:1.0 to 7.9:1.0, 4.2:1.0 to 7.8:1.0, 4.3:1.0 to 7.7:1.0, 4.4:1.0 to 7.6:1.0, 4.5:1.0 to 7.5:1.0, 4.6:1.0 to 7.4:1.0, 4.7:1.0 to 7.3:1.0, 4.8:1.0 to 7.2:1.0, 4.9:1.0 to 7.1:1.0, or 5.0:1.0 to 7.0:1.0. 177 The molar ratio of PSMA I&T to Lu is 5.0:1.0 to 7.6:1.0, 5.1:1.0 to 7.5:1.0, 5.2:1.0 to 7.4:1.0, 5.3:1.0 to 7.3:1.0, or 5.4:1.0 to 7.2:1.0. 177 The molar ratios to Lu were 8.0:1.0 to 10.0:1.0, 8.1:1.0 to 10.0:1.0, 8.2:1.0 to 10.0:1.0, 8.3:1.0 to 10.0:1.0, 8.4:1.0 to 10.0:1.0, 8.5:1.0 to 10.0:1.0, 8.6:1.0 to 10.0:1.0, 8.7:1.0 to 10.0:1.0, 8.8:1.0 to 10.0:1.0, and 8.9:1.0 to 10.0:1.0. 9.0:1.0 to 10.0:1.0, 9.1:1.0 to 10.0:1.0, 9.2:1.0 to 10.0:1.0, 9.3:1.0 to 10.0:1.0, 9.4:1.0 to 10.0:1.0, 9.5:1.0 to 10.0:1.0, 9.6:1.0 to 10.0:1.0, 9.7:1.0 to 10.0:1.0, 9.8:1.0 to 10.0:1.0, or 9.9:1.0 to 10.0:1.0. 177The molar ratios to Lu were 8.0:1.0 to 11.0:1.0, 8.1:1.0 to 11.0:1.0, 8.2:1.0 to 11.0:1.0, 8.3:1.0 to 11.0:1.0, 8.4:1.0 to 11.0:1.0, 8.5:1.0 to 11.0:1.0, 8.6:1.0 to 11.0:1.0, 8.7: 1.0~11.0:1.0, 8.8:1.0~11.0:1.0, 8.9:1.0~11.0:1.0, 9.0:1.0~11.0:1.0, 9.1:1.0~11.0:1.0, 9.2:1.0~11.0:1.0, 9.3:1.0~11.0:1.0, 9.4:1.0~11.0:1.0, 9. 5:1.0~11.0:1.0, 9.6:1.0~11.0:1.0, 9.7:1.0~11.0:1.0, 9.8:1.0~11.0:1.0, 9.9:1.0~11.0:1.0, 10.0:1.0~11.0:1.0, 10.1:1.0~11.0:1.0, 10.2:1.0~11.0:1 10.0, 10.3:1.0 to 11.0:1.0, 10.4:1.0 to 11.0:1.0, 10.5:1.0 to 11.0:1.0, 10.6:1.0 to 11.0:1.0, 10.7:1.0 to 11.0:1.0, 10.8:1.0 to 11.0:1.0, or 10.9:1.0 to 11.0:1.0. 177 The molar ratios to Lu were 3.0:1.0–12.0:1.0, 3.5:1.0–12.0:1.0, 4.0:1.0–12.0:1.0, 4.4:1.0–12.0:1.0, 4.4:1.0–11.5:1.0, 4.4:1.0–11.0:1.0, 4.4:1.0–10.5:1.0, 4.4:1.0–10.0:1.0, 4.4:1.0–9.5:1.0, and 4.4:1.0–9. The ratio may be 0:1.0, 4.4:1.0 to 8.5:1.0, 4.4:1.0 to 8.0:1.0, 4.4:1.0 to 7.5:1.0, 4.4:1.0 to 7.0:1.0, 4.4:1.0 to 6.5:1.0, 4.4:1.0 to 6.0:1.0, 4.5:1.0 to 5.9:1.0, 4.6:1.0 to 4.7:1.0, 4.8:1.0 to 5.7:1.0, or 4.9:1.0 to 5.6:1.0. 177The molar ratios to Lu were 5.0:1.0 to 12.0:1.0, 5.0:1.0 to 11.5:1.0, 5.0:1.0 to 11.0:1.0, 5.0:1.0 to 10.5:1.0, 5.0:1.0 to 10.0:1.0, 5.0:1.0 to 9.5:1.0, 5.0:1.0 to 9.0:1.0, 5.0:1.0 to 8.5:1.0, 5.0:1.0 to 8.0: The ratio may be 5.0:1.0 to 7.5:1.0, 5.0:1.0 to 7.0:1.0, 5.0:1.0 to 6.5:1.0, 5.0:1.0 to 6.0:1.0, 5.1:1.0 to 5.9:1.0, 5.2:1.0 to 5.8:1.0, 5.3:1.0 to 5.7:1.0, 5.4:1.0 to 5.6:1.0, or 5.45:1.0 to 5.55:1.0. 177 The molar ratios to Lu were 8.0:1.0 to 12.0:1.0, 8.0:1.0 to 11.5:1.0, 8.0:1.0 to 11.0:1.0, 8.0:1.0 to 10.5:1.0, 8.0:1.0 to 10.4:1.0, 8.0:1.0 to 10.3:1.0, 8.0:1.0 to 10.2:1.0, 8.0:1.0 to 10.1:1.0, 8.0:1.0 to 10.0 ... The ratio may be 8.0:1.0 to 9.9:1.0, 8.0:1.0 to 9.8:1.0, 8.0:1.0 to 9.7:1.0, 8.0:1.0 to 9.6:1.0, 8.0:1.0 to 9.5:1.0, 8.0:1.0 to 9.4:1.0, 8.0:1.0 to 9.3:1.0, 8.0:1.0 to 9.2:1.0, 8.0:1.0 to 9.1:1.0, or 8.0:1.0 to 9.0:1.0. 177 The molar ratio to Lu can be 9.0:1.0 to 12.0:1.0, 9.0:1.0 to 11.5:1.0, 9.0:1.0 to 11.0:1.0, 9.0:1.0 to 10.5:1.0, 9.0:1.0 to 10.4:1.0, 9.0:1.0 to 10.3:1.0, 9.0:1.0 to 10.2:1.0, 9.0:1.0 to 10.1:1.0, 9.0:1.0 to 10.0:1.0, 9.0:1.0 to 9.9:1.0, 9.0:1.0 to 9.8:1.0, 9.0:1.0 to 9.7:1.0, 9.0:1.0 to 9.6:1.0, or 9.0:1.0 to 9.5:1.0.

[0305] PSMA I&T 177The molar ratio of Lu to Lu can be 11.0:1.0 to 12.0:1.0, 11.1:1.0 to 11.9:1.0, 11.2:1.0 to 11.8:1.0, 11.3:1.0 to 11.7:1.0, or 11.4:1.0 to 11.6:1.0. 177 The molar ratio of Lu to Lu can be 10.0:1.0 to 11.0:1.0, 10.1:1.0 to 10.9:1.0, 10.2:1.0 to 10.8:1.0, 10.3:1.0 to 10.7:1.0, or 10.4:1.0 to 10.6:1.0. 177 The molar ratio of Lu to Lu can be 9.0:1.0 to 10.0:1.0, 9.1:1.0 to 9.9:1.0, 9.2:1.0 to 9.8:1.0, 9.3:1.0 to 9.7:1.0, or 9.4:1.0 to 9.6:1.0. 177 The molar ratio of Lu to Lu can be 8.0:1.0 to 9.0:1.0, 8.1:1.0 to 8.9:1.0, 8.2:1.0 to 8.8:1.0, 8.3:1.0 to 8.7:1.0, or 8.4:1.0 to 8.6:1.0. 177 The molar ratio of Lu to Lu can be 7.0:1.0 to 8.0:1.0, 7.1:1.0 to 7.9:1.0, 7.2:1.0 to 7.8:1.0, 7.3:1.0 to 7.7:1.0, or 7.4:1.0 to 7.6:1.0. 177 The molar ratio of Lu to Lu can be 6.0:1.0 to 7.0:1.0, 6.1:1.0 to 6.9:1.0, 6.2:1.0 to 7.8:1.0, 7.3:1.0 to 7.7:1.0, or 7.4:1.0 to 6.6:1.0. 177 The molar ratio of Lu to Lu can be 5.0:1.0 to 6.0:1.0, 5.1:1.0 to 5.9:1.0, 5.2:1.0 to 5.8:1.0, 5.3:1.0 to 5.7:1.0, or 5.4:1.0 to 5.6:1.0. 177 The molar ratio to Lu can be 4.4:1.0 to 5:0:1.0, 4.5:1.0 to 5:0:1.0, 4.6:1.0 to 5:0:1.0, 4.7:1.0 to 5:0:1.0, 4.8:1. to 5:0:1.0, or 4.9:1. to 5:0:1.0.

[0306] PSMA I&T 177 The molar ratio to Lu is about 5.0:1.0 to about 5.5:1.0, about 5.5:1.0 to about 6.0:1.0, about 6.0:1.0 to about 6.5:1.0, about 6.5:1.0 to about 7.0:1.0, about 7.0:1.0 to about 7.5:1.0, about 7.5:1.0 to about 8.0:1.0, about 8.0:1.0 to about 8.5:1.0, about 8.5 ... The ratio may be from about 0.5:1.0 to about 9.0:1.0, from about 9.0:1.0 to about 9.5:1.0, from about 9.5:1.0 to about 10.0:1.0, from about 10.0:1.0 to about 10.5:1.0, from about 10.5:1.0 to about 11.0:1.0, from about 11.0:1.0 to about 11.5:1.0, or from about 11.5:1.0 to about 12.0:1.0.

[0307] In another embodiment, the compositions, kits, and methods described herein can have a ratio of PSMA I&T to [177Lu]Lu3+ at μg:mCi of 0.65 or less, 0.64 or less, 0.63 or less, 0.62 or less, 0.61 or less, or 0.60 or less. In another embodiment, the compositions, kits, and methods described herein can have a ratio of PSMA I&T to [177Lu]Lu3+ at μg:mCi of about 0.20 to about 0.64, about 0.20 to about 0.63, about 0.20 to about 0.62, about 0.20 to about 0.61, or about 0.20 to about 0.60 ... The ratio of I&T to [177Lu]Lu3+ is about 0.21 to about 0.59, about 0.22 to about 0.58, about 0.23 to about 0.57, about 0.24 to about 0.56, about 0.25 to about 0.55, about 0.26 to about 0.54, about 0.27 to about 0.53, about 0.28 to about 0.52, about 0.29 to about 0. 51, about 0.30 to about 0.50, about 0.31 to about 0.49, about 0.32 to about 0.48, about 0.33 to about 0.47, about 0.34 to about 0.46, about 0.35 to about 0.45, about 0.36 to about 0.44, about 0.37 to about 0.43, about 0.38 to about 0.42, or about 0.39 to about 0.41. In another embodiment, in the compositions, kits, and methods described herein, the ratio of PSMA I&T to [177Lu]Lu3+ in μg:mCi can be about 0.50 to about 0.64, about 0.50 to about 0.63, about 0.50 to about 0.62, about 0.50 to about 0.61, about 0.50 to about 0.60, about 0.50 to about 0.59, about 0.50 to about 0.58, about 0.50 to about 0.57, about 0.50 to about 0.56, about 0.50 to about 0.55, about 0.50 to about 0.54, about 0.50 to about 0.53, about 0.50 to about 0.52, or about 0.50 to about 0.51.In another embodiment, in the compositions, kits, and methods described herein, the ratio of PSMA I&T to [177Lu]Lu3+ in μg:mCi is about 0.40 to about 0.64, about 0.40 to about 0.63, about 0.40 to about 0.62, about 0.40 to about 0.61, about 0.40 to about 0.60, about 0.40 to about 0.59, about 0.40 to about 0.58, about 0.40 to about 0.57, about 0.40 to about 0.56, about 0.40 to about 0.55, about 0.40 to about 0.54, about 0. In another embodiment, the compositions, kits, and methods described herein may be used to administer PSMA in μg:mCi. The ratio of I&T to [177Lu]Lu3+ is about 0.35 to about 0.64, about 0.35 to about 0.63, about 0.35 to about 0.62, about 0.35 to about 0.61, about 0.35 to about 0.60, about 0.35 to about 0.59, about 0.35 to about 0.58, about 0.35 to about 0.57, about 0.35 to about 0.56, about 0.35 to about 0.55, about 0.35 to about 0.54, about 0.35 to about 0.53, about 0.35 to about 0.52, about 0.35 to about 0.5 1, about 0.35 to about 0.50, about 0.35 to about 0.49, about 0.35 to about 0.48, about 0.35 to about 0.47, about 0.35 to about 0.46, about 0.35 to about 0.45, about 0.35 to about 0.44, about 0.35 to about 0.43, about 0.35 to about 0.42, about 0.35 to about 0.41, about 0.35 to about 0.40, about 0.35 to about 0.39, about 0.35 to about 0.38, about 0.35 to about 0.37, or about 0.35 to about 0.36.In another embodiment, in the compositions, kits, and methods described herein, the ratio of PSMA I&T to [177Lu]Lu3+ in μg:mCi is about 0.30 to about 0.64, about 0.30 to about 0.63, about 0.30 to about 0.62, about 0.30 to about 0.61, about 0.30 to about 0.60, about 0.30 to about 0.59, about 0.30 to about 0.58, about 0.30 to about 0.57, about 0.30 to about 0.56, about 0.30 to about 0.55, about 0.30 to about 0.54, about 0.30 to about 0.53, about 0.30 to about 0.52, about 0.30 to about 0.51, about 0.30 to about 0.50, about 0.30 to about 0.49, about 0.30 to about 0.5 It can be 0 to about 0.48, about 0.30 to about 0.47, about 0.30 to about 0.46, about 0.30 to about 0.45, about 0.30 to about 0.44, about 0.30 to about 0.43, about 0.30 to about 0.42, about 0.30 to about 0.41, about 0.30 to about 0.40, about 0.30 to about 0.39, about 0.30 to about 0.38, about 0.30 to about 0.37, about 0.30 to about 0.36, about 0.30 to about 0.35, about 0.30 to about 0.34, about 0.30 to about 0.33, about 0.30 to about 0.32, or about 0.30 to about 0.31.In another embodiment, the compositions, kits, and methods described herein comprise administering to a subject a therapeutically effective amount of PSMA in μg:mCi. The ratio of I&T to [177Lu]Lu3+ is about 0.25 to about 0.64, about 0.25 to about 0.63, about 0.25 to about 0.62, about 0.25 to about 0.61, about 0.25 to about 0.60, about 0.25 to about 0.59, about 0.25 to about 0.58, about 0.25 to about 0.57, about 0.25 to about 0.56, about 0.25 to about 0.55, about 0.25 to about 0.54, about 0.25 to about 0.53, about 0.25 to about 0.52, about 0.25 to about 0.51, about 0.25 to about 0.50, about 0.25 to about 0.49, about 0.25 to about 0.48, about 0.25 to about 0.47, about 0.25 to about 0.46 , about 0.25 to about 0.45, about 0.25 to about 0.44, about 0.25 to about 0.43, about 0.25 to about 0.42, about 0.25 to about 0.41, about 0.25 to about 0.40, about 0.25 to about 0.39, about 0.25 to about 0.38, about 0.25 to about 0.37, about 0.25 to about 0.36, about 0.25 to about 0.35, about 0.25 to about 0.34, about 0.25 to about 0.33, about 0.25 to about 0.32, about 0.25 to about 0.31, about 0.25 to about 0.30, about 0.25 to about 0.29, about 0.25 to about 0.28, about 0.25 to about 0.27, or about 0.25 to about 0.26. In another embodiment, in the compositions, kits, and methods described herein, the ratio of PSMA I&T to [177Lu]Lu3+ in μg:mCi can be about 0.20 to about 0.30.

[0308] In certain embodiments, provided herein are methods of treating cancer in a patient in need thereof. In another embodiment, the method comprises: 177 In another embodiment, the method further comprises administering to a human patient a composition comprising Lu-PSMA I&T. 177 The molar ratio of Lu to Lu is 5.0:1.0 to 12.0:1.0, for example, about 4.0:1 to about 8.0:1, about 4.5:1 to about 5.5:1, or about 5.0:1 to about 6.0:1. In another embodiment, the patient is treatment-naive. In another embodiment, the patient is not treatment-naive.

[0309] In one embodiment, the pharmaceutical composition is administered to a cancer patient as a first-line therapy. In another embodiment, the pharmaceutical composition is administered to a patient as a regimen. In another embodiment, the administered pharmaceutical composition has a radiochemical purity of greater than 95% at the time of administration.

[0310] In one embodiment, the method of treating cancer extends the time to disease progression of the cancer in the patient. In another embodiment, the method of treating cancer extends the survival of the patient. In another embodiment, the method of treating cancer increases the progression-free survival of the patient. In another embodiment, the cancer is metastatic castration-resistant prostate cancer (mCRPC).

[0311] In some embodiments, patients also have histologically or pathologically confirmed prostate adenocarcinoma without a predominant small cell component and progressive disease according to one or more of the following criteria: a) progression of serum / plasma PSA, defined as two consecutive increases in PSA relative to a previous reference value, measured at least one week apart with a minimum starting value of >2 ng / mL; or b) measurable disease progression (RECIST 1.1) or the presence of at least two new bone lesions (PCWG3 criteria), and / or have received previous treatment with next-generation androgen receptor (AR)-directed therapy (e.g., abiraterone, enzalutamide, apalutamide, darolutamide). In additional embodiments, patients may have effective castration with serum testosterone levels below 50 ng / dL and may plan to continue chronic medical or surgical castration. Patients with mCRPC should receive hormonal therapy and chemotherapy, as well as bone-targeted therapy, if indicated.

[0312] In at least one example, 177 Patients requiring RLT using Lu-PSMA I&T may meet the following criteria:

[0313] 1) mCRPC with PSMA-positive metastatic disease based on PSMA-PET or SPECT imaging. There are no restrictions on the number or location of metastases, i.e., bone or soft tissue metastases. For example, attention should be paid to patients with diffuse bone marrow, perineural, and brain metastases.

[0314] 2) After initial hormone therapy (LH-RH agonist / antagonist), patients with progressive disease (i.e., biochemical and / or radiological progression) despite newly developed hormone therapies (abiraterone / enzalutamide) or these medications can be avoided by patients with progressive disease despite chemotherapy (docetaxel and cabazitaxel), or patients who are unsuitable for or avoid chemotherapy.

[0315] 3) due to extraosseous or diffuse bone marrow metastases or avoided by the patient; 153 Sm-EDTMP or [ 223 Ra]RaCl or other locally available radiopharmaceuticals for bone-targeted therapy. Such therapy may provide pain relief or exacerbation in patients who do not adequately respond to bone-targeted therapy. 177 RLT using Lu-PSMA I&T can be evaluated.

[0316] 4) Life expectancy greater than 4-6 months.

[0317] 5) Salvage therapy decisions made by the institution's interdisciplinary tumor board.

[0318] In summary, patients with mCRPC should receive hormonal therapy and chemotherapy, as well as bone-targeted therapy, when indicated. Contraindications to any of these therapies should be discussed and documented in a multidisciplinary tumor board setting.

[0319] Contraindications are: (1) WBC ≤ 1 × 10 9 / l. (2) Hb≦80 g / L. (If symptomatic anemia occurs, red blood cell transfusion should be administered before treatment.) 177 RLT with Lu-PSMA I&T may have a positive effect on bone marrow depression, reducing the need for transfused blood due to tumor regression in the bone marrow. It should be noted that pure anemia without thrombocytopenia and leukopenia is not a contraindication to RLT. (3) Platelets ≤ 70 × 10 9 / l. (4) Renal failure with creatinine >1.5UNL and creatinine clearance <30mL / min (5) Absolute obstruction in renal excretion. (6) Previous chemotherapy or bone-targeted radionuclide therapy and extended external beam radiation to bone marrow (pelvis, spine) if administered within 4 weeks prior to RLT (7) ECOG performance status >2. (8) Hypersensitivity to any of the active substances or excipients.

[0320] After a patient in need thereof has been identified, the activity of the radiopharmaceutical composition may be confirmed prior to administration. 177 The radioactivity of the Lu-PSMA I&T composition can be 6.5-7.5 GBq, or can be in the range of 6.0-8.0 GBq. The radioactivity can be reduced to 4.0-5.0 GBq in cases of renal dysfunction (e.g., creatinine within 1.0-1.5 UNL).

[0321] The radiopharmaceutical composition solution may be infused intravenously as a slow bolus (over approximately 10-15 minutes), followed by 500-1000 ml of Ringer's solution or NaCl solution. Patients may be encouraged to urinate as frequently as possible and to drink approximately 2 liters of water per day. Patients with extensive non-obstructive renal disease may be given diuretics.

[0322] The pharmaceutical composition may be administered as a cycle of 2 to 11 RLTs every 5 to 8 weeks. If PSA continues to increase or if the patient's performance status worsens after the first two cycles, the indication for further RLT may be reevaluated. If PSA falls below 1.0 μg / L during a therapy cycle, or if post-injection SPECT studies are not sufficiently informative, PSMA imaging may be performed to assess the presence of small PSMA-positive metastases after completion of RLT. In the event of a significant decrease in platelets or white blood cells, the time interval between two cycles may be extended.

[0323] At least one whole-body scan (preferably by SPECT / CT) may be performed 24-48 hours after injection. Patients with diffuse bone and bone marrow metastases, as well as patients with brain metastases, may be administered concomitant corticosteroid therapy (e.g., prednisolone 20 mg / day) for the first two weeks after administration of the radiopharmaceutical composition.

[0324] In some embodiments, after administration of the radiopharmaceutical composition, patients may have improved radiographic progression-free survival (rPFS). Patients administered the radiopharmaceutical composition may have an rPFS of about 6 to about 12 months after initiation of administration of the radiopharmaceutical composition. In various embodiments, patients administered the radiopharmaceutical composition may have an rPFS of at least 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months after initiation of administration of the radiopharmaceutical composition. For example, 177 Treatment of patients with Lu-PSMA I&T may increase rPFS from 6 months with standard therapy to up to 10 months with the radiopharmaceutical composition. Radiographic progression-free survival may be defined as the time from randomization to radiographic progression (using PCWG3 and RECIST 1.1 criteria as assessed by blinded independent central review [BICR]) or death from any cause.

[0325] In certain embodiments, patients may experience improved overall survival (OS) after initiating administration of the radiopharmaceutical composition. Patients administered the radiopharmaceutical composition may have an overall survival of about 18 to about 26 months after initiating administration of the radiopharmaceutical composition. In various embodiments, patients administered the radiopharmaceutical composition may have an OS of at least 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, or 26 months after initiating administration of the radiopharmaceutical composition. For example, 177 Treating patients with Lu-PSMA I&T can increase OS from 18 months with standard therapy to up to 25 months with the radiopharmaceutical composition.

[0326] In another embodiment, the patient may experience an improvement in second radiographic progression-free survival (rPFS 2) after starting administration of the radiopharmaceutical composition.

[0327] In some embodiments, the patient may have an improved progression-free survival after initiating administration of the radiopharmaceutical composition. In additional embodiments, the patient may have an improved second progression-free survival after initiating administration of the radiopharmaceutical composition. The second progression-free survival may be a second occurrence of PCWG3 progression, clinical / symptomatic progression and / or pain progression, or death from any cause.

[0328] In one embodiment, the patient has an improved PSA after starting administration of the radiopharmaceutical composition. 50 May have a response rate. PSA 50 The response rate can be the rate of patients achieving a 50% or greater decrease in PSA from the baseline PSA assessment.

[0329] In certain embodiments, patients may have an improved time to first symptomatic skeletal event (SSE) after starting administration of the radiopharmaceutical composition. An SSE may be the occurrence of either bone-directed radiation therapy for the relief of bone pain, a new symptomatic pathological fracture, spinal cord compression, or tumor-related orthopedic surgery.

[0330] In certain embodiments, patients may have improved time to soft tissue progression (STP) after initiating administration of the radiopharmaceutical composition. STP may include the occurrence of radiographic progression in soft tissue. In another embodiment, patients may have improved time to chemotherapy (TTC) after initiating administration of the radiopharmaceutical composition.

[0331] In certain embodiments, patients may have improved results on a Quality of Life Questionnaire after starting administration of the radiopharmaceutical composition. For example, quality of life (QoL) may be assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30). The EORTC QLQ-C30 is a questionnaire of 30 quality of life (QoL) questions developed to assess the QoL of cancer patients. The EORTC QLQ-C30 contains 30 items, 24 of which are summarized into 9 multi-item scales with a scoring range of 0 to 100. [Example]

[0332] The following non-limiting examples are provided for illustrative purposes only and therefore should not be viewed in a limiting sense.

[0333] Example 1: 177 Methods for producing Lu-PSMA I&T radiopharmaceutical formulations Several radiopharmaceutical compositions were produced using the process outlined in Tables 2A and 2B below. The radiolabel was added as a non-carrier-added [ 177

[0013] LuLuCl3 was used. Compositions 1 and 2 are essentially the same. For Composition 3, the pH of the ascorbic acid solution was adjusted to 4.5, the amount of ascorbic acid was reduced, the amount of ethanol was reduced, and the pH of the final radiopharmaceutical composition was adjusted to 4.5. This resulted in Composition 3 having an extended shelf life compared to Compositions 1 and 2. ●177 The synthesis of Lu-PSMA I&T utilizes an automated synthesis module in a controlled environment. 177 Lu] lutetium chloride ([ 177 The labeling solution containing [Lu]LuCl3) is connected to a synthesis cassette containing the other chemical components required for the labeling process. 177 The LuCl solution may be transferred to a reaction vessel for radiolabeling and rinsed with the necessary additional amount of 0.04 M HCl solution. 177 The volume varies depending on the Lu activity. ●[ 177 The [Lu]LuCl solution is mixed with a solution of diluted PSMA I&T precursor in 0.4 M sodium acetate buffer in a reaction chamber. The solution is heated in the reactor. After heating, the generated 177 Lu-PSMA I&T is captured on a C18 cartridge preconditioned with water. The cartridge is rinsed with sterile water and the final product is eluted from the C18 cartridge into a bulk vial with 1.5 ml of 50% sterile ethanol. The drug substance is formed in situ and directly formulated into a drug product. For final volume adjustment, a formulation matrix containing 50 mg / ml ascorbic acid and ethanol in water for injection is added to the bulk vial. The composition of the final product is fixed and the amount of formulation matrix added is determined by the amount used in the batch. 177 Depends on the radioactivity of Lu. The formulation matrix is ​​prepared from a solution of ascorbic acid diluted to a concentration of 50 mg / ml with water for injection. The ethanol concentration is adjusted to 3.8% ± 1.0% (v / v) to match the concentration of the synthetic bulk product, regardless of dilution. • The synthesis is a one-step labeling process with C18 purification using injection grade ethanol and water as the only solvents, so there are no residual solvents. Radiochemical impurities are quantified by chromatographic methods (HPLC and TLC). Radiochemical purity as determined by HPLC must be 95.0% or greater. • Depending on the total radioactivity generated, the bulk product is diluted to a fixed radioactivity concentration of approximately 500MBq / ml. The solution is filtered through a 0.22 μm membrane filter into a sterile product vial. In addition to patient doses, sample vials are also dispensed from each production batch (chemical QC samples, microbiological QC samples, and reference samples for retention). The final product is dispensed in a Grade A controlled environment. Filter integrity is tested after filtration by performing a bubble point test before product release. Fill weight / volume and radioactivity are verified for dispensed patient vials. This solution can be used for pre-release quality control and after QP release. • Radioactivity is monitored by a dose calibrator after the labeling process to ensure successful labeling and verify the dispensed dose during dispensing. [Table 2A] • Compositions 1-3 obtained from Processes 1-3 are provided below in Table 2B, which provides the composition for each composition for both the 1 ml volume and the 10 ml or 20 ml vial. [Table 2B]

[0334] Example 2: Stability of Radiochemical Compositions ● 177 The stability of Lu-PSMA I&T Composition 1 was tested and the radiochemical purity and chemical properties were shown to provide sufficient stability for 48 hours from the end of synthesis for samples stored at +5°C, +20°C, and +40°C (Table 3). Stability studies were performed with ascorbic acid 31 mg / ml and ethanol 3.8% (v / v) at pH 4.5. 177 [Lu]Lu-PSMA I&T Composition 3 (Tables 4A-H) 177 [Lu]Lu-PSMA I&T Composition 1 showed improved stability and extended shelf life compared to I&T Composition 1. ●Preparation composition 3 [ 177The radiochemical purity and chemical properties (pH, impurities, visual properties) of [Lu]Lu-PSMA I&T were tested in seven batches over a time span of 70-72 hours from the end of synthesis. Stability samples of typical therapeutic dose activity and volume were stored at different conditions encompassing typical storage, shipping, and use of the product, including temperatures ranging from +5°C to +40°C. ●The final radioactivity concentration in the sample solution varied from 497MBq / ml to 642MBq / ml at the end of dispensing. All stability samples met the established acceptance criteria. In all analyzed samples, the radiochemical purity was 95.7% or higher 70 or 72 hours after the end of synthesis. Based on the results, the formulation composition 3 177 The Lu-PSMA I&T solution was stable under the different storage conditions tested. [Table 3] [Table 4A-1] [Table 4A-2] [Table 4B-1] [Table 4B-2] [Table 4D-1] [Table 4D-2] [Table 4E-1] [Table 4E-2] [Table 4F] [Table 4G-1] [Table 4G-2] [Table 4H-1] [Table 4H-2] [Table 4I-1] [Table 4I-2] [Table 4J] ●[ 177 The specifications for the [Lu]Lu-PSMA I&T solution are shown below in Table 5. The listed specifications were used as release parameters, with the exception of sterility testing, which was tested on all batches after release. [Table 5-1]

[0335] Example 3: In different formulation compositions 177 Radiochemical purity of Lu-PSMA I&T This example demonstrates the effectiveness of the hydroxybenzoates in formulations at different pH values. 177 1 shows the radiochemical stability of Lu-PSMA I&T. 177 The shelf life of Lu-PSMA I&T is limited by its high radioactive degradation rate during preparation and storage. 177 This leads to the degradation of Lu-PSMA I&T and the formation of radiochemical impurities. 177 The radiochemical purity of the Lu-PSMA I&T solution will fall below the acceptable limit of 95.0%. ● 177Formation of a specific radiochemical impurity of Lu-PSMA I&T has been observed with a retention time of approximately 5.2 minutes by HPLC on a Phenomenex Luna C18 column (3 μm, 150 mm × 4.6 mm) using an isocratic method of 0.1% trifluoroacetic acid in water (mobile phase A) and 0.1% trifluoroacetic acid:acetonitrile (10:90% v / v) in water (mobile phase B) and 23% mobile phase B at a temperature of 40° C. The impurity referred to herein as having a retention time of approximately 5.2 minutes is illustrated in the chromatograms of Figures 6A-11B. In previous experiments, lowering the radioactivity concentration of the formulation was sufficient to reduce the formation of an impurity that elutes at approximately 5.2 minutes. 177 The radiochemical stability of the [Lu]Lu-PSMA I&T solution was maintained above 95.0% over 72 hours. In this example, different formulation compositions with various ascorbic acid concentrations, pH, and radioactivity concentrations were used. 177 Six experiments were performed in which [Lu]Lu-PSMA I&T was prepared. Product formulation details are listed in Table 6. [Table 6-1] High radioactivity concentrations (high RAC) in the sample solutions were 1278 MBq / ml, 1281 MBq / ml, and 1311 MBq / ml when measured at the end of the synthesis. Low radioactivity concentrations (low RAC) in the sample solutions were 579 MBq / ml, 589 MBq / ml, and 626 MBq / ml when measured at the end of the synthesis. Radiochemical purity of each solution was followed by HPLC up to 71-93 hours after radiolabeling. All solutions were stored at 22.5°C. Figure 5 shows the results of the radiochemical purity analysis at different time points as measured by HPLC. Figures 6A and 6B show the HPLC radiochromatograms of Experiment 1 at 0 and 71 hours after EOS, respectively. Figures 7A and 7B show the HPLC radiochromatograms of Experiment 2 at 0 and 71 hours after EOS, respectively. Figures 8A and 8B show the HPLC radiochromatograms of Experiment 3 at 0 and 90 hours after EOS, respectively. Figures 9A and 9B show the HPLC radiochromatograms of Experiment 4 at 0 and 92 hours after EOS, respectively. Figures 10A and 10B show the HPLC radiochromatograms of Experiment 5 at 0 and 71 hours after EOS, respectively. Figures 11A and 11B show the HPLC radiochromatograms of Experiment 6 at 0 and 93 hours after EOS, respectively. The radiochemical stability results for each experiment at different time points are provided in Tables 5-10. [Table 5-2] [Table 6-2] [Table 7] [Table 8] [Table 9] [Table 10] In the examples, the pH of the formulation composition is as illustrated in Figures 6A to 11B. 177 This had a significant impact on the radiochemical stability of Lu-PSMA I&T, more specifically on the formation of a radiochemical impurity that eluted at approximately 5.2 min. In high RAC solutions, the decrease in radiochemical purity over time at pH 4.5 was two times slower than at pH 7. Further reduction of the formulation pH to 3.5 did not show a measurable improvement in radiochemical stability compared to the pH 4.5 solution. Although the pH 4.5 ascorbic acid solution is close to the pKa value of ascorbic acid, 177It is possible that the protons already possess a sufficient amount to act as an inhibitor to the radiolysis of the Lu-PSMA I&T and reduce the formation of a radiochemical impurity that elutes at approximately 5.2 minutes. • By incorporating a pH 4.5 solution into a lower RAC formulation, 177 Further improved the radiochemical stability of Lu-PSMA I&T. In lower RAC formulations, changing the formulation pH from 5 to 4.5 had a similar effect on radiochemical stability as increasing the ascorbic acid concentration from 21 mg / ml to 31 mg / ml. 10ml of high RAC containing 42.5mg / ml ascorbic acid as measured by HPLC 177 The radiochemical purity of the Lu-PSMA I&T formulation composition is at least about 99% at 0 hours post-EOS and at least about 93.3% at 46 hours post-EOS. As the pH of the formulation increases from pH 4.5, the radiochemical purity decreases. 20ml of low RAC containing 31mg / ml ascorbic acid as measured by HPLC 177 The radiochemical purity of the Lu-PSMA I&T formulation is at least about 99.1% at 0 hours after EOS. The rate at which radiochemical purity decreases over time is significantly greater at low RAC with a pH of 4.5 compared to a pH of 5. 177 slower for the Lu-PSMA-I&T formulation. The results show that formulation compositions having a pH of 5 or less can substantially reduce the formation of the radiochemical impurity eluting at about 5.2 minutes, and therefore, compared to formulation compositions having a pH greater than 5. 177 This indicates that the radiochemical stability of Lu-PSMA I&T can be improved. 177 The radiochemical stability of Lu-PSMA I&T can be further improved by incorporating a lower solution RAC. 177 The Lu-PSMA I&T solution showed the highest radiochemical stability in a low RAC solution at pH 4.5 and an ascorbic acid concentration of 31 mg / ml. This formulation minimized the formation of radiochemical impurities. 177This is believed to be a preferred composition for maintaining the radiochemical stability of Lu-PSMA I&T at greater than 95.0% for 72 hours or more.

[0336] Example 4 - Dosimetry Study Results This example presents the biodistribution, dosimetry, and pharmacokinetic (PK) results of a PK / dosimetry substudy conducted as part of a Phase III trial. 177 Patients were administered 7.4±10% GBq of target activity of Lu-PSMA-I&T and underwent single-photon emission computed tomography (SPECT) / computed tomography (CT) imaging at four time points (4 hours, 24 hours, 48 ​​hours, and 168 hours). Image data were analyzed to determine the significance and relevance of each organ of interest and the relevance and relevance of each organ of interest. 177 Time-activity curves (TACs) and subsequent time-integrated activity coefficients (TIACs) were calculated for organs exhibiting Lu-PSMA-I&T activity. Organ-level internal dose assessment (OLINDA 2.2.3) was used to calculate organ and whole-body absorbed radiation doses for each patient.

[0337] Additionally, whole blood samples were collected at six time points (pre-infusion, 1 hour, 4 hours, 24 hours, 48 ​​hours, and 168 hours) and processed to extract plasma for PK evaluation. All plasma samples were locally gamma-counted for pharmacokinetic analysis.

[0338] 177 Organs with moderate or higher absorbed doses of Lu-PSMA-I&T were organs involved in the clearance of the radioligand and / or expressing PSMA, namely, kidney (0.41±0.15 Gy / GBq), bladder (0.41±0.05 Gy / GBq), salivary and lacrimal glands (0.19±0.16 and 0.40±0.36 Gy / GBq, respectively), and parts of the gastrointestinal (GI) tract (left colon, 0.47±0.31 Gy / GBq and rectum, 0.44±0.30 Gy / GBq).

[0339] The mean red bone marrow absorbed radiation dose was 0.08 ± 0.12 Gy / GBq. The relatively high variability in bone marrow absorbed dose was due to some patients with diffuse intraosseous metastatic disease, resulting in increased bone uptake and therefore a higher estimated bone marrow absorbed dose. Furthermore, in a small number of patients, the presence of metastases in the lumbar vertebrae L2-L4, the region used for bone marrow dosimetry imaging, potentially led to an overestimation of bone marrow dose.

[0340] The systemic time-activity curve was fitted with a biexponential equation, and the distribution half-life was 2.16 ± 1.30 h and the elimination half-life was 46.29 ± 23.83 h.

[0341] PK evaluation, performed based on plasma radioactivity concentration data, showed that the mean distribution half-life was 1.89±0.34 hours and the mean elimination half-life was 14.7±10.1 hours.

[0342] A subset of patients (16 / 27) underwent imaging after both the first and third treatment cycles to assess organ dose after multiple treatment cycles. By comparing organ absorbed doses between cycles 1 and 3 for these 16 patients, it was observed that normal organ absorbed doses remained similar between the two cycles. This finding supports the validity of estimating cumulative organ-absorbed radiation doses by extrapolation from cycle 1 data.

[0343] Introduction This compares with hormone therapy in men with metastatic castration-resistant prostate cancer (mCRPC). 177 This is a phase 3, open-label, multicenter, randomized trial evaluating the safety and efficacy of Lu-PSMA-I&T radioligand therapy. 177 Lu-PSMA I&T is a radiotherapeutic agent that specifically targets prostate-specific membrane antigen (PSMA), which is expressed on both primary and metastatic prostate cancer cells.

[0344] The patient is first and third 177After Lu-PSMA I&T injection, PK sampling and SPECT / CT imaging were performed. 177 A substudy was conducted to evaluate the PK and radiological dosimetry of Lu-PSMA-I&T.

[0345] method Data Acquisition All participating centers underwent a rigorous center setup process in which all dose calibrators, scanners, and gamma counters used in the substudy were calibrated. Centers were permitted to enroll patients in the substudy only after completion and approval of all center setup processes by Invicro. Patients received 7.4±10% GBq of target dose in cycle 1. 177 After administration of Lu-PSMA-I&T, patients underwent SPECT / CT imaging, with anatomic coverage typically extending from the salivary glands to the pelvis. SPECT / CT imaging was performed at four time points: 4 hours, 24 hours, 48 ​​hours, and 168 hours after injection. In addition, a subset of patients imaged in Cycle 1 (16 of 27) were also imaged in Cycle 3 (Table 2). [Table 2]

[0346] Image acquisition and reconstruction protocols were standardized across all imaging time points and patients at each center, and each center consistently utilized the same SPECT / CT scanner throughout the study period to ensure uniformity.

[0347] Typically, raw prediction data were acquired in a 128 × 128 matrix with medium energy general-purpose (MEGP) collimation using step-and-shoot acquisition mode, with an acquisition zoom of 1.0, an energy window of 20% (±10%) centered at 208 keV, and 20 seconds per prediction, with 60 predictions per detector (180° rotation per detector).

[0348] A low-dose CT scan was performed before the SPECT scan for attenuation correction. Facilities were instructed to use their standard parameters for low-dose CT acquisition. Standard facility reconstruction parameters were used. Scatter correction was required using a 20% (±10%) scatter window centered at 170 keV.

[0349] PK plasma samples were collected pre-infusion, 1 hour, 4 hours, 24 hours, 48 ​​hours, and 168 hours and counted for radioactivity. Blood samples were first centrifuged to extract the plasma, and then the radioactivity in the plasma was counted in a gamma counter.

[0350] Please refer to the Technical Operations Manual (TOM) for a detailed overview of facility qualifications and setup, as well as data acquisition procedures.

[0351] Image analysis methods Imaging data were analyzed using Invicro's VivoQuant software, a validated software used in workflows compliant with 21 CFR § 11. The general quantification approach was based on the principles detailed in Medical Internal Radiation Dose (MIRD) Pamphlets No. 16, No. 23, and No. 26, as appropriate.

[0352] SPECT images were calibrated in units of becquerels (Bq) using calibration factors derived from known active sources and measured during the institutional setting with the same acquisition and reconstruction parameters used for patient imaging. Patient-specific calibration factors were also derived at each clinical time point after patient SPECT / CT acquisition. As a quality control measure, investigations were conducted if the patient-specific calibration factor differed from the institutional calibration factor by more than 10%.

[0353] Volumes of interest (VOIs) (kidneys, bladder, liver, lumbar vertebrae L2-L4, lacrimal glands, salivary glands [parotid and submandibular], and whole body) were contoured in each dataset by trained image analysts. The gastrointestinal tract and spleen were contoured only in the subset of patients in which these organs showed visible uptake. Organs were segmented either by drawing the entire organ outline or by placing a sphere over a representative region of the organ and then multiplying by the organ's effective mass (based on the patient's height and weight). The segmentation method for each organ is specified in Table 3 and was applied consistently to each patient. [Table 14]

[0354] Plasma quantitative analysis Whole blood samples were collected as detailed in the protocol event schedule, i.e., before injection, then 1 hour, 4 hours, 24 hours, 48 ​​hours, and 168 hours after injection. Samples were first centrifuged to separate the plasma, and then radioactivity in the plasma was measured using a gamma counter. Plasma concentrations were then fitted with a biexponential function to derive outcome parameters such as half-life and clearance rate of the radiopharmaceutical in plasma.

[0355] Normal organ dosimetry analysis Radiopharmaceutical clearance was derived from an appropriate fit to the TAC data for each organ. Depending on the shape of the TAC, the data were fitted by a single-, double-, or triple-exponential sum or using a rise-and-fall model. Fitting was performed using in-house Python software. TIAC was calculated by analytical integration of the curve fit extrapolated to infinity. If no appropriate fit was found, the area under the curve (AUC) was estimated using the sum of the trapezoidal integrals of the image measurements and physical attenuation from the last time point (the fraction of injected activity at t = 0 was set to zero for organs and 1 for the whole body). Whole-body TAC was derived from contouring the imaged body. Residual activity was determined by subtracting the cumulative organ TIAC from the whole-body TIAC.

[0356] Organ TIACs were entered into OLINDA 2.2.3 for calculation of organ and whole-body absorbed doses using International Commission on Radiological Protection (ICRP)-103 weighting factors. A male phantom from ICRP-89 was used for dose estimation. Organ and body masses, as defined by ICRP-89, were scaled based on height and mass using the patient effective mass. 4 A voiding bladder model implemented in OLINDA was used to determine bladder TIAC, assuming a 4-h voiding interval. The human gastrointestinal tract model (HAT model) described in ICRP100 and implemented in OLINDA was used to calculate doses to the patient's small intestine, right colon, left colon, and rectum, representing clearance through the gastrointestinal tract. The fraction of injected activity removed via the gastrointestinal tract (fIA) was determined by taking the peak fIA within the gastrointestinal tract across all imaging time points. Red bone marrow dose estimates were derived from segmenting the lumbar vertebrae L2-L4 as seen on CT. The red bone marrow mass at L2-L4 was assumed to be 6.7% of the total red bone marrow mass.

[0357] To assess potential changes in tracer kinetics and uptake after multiple treatment cycles, 16 of the 27 patients included in the dosimetry substudy were imaged in both cycle 1 and cycle 3. Of these, three patients were imaged at all four time points in cycle 3, while the other 13 were imaged at only one or two time points (24 h, 48 h, or both 24 and 48 h) (Table 2). For these 13 patients, the TAC obtained in cycle 1 was used for each source organ and scaled to the normalized activity value(s) measured in cycle 3. For patients imaged at two time points, the TAC was preferably scaled using the average scaling factor between the two time points. If the two time points yielded significantly different scaling factors, the more conservative time point was preferred, provided the derived dose estimates were valid.

[0358] Data Acquisition Quality Control The quantitative accuracy of each SPECT image is based on the known activity 177 Lu reference standard was used for control. Prior to scanning the patient, the reference standard was prepared by injecting 100 μCi (taken from the patient dose vial) into a 100 mL saline bag. The saline bag's radioactivity was then imaged immediately after each imaging time point using the same acquisition and reconstruction parameters. The number of counts in the image attributable to reference standard activity was measured, and a calibration factor was obtained by dividing the number of counts by the known activity in the reference standard at the time of imaging. This calibration factor is expected to be the same (less than 10% difference compared to the value determined at the facility setting) for all images acquired with the same SPECT / CT system. For patients whose calibration factor differed by more than 10% compared to the facility setting, the source of this variation was determined and investigated to determine whether it reflected differences in the acquisition and / or reconstruction of patient data.

[0359] Gamma counting plasma samples were prepared by measuring 0.5 mL of the 100 mL saline solution in a bag. 177Quality control was performed using a Lu reference standard. For each patient, three duplicates were generated and measured immediately before all plasma samples were counted. Long-lived isotopes were also counted to ensure that the protocol was properly followed by each facility. As with the imaging standard, if the gamma counter efficiency factor differed by more than 10% compared to the facility setting, the source of this variation was determined and investigated to see if it reflected differences in data acquisition.

[0360] result All 27 patients enrolled in the substudy had SPECT / CT images for dosimetry purposes in Cycle 1. Sixteen of the 27 patients were additionally imaged in Cycle 3. The activity injected into each patient in Cycles 1 and 3 is shown in Table 15. [Table 15-1] [Table 15-2]

[0361] The dosimetry analysis included all acquired and / or evaluable scans. Patient 37-016 did not have a SPECT / CT scan at 168 hours, so the results were based on only three time points for this patient. For patient 12-004, the 48-hour scan showed unrealistically high values ​​(first 177 Although no additional activity was administered to patients after Lu-PSMA-I&T injection, the total body fraction of injected activity at 48 hours exceeded that at 4 and 24 hours. In addition, the quality of the 48-hour images was unusually poor for unknown reasons. Therefore, this time point was excluded from further analysis, and dosimetry was performed using SPECT images at 4, 24, and 168 hours.

[0362] Cycle 1 Biodistribution Based on imaging and dosimetry data, 177Physiological uptake of Lu-PSMA-I&T was observed primarily in the kidney, bladder, lacrimal gland, gastrointestinal tract, and salivary gland. 177 Lu-PSMA-I&T was primarily excreted via urine, as indicated by visible accumulation in the bladder. Intestinal uptake was observed in 25 patients, but no significant uptake was seen in two of the analyzed patients (80-004 and 25-005). Salivary glands were not seen within the SPECT / CT field of view in one patient (12-004), and lacrimal glands were outside the field of view in five patients (12-004, 25-009, 42-027, 80-018, 66-024). In patients imaged over time, 177 Lu-PSMA-I&T distribution is shown in Figure 14.

[0363] Individual time-activity curves for each source organ, expressed as fIA at different time points, are shown in Figures 17-25. NOTE: The time-activity curves in these figures have not been decay-corrected for the time of injection.

[0364] All patients showed similar systemic clearance, except for patient 42-030, who had visually slow clearance. This slow clearance was likely due to the patient's diffuse bone metastatic disease and was confirmed by exposure measurements performed by the facility 24 hours after the investigational drug (IP) injection. The ionization chamber (Ludlum 9DP) * ) was used for the measurements, which were performed 1 meter away from the patient. After each cycle, this patient had a dose rate approximately three times higher than that of two other patients from the same institution: ●Patient 42-027: 7uSv / h, 6uSv / h, 5uSv / h. ●Patient 42-028: 6uSv / h, 8uSv / h, 5uSv / h. ●Patient 42-030: 16uSv / h, 18uSv / h, 17uSv / h.

[0365] Given the significant bone involvement, this patient was deemed eligible for a superscan by the site's principal investigator (PI), an exclusion criterion. Consistent with this patient's high bone involvement, the estimated bone marrow uptake was also high, as shown in Figure 18. As a result, this patient's biodistribution and dose values ​​were removed from all summary data (means, standard deviations, and mean curves) in this report, even though dosimetry and PK analyses were performed.

[0366] The whole-body time-activity curves were fitted to a biexponential equation, and the two components were used for the distribution and elimination half-lives. The mean half-lives (excluding patient 42-030) were a distribution half-life of 2.16 ± 1.30 h and an elimination half-life of 46.29 ± 23.83 h.

[0367] Regarding TAC in various organs (kidney, liver, spleen, salivary gland, lacrimal gland, gastrointestinal tract), the profiles were rather similar between different patients, with some expected variability, which, not surprisingly, was more pronounced in the gastrointestinal tract.

[0368] Figure 15 reports the TAC of all source organs averaged across all analyzed patients (excluding patient 42-030, who underwent a superscan). As already observed from the individual profiles, the whole-body TAC showed an initial rapid clearance with a mean activity retention of 44% ± 13% (min = 24%, max = 78%) at 4 hours, followed by a second phase characterized by slower clearance.

[0369] The mean TAC in other organs shows similar behavior, especially during the elimination phase.

[0370] Cycle 1 Dosimetry Reflecting the biodistribution data, the absorbed radiation dose per gram of tissue was higher in organs involved in tracer clearance, i.e., the kidney (0.41 ± 0.15 Gy / GBq), urinary bladder (0.41 ± 0.05 Gy / GBq), and some parts of the gastrointestinal tract, i.e., the left colon (0.47 ± 0.31 Gy / GBq) and rectum (0.44 ± 0.30 Gy / GBq). The salivary and lacrimal glands also showed moderate absorbed radiation doses (0.19 ± 0.16 and 0.40 ± 0.36 Gy / GBq, respectively). Note that for patient 12-004, the salivary glands were not within the field of view of the scan, so salivary gland TIAC could not be calculated, and this patient was excluded from the salivary gland absorbed dose calculation criteria.

[0371] The mean bone marrow absorbed dose was 0.08 ± 0.12 Gy / GBq. The high variability in bone marrow dose was due to several patients with abnormally high doses to the bone marrow (42-027, 62-032, 80-018, 80-024, 37-013, and 37-016). In two of these six patients (42-027 and 62-032), the high bone marrow dose estimates were likely due to the presence of isolated metastases in the vertebrae segmented to obtain image-based bone marrow dosimetry (L2-L4). Due to the bone marrow dose estimation methodology, the presence of metastatic disease within the VOI leads to an overestimation of the radiation dose absorbed by the bone marrow. In the other four patients, images showed diffuse bone metastatic disease, resulting in a higher and more diffuse distribution of radioactivity in the bone tissue and consequently in higher bone marrow dose estimates. Excluding these six specific cases and the patient with the superscan, the remaining 20 patients would have had a mean red bone marrow absorbed dose of 0.02±0.02 Gy / GBq.

[0372] The mean doses to all target organs are reported in Table 16. [Table 16]

[0373] Calibration coefficients for individual patients were similar to those determined in the institutional setting (less than 10% difference), with the exception of two patients in cycle 1 from one institution.

[0374] These two patients (80-018 and 80-023) showed discrepancies in both the calibration and efficiency factors, with discrepancies of approximately +135% and -45%, respectively, from the reference values ​​determined in the facility setting (Table 6). Because the same discrepancies were found in the SPECT calibration factor and the gamma counter efficiency factor, we concluded that these discrepancies could be due to errors in the measurement of standard reference values. After quality control of acquisition and reconstruction parameters, we concluded that whole-body images of these two patients were correctly acquired and that the problem appeared to be limited to the measurement of the calibration factor. This conclusion was supported by the dosimetric results for these two patients, which were well within the range of other patients. [Table 17]

[0375] Cycle 1 PK Monitoring Plasma PK modeling results are reported in Tables 7A and 7B. Plasma data were fitted with a bi-exponential curve. As shown in Figure 16, plasma concentrations declined over time with a similar profile in all patients, with an initial, faster decline (mean distribution half-life was 1.89 ± 0.34 hours) followed by a slower, longer decline. The mean elimination half-life was 14.70 ± 10.10 hours. Patient 42-030 showed an outlier half-life value of 113.96 hours, consistent with the patient's total body and bone marrow TAC, in which radioactivity was taken up by multiple bone metastases.

[0376] The time of peak concentration always corresponds to the time of the first post-dose blood sample, which was taken 1 hour after injection. Presumably, peak values ​​occurred immediately after injection but were not captured by the sampling schedule applied in this study. Therefore, peak concentration values ​​reflect the values ​​measured at the first time point.

[0377] Notably, the time to peak for patient 80-007 is 127 minutes post-injection instead of 1 hour, due to the delayed acquisition of that patient's first post-dose sample.

[0378] It should be noted that the elimination phase of the plasma profile appears to be prolonged in most patients, although concentration levels at later time points are very low. Indeed, the clearance value (13.06±16.50 L / h) indicates a fairly rapid clearance of most of the injected dose from the body. As indicated by the moderate to high volume of distribution, a portion of the injected activity is trapped in target-expressing tissues and tumors. [Table 18] [Table 19]

[0379] Cycle 3 Biodistribution and Dosimetry Results A subgroup of 16 of the 27 patients underwent additional dosimetry evaluations in cycle 3. Of these, 3 patients had dosimetry based on images taken at four time points, and the remaining patients had dosimetry at only 1 or 2 imaging time points.

[0380] Similar to Cycle 1, the highest uptakes and organ-absorbed radiation doses in Cycle 3 were primarily seen in the kidneys, bladder, lacrimal gland, gastrointestinal tract, and salivary gland.

[0381] For the same subset of patients, organ-absorbed radiation doses were compared to the mean organ-absorbed radiation doses from Cycle 1, as shown in Tables 8A and 8B. Dosimetry estimates obtained in Cycle 3 align closely with the dose estimates from Cycle 1. At this time point, the kidneys had the highest dose (0.49±0.19 Gy / GBq), but for most organs, estimated absorbed dose values ​​were similar or lower compared to Cycle 1. The mean absorbed doses to the kidneys and bladder wall were slightly higher in Cycle 3 compared to Cycle 1, but this difference remains within the expected range of variation.

[0382] For the three patients whose cycle 3 dosimetry was calculated using four imaging time points, organ-absorbed radiation dose values ​​were also within the range of variation observed in cycle 1.

[0383] In conclusion, the dosimetry estimates performed in Cycle 3 support the approach to predicting cumulative absorbed dose based on extrapolation from Cycle 1 data in this patient population. [Table 20] [Table 21]

[0384] Cycle 3 PK Modeling In Cycle 3, blood samples were obtained for 15 of the 16 patients. Patient 12-004 was not included in the plasma PK analysis because blood was drawn only at 24 hours. Consistent with Cycle 1, the time courses of plasma concentrations were similar between patients. The ranges of PK parameters obtained in Cycle 3 were similar to those obtained from the Cycle 1 data (Tables 9A and 9B). [Table 22] [Table 23]

[0385] conclusion 177 Biodistribution, PK, and dosimetry analyses of patient populations injected with Lu-PSMA-I&T indicate that organs with moderate to high physiological uptake and absorbed doses are primarily those involved in the clearance of the radiopharmaceutical and / or those that express PSMA. These include the kidney (0.41±0.15 Gy / GBq), bladder (0.41±0.05 Gy / GBq), salivary and lacrimal glands (0.19±0.16 and 0.40±0.36 Gy / GBq, respectively), and several parts of the gastrointestinal tract (left colon, 0.47±0.31 Gy / GBq, and rectum, 0.44±0.30 Gy / GBq).

[0386] The mean red bone marrow absorbed radiation dose was 0.08 ± 0.12 Gy / GBq. The high variability observed for this parameter, calculated using image-based methods, is due to the presence of diffuse bone metastatic disease in some patients. 177 Increased bone uptake of Lu-PSMA-I&T results in a higher absorbed radiation dose in the bone marrow. In addition, in the few patients with metastases in the lumbar region (L2-L4) where imaging for bone marrow dosimetry is available, these cases may lead to an overestimation of the bone marrow absorbed dose.

[0387] PK results showed a consistent elimination profile of the radiopharmaceutical from plasma across patients. In particular, plasma kinetics showed a monotonically decreasing trend across all patients and fitted well with a double exponential model.

[0388] Overall, dosimetry data for the main organs of interest were derived from a variety of studies using different dosimetry methodologies. 177 Compared with published values ​​for Lu-PSMA-I&T, this was within the expected range.

[0389] Notably, cycle 3 data showed similar dosimetry and PK values ​​to those from cycle 1. This consistency suggests that values ​​obtained in cycle 1 can be reliably used to estimate cumulative absorbed dose in subsequent cycles.

[0390] All references cited herein are incorporated herein by reference. The foregoing is provided primarily for illustrative purposes. It will be readily apparent to those skilled in the art that additional agents may be included, and that the components, additives, proportions, formulation methods, methods of use, and other parameters described herein may be further modified or substituted in various ways without departing from the spirit and scope of the present invention.

[0391] Example 5: Efficacy of steroids compared to hormone therapy in men with metastatic castration-resistant prostate cancer (mCRPC) 177 To evaluate the safety and efficacy of Lu-PSMA-I&T radioligand therapy Eclipse compared with hormone therapy in men with metastatic castration-resistant prostate cancer (mCRPC) 177 This is a phase 3, open-label, multicenter, randomized trial evaluating the safety and efficacy of Lu-PSMA-I&T radioligand therapy. 177 Lu-PSMA I&T is a radiotherapeutic agent that specifically targets prostate-specific membrane antigen (PSMA), which is expressed on both primary and metastatic prostate cancer cells.

[0392] The patient is first and third 177 After Lu-PSMA I&T injection, PK sampling and SPECT / CT imaging were performed. 177 A substudy was conducted to evaluate the PK and radiological dosimetry of Lu-PSMA-I&T.

[0393] method Data Acquisition: All participating sites underwent a rigorous site setup process in which all dose calibrators, scanners, and gamma counters used in the substudy were calibrated. Sites were permitted to enroll patients in the substudy only after completion and approval of all site setup processes by Invicro.

[0394] Patients achieved 7.4±10% GBq of target in cycle 1. 177After administration of Lu-PSMA-I&T, patients underwent SPECT / CT imaging, with anatomical coverage typically extending from the salivary glands to the pelvis. SPECT / CT imaging was performed at four time points: 4 hours, 24 hours, 48 ​​hours, and 168 hours after injection. In addition, a subset of patients imaged in Cycle 1 (16 of 27) were also imaged in Cycle 3 (Table 7 in Appendix 1).

[0395] Image acquisition and reconstruction protocols were standardized across all imaging time points and patients at each center, and each center consistently utilized the same SPECT / CT scanner throughout the study period to ensure uniformity.

[0396] Typically, raw prediction data were acquired in a 128 × 128 matrix with medium energy general-purpose (MEGP) collimation using step-and-shoot acquisition mode, with an acquisition zoom of 1.0, an energy window of 20% (±10%) centered at 208 keV, and 20 seconds per prediction, with 60 predictions per detector (180° rotation per detector).

[0397] A low-dose CT scan was performed before the SPECT scan for attenuation correction. Facilities were instructed to use their standard parameters for low-dose CT acquisition. Standard facility reconstruction parameters were used. Scatter correction was required using a 20% (±10%) scatter window centered at 170 keV.

[0398] PK plasma samples were collected pre-infusion, 1 hour, 4 hours, 24 hours, 48 ​​hours, and 168 hours and counted for radioactivity. Blood samples were first centrifuged to extract the plasma, and then the radioactivity in the plasma was counted in a gamma counter.

[0399] For a detailed overview of facility qualifications and setup, as well as data acquisition procedures, please refer to the Technical Operations Manual (TOM) (Appendix 2).

[0400] Image analysis methods Image preprocessing and segmentation Imaging data were analyzed using Invicro's VivoQuant software, a validated software used in workflows compliant with 21 CFR § 11. The general quantification approach was based on the Medical Internal Radiation Dose (MIRD) Pamphlet No. 16, where appropriate. 1 , No. 23 2 and No. 26 3 It was based on the principles detailed in

[0401] SPECT images were calibrated in units of becquerels (Bq) using calibration factors derived from known active sources and measured during the institutional setting with the same acquisition and reconstruction parameters used for patient imaging. Patient-specific calibration factors were also derived at each clinical time point after patient SPECT / CT acquisition. As a quality control measure, investigations were conducted if the patient-specific calibration factor differed from the institutional calibration factor by more than 10%.

[0402] Volumes of interest (VOIs) (kidneys, bladder, liver, lumbar vertebrae L2-L4, lacrimal glands, salivary glands [parotid and submandibular], and whole body) were contoured in each dataset by trained image analysts. The gastrointestinal tract and spleen were contoured only in the subset of patients in which these organs showed visible uptake. Organs were segmented either by drawing the entire organ outline or by placing a sphere over a representative region of the organ and then multiplying by the organ's effective mass (based on the patient's height and weight). 4 The segmentation method for each organ is specified in Table 1 and was applied consistently for each patient.

[0403] FIG. 27 shows a maximum intensity projection (MIP) CT image with segmented regions for a representative patient. [Table 24]

[0404] Plasma quantitative analysis Whole blood samples were collected as detailed in the protocol event schedule, i.e., before injection, then 1 hour, 4 hours, 24 hours, 48 ​​hours, and 168 hours after injection. Samples were first centrifuged to separate the plasma, and then radioactivity in the plasma was measured using a gamma counter. Plasma concentrations were then fitted with a biexponential function to derive outcome parameters such as half-life and clearance rate of the radiopharmaceutical in plasma.

[0405] Normal organ dosimetry analysis Radiopharmaceutical clearance was derived from an appropriate fit to the TAC data for each organ. Depending on the shape of the TAC, the data were fitted by a single-, double-, or triple-exponential sum or using a rise-and-fall model. Fitting was performed using in-house Python software. TIAC was calculated by analytical integration of the curve fit extrapolated to infinity. If no appropriate fit was found, the area under the curve (AUC) was estimated using the sum of the trapezoidal integrals of the image measurements and physical attenuation from the last time point (the fraction of injected activity at t = 0 was set to zero for organs and 1 for the whole body). Whole-body TAC was derived from contouring the imaged body. Residual activity was determined by subtracting the cumulative organ TIAC from the whole-body TIAC.

[0406] Organ TIACs were entered into OLINDA 2.2.3 for calculation of organ and whole-body absorbed doses using International Commission on Radiological Protection (ICRP)-103 weighting factors. A male phantom from ICRP-89 was used for dose estimation. Organ and body masses, as defined by ICRP-89, were scaled based on height and mass using the patient effective mass. 4A voiding bladder model implemented in OLINDA was used to determine bladder TIAC, assuming a 4-h voiding interval. The human gastrointestinal tract model (HAT model) described in ICRP100 and implemented in OLINDA was used to calculate doses to the patient's small intestine, right colon, left colon, and rectum, representing clearance through the gastrointestinal tract. The fraction of injected activity removed via the gastrointestinal tract (fIA) was determined by taking the peak fIA within the gastrointestinal tract across all imaging time points. Red bone marrow dose estimates were derived from segmenting the lumbar vertebrae L2-L4 as seen on CT. The red bone marrow mass at L2-L4 was assumed to be 6.7% of the total red bone marrow mass. 5

[0407] Cycle 3 of single time point dose analysis To assess potential changes in tracer kinetics and uptake after multiple treatment cycles, 16 of the 27 patients included in the dosimetry substudy were imaged in both Cycle 1 and Cycle 3. Of these, 3 patients were imaged at all four time points in Cycle 3, while the other 13 were imaged at only one or two time points (24 h, 48 h, or both 24 and 48 h) (Table 7 in Appendix 1). For these 13 patients, the TAC obtained in Cycle 1 was used for each source organ and scaled to the normalized activity value(s) measured in Cycle 3. For patients imaged at two time points, the TAC was preferably scaled using the average scaling factor between the two time points. If the two time points yielded significantly different scaling factors, the more conservative time point was preferred, provided the derived dose estimates were valid.

[0408] Data Acquisition Quality Control The quantitative accuracy of each SPECT image is based on the known activity 177Lu reference standard was used for control. Prior to scanning the patient, the reference standard was prepared by injecting 100 μCi (taken from the patient dose vial) into a 100 mL saline bag. The saline bag's radioactivity was then imaged immediately after each imaging time point using the same acquisition and reconstruction parameters. The number of counts in the image attributable to reference standard activity was measured, and a calibration factor was obtained by dividing the number of counts by the known activity in the reference standard at the time of imaging. This calibration factor is expected to be the same (less than 10% difference compared to the value determined at the facility setting) for all images acquired with the same SPECT / CT system. For patients whose calibration factor differed by more than 10% compared to the facility setting, the source of this variation was determined and investigated to determine whether it reflected differences in the acquisition and / or reconstruction of patient data.

[0409] Gamma counting plasma samples were prepared by measuring 0.5 ml of the 100 ml in the saline bag. 177 Quality control was performed using a Lu reference standard. For each patient, three duplicates were generated and measured immediately before all plasma samples were counted. Long-lived isotopes were also counted to ensure that the protocol was properly followed by each facility. As with the imaging standard, if the gamma counter efficiency factor differed by more than 10% compared to the facility setting, the source of this variation was determined and investigated to see if it reflected differences in data acquisition.

[0410] result All 27 patients enrolled in the substudy had SPECT / CT images for dosimetry purposes in Cycle 1. Sixteen of the 27 patients were additionally imaged in Cycle 3, as described in Section 4.4.1. The active substance injected into each patient in Cycles 1 and 3 is shown in Table 25. [Table 25]

[0411] The dosimetry analysis included all acquired and / or evaluable scans. Patient 37-016 did not have a SPECT / CT scan at 168 hours, so the results were based on only three time points for this patient. For patient 12-004, the 48-hour scan showed unrealistically high values ​​(first 177 Although no additional activity was administered to patients after Lu-PSMA-I&T injection, the total body fraction of injected activity at 48 hours exceeded that at 4 and 24 hours. In addition, the quality of the 48-hour images was unusually poor for unknown reasons. Therefore, this time point was excluded from further analysis, and dosimetry was performed using SPECT images at 4, 24, and 168 hours.

[0412] Cycle 1 Biodistribution Based on imaging and dosimetry data, 177 Physiological uptake of Lu-PSMA-I&T was observed primarily in the kidney, bladder, lacrimal gland, gastrointestinal tract, and salivary gland. 177 Lu-PSMA-I&T was primarily excreted via urine, as indicated by visible accumulation in the bladder. Intestinal uptake was observed in 25 patients, but no significant uptake was seen in two of the analyzed patients (80-004 and 25-005). Salivary glands were not seen within the SPECT / CT field of view in one patient (12-004), and lacrimal glands were outside the field of view in five patients (12-004, 25-009, 42-027, 80-018, 66-024). In patients imaged over time, 177 Lu-PSMA-I&T distribution is shown in Figure 27.

[0413] Individual time-activity curves for each source organ, expressed as fIA at different time points, are shown in Figures 17-25. NOTE: The time-activity curves in these figures have not been decay-corrected for the time of injection.

[0414] All patients showed similar systemic clearance, except for patient 42-030, who had visually slow clearance. This slow clearance was likely due to the patient's diffuse bone metastatic disease and was confirmed by exposure measurements performed by the facility 24 hours after the investigational drug (IP) injection. The ionization chamber (Ludlum 9DP) * ) was used for the measurements, which were performed 1 meter away from the patient. After each cycle, this patient had a dose rate approximately three times higher than that of the other two patients from the same institution. Patient 42-027: 7uSv / h, 6uSv / h, 5uSv / h. Patient 42-028: 6uSv / h, 8uSv / h, 5uSv / h. Patient 42-030: 16uSv / h, 18uSv / h, 17uSv / h.

[0415] Given the significant bone involvement, this patient was deemed eligible for a superscan by the site's principal investigator (PI), an exclusion criterion. Consistent with this patient's high bone involvement, the estimated bone marrow uptake was also high, as shown in Figure 18. As a result, this patient's biodistribution and dose values ​​were removed from all summary data (means, standard deviations, and mean curves) in this report, even though dosimetry and PK analyses were performed.

[0416] The whole-body time-activity curves were fitted to a biexponential equation, and the two components were used for the distribution and elimination half-lives. The mean half-lives (excluding patient 42-030) were a distribution half-life of 2.16 ± 1.30 h and an elimination half-life of 46.29 ± 23.83 h.

[0417] Regarding TAC in various organs (kidney, liver, spleen, salivary gland, lacrimal gland, gastrointestinal tract), the profiles were rather similar between different patients, with some expected variability, which, not surprisingly, was more pronounced in the gastrointestinal tract.

[0418] Cycle 1 Dosimetry Reflecting the biodistribution data, the absorbed radiation dose per gram of tissue was higher in organs involved in tracer clearance, i.e., the kidney (0.41 ± 0.15 Gy / GBq), urinary bladder (0.41 ± 0.05 Gy / GBq), and some parts of the gastrointestinal tract, i.e., the left colon (0.47 ± 0.31 Gy / GBq) and rectum (0.44 ± 0.30 Gy / GBq). The salivary and lacrimal glands also showed moderate absorbed radiation doses (0.19 ± 0.16 and 0.40 ± 0.36 Gy / GBq, respectively). Note that for patient 12-004, the salivary glands were not within the field of view of the scan, so salivary gland TIAC could not be calculated, and this patient was excluded from the salivary gland absorbed dose calculation criteria.

[0419] The mean bone marrow absorbed dose was 0.08 ± 0.12 Gy / GBq. The high variability in bone marrow dose was due to several patients with abnormally high doses to the bone marrow (42-027, 62-032, 80-018, 80-024, 37-013, and 37-016). In two of these six patients (42-027 and 62-032), the high bone marrow dose estimates were likely due to the presence of isolated metastases in the vertebrae segmented to obtain image-based bone marrow dosimetry (L2-L4). Due to the bone marrow dose estimation methodology, the presence of metastatic disease within the VOI leads to an overestimation of the radiation dose absorbed by the bone marrow. In the other four patients, images showed diffuse bone metastatic disease, resulting in a higher and more diffuse distribution of radioactivity in the bone tissue and consequently in higher bone marrow dose estimates. Excluding these six specific cases and the patient with the superscan, the remaining 20 patients would have had a mean red bone marrow absorbed dose of 0.02±0.02 Gy / GBq.

[0420] The mean doses to all target organs are reported in Table 26, and the individual doses are reported in Appendix 1. [Table 26]

[0421] Data Quality Control Results Calibration coefficients for individual patients were similar to those determined in the institutional setting (less than 10% difference), with the exception of two patients in cycle 1 from one institution.

[0422] These two patients (80-018 and 80-023) showed discrepancies in both the calibration and efficiency factors, respectively, with differences of approximately +135% and -45% from the reference values ​​determined in the facility setting (Table 8 in Appendix 1). Because the same discrepancies were found in the SPECT calibration factor and the gamma counter efficiency factor, we concluded that these discrepancies could be due to errors in the measurement of standard reference values. After quality control of acquisition and reconstruction parameters, we concluded that whole-body images of these two patients were correctly acquired and that the problem appeared to be limited to the measurement of the calibration factor. This conclusion was supported by the dosimetric results for these two patients, which were well within the range of other patients.

[0423] Cycle 1 PK Modeling Plasma PK modeling results are reported in Table 4; see also Figures 12-13 and 14-25. Plasma data were fitted with a biexponential curve. Plasma concentrations declined over time with a similar profile in all patients, with an initial, faster decline (mean distribution half-life was 1.89 ± 0.34 hours), followed by a slower, longer decline. The mean elimination half-life was 14.70 ± 10.10 hours. Patient 42-030 showed an outlier half-life value of 113.96 hours, consistent with the patient's systemic and bone marrow TAC, in which radioactivity was taken up by multiple bone metastases.

[0424] The time of peak concentration always corresponds to the time of the first post-dose blood sample, which was taken 1 hour after injection. Presumably, a peak value occurred immediately after injection but was not captured by the sampling schedule applied in this study. Therefore, the peak concentration value reflects the value measured at the time of the first sample and not the true peak value in plasma. Notably, the time to peak for patient 80-007 was 127 minutes after injection, rather than 1 hour, due to the delayed acquisition of that patient's first post-dose sample.

[0425] It should be noted that the elimination phase of the plasma profile appears to be prolonged in most patients, although concentration levels at later time points are very low. Indeed, the clearance value (13.06±16.50 L / h) indicates a fairly rapid clearance of most of the injected dose from the body. As indicated by the moderate to high volume of distribution, a portion of the injected activity is trapped in target-expressing tissues and tumors. [Table 27]

[0426] Cycle 3 Biodistribution and Dosimetry Results A subgroup of 16 of the 27 patients underwent additional dosimetric evaluations in Cycle 3. Of these, 3 patients underwent dosimetry based on images taken at four time points, and the remaining patients underwent dosimetry at only 1 or 2 imaging time points, as described in Section 4.4.1.

[0427] Similar to Cycle 1, the highest uptake and organ-absorbed radiation doses in Cycle 3 were primarily found in the kidneys, bladder, lacrimal gland, gastrointestinal tract, and salivary gland (individual and aggregate values ​​for TIAC of target organs are in Appendix 1).

[0428] For the same subset of patients, organ-absorbed radiation doses were compared to the mean organ-absorbed radiation doses from Cycle 1, as shown in Table 5. The dosimetry estimates obtained in Cycle 3 align closely with the dose estimates from Cycle 1. See Figure 26. At this time point, the kidneys had the highest dose (0.49±0.19 Gy / GBq), but for most organs, the estimated absorbed dose values ​​were similar or lower compared to Cycle 1. The mean absorbed doses to the kidneys and bladder wall were slightly higher in Cycle 3 compared to Cycle 1, but this difference remains within the expected range of variation.

[0429] For the three patients whose cycle 3 dosimetry was calculated using four imaging time points, organ-absorbed radiation dose values ​​were also within the range of variation observed in cycle 1.

[0430] In conclusion, the dosimetry estimates performed in Cycle 3 support the approach to predicting cumulative absorbed dose based on extrapolation from Cycle 1 data in this patient population. [Table 28]

[0431] Cycle 3 PK Modeling In Cycle 3, blood samples were obtained for 15 of the 16 patients. Patient 12-004 was not included in the plasma PK analysis because blood was drawn only at 24 hours. Consistent with Cycle 1, the time courses of plasma concentrations were similar between patients. The ranges of PK parameters obtained in Cycle 3 were similar to those obtained from the Cycle 1 data (Table 29). See Table 29. Cycle 3 PK Plasma Modeling Results (n=15) [Table 29]

[0432] conclusion 177Biodistribution, PK, and dosimetry analyses of patient populations injected with Lu-PSMA-I&T indicate that organs with moderate to high physiological uptake and absorbed doses are primarily those involved in the clearance of the radiopharmaceutical and / or those that express PSMA. These include the kidney (0.41±0.15 Gy / GBq), bladder (0.41±0.05 Gy / GBq), salivary and lacrimal glands (0.19±0.16 and 0.40±0.36 Gy / GBq, respectively), and several parts of the gastrointestinal tract (left colon, 0.47±0.31 Gy / GBq, and rectum, 0.44±0.30 Gy / GBq).

[0433] The mean red bone marrow absorbed radiation dose was 0.08 ± 0.12 Gy / GBq. The high variability observed for this parameter, calculated using image-based methods, is due to the presence of diffuse bone metastatic disease in some patients. 177 Increased bone uptake of Lu-PSMA-I&T results in a higher absorbed radiation dose in the bone marrow. In addition, in the few patients with metastases in the lumbar region (L2-L4) where imaging for bone marrow dosimetry is available, these cases may lead to an overestimation of the bone marrow absorbed dose.

[0434] PK results showed a consistent elimination profile of the radiopharmaceutical from plasma across patients. In particular, plasma kinetics showed a monotonically decreasing trend across all patients and fitted well with a double exponential model.

[0435] Overall, dosimetry data for the main organs of interest were derived from a variety of studies using different dosimetry methodologies. 177 Compared with published values ​​for Lu-PSMA-I&T, this was within the expected range.

[0436] Notably, cycle 3 data showed similar dosimetry and PK values ​​to those from cycle 1. This consistency suggests that values ​​obtained in cycle 1 can be reliably used to estimate cumulative absorbed dose in subsequent cycles.

[0437] Example 6: Imaging Center Training and Setup Technical Operation Manual SPECTICT & Gamma Counter Data Always ensure that consistent scan parameters are used between time points. Unless otherwise approved by Invicro or the sponsor, the same scanner must be used for all assessments within and across all patients.

[0438] Acquire images according to study-specific process criteria within and in accordance with the protocol's schedule of activities. Image acquisition and documentation should not deviate from the clinical trial protocol; however, the TOM may provide expanded information and processes. ...

Claims

1. 1. A method comprising: １７７ and administering to a human patient in need thereof a radiopharmaceutical composition comprising the Lu-PSMA I&T, １７７ Lu has a molar ratio of 3.0:1.0 to 8.0:1.0, wherein the composition comprises a radiochemical purity of 95% or greater for at least 72 hours after manufacture, and the absorbed radiation dose per gram of tissue in the kidney of the human patient is from about 0.2 Gy / GBq to about 0.6 Gy / GBq, from about 0.25 Gy / GBq to about 0.55 Gy / GBq, from about 0.3 Gy / GBq to about 0.5 Gy / GBq, or from about 0.35 Gy / GBq to about 0.45 Gy / GBq.

2. 10. The method of claim 1, wherein the absorbed radiation dose per gram of tissue in the kidney of the human patient is from about 0.25 Gy / GBq to about 0.55 Gy / GBq.

3. 10. The method of claim 1, wherein the absorbed radiation dose per gram of tissue in the kidney of the human patient is from about 0.3 Gy / GBq to about 0.5 Gy / GBq.

4. 10. The method of claim 1, wherein the average absorbed radiation dose per gram of tissue in the kidney of the human patient is about 0.39±0.15 Gy / GBq.

5. 10. The method of claim 1, wherein the average absorbed radiation dose per gram of tissue in the kidney of the human patient is about 0.40±0.15 Gy / GBq.

6. 10. The method of claim 1, wherein the average absorbed radiation dose per gram of tissue in the kidney of the human patient is about 0.41±0.15 Gy / GBq.

7. 10. The method of claim 1, wherein the average absorbed radiation dose per gram of tissue in the kidney of the human patient is about 0.42±0.15 Gy / GBq.

8. 10. The method of claim 1, wherein the average absorbed radiation dose per gram of tissue in the kidney of the human patient is about 0.43±0.15 Gy / GBq.

9. 10. The method of claim 1, wherein the average absorbed radiation dose per gram of tissue in the kidney of the human patient is about 0.45±0.15 Gy / GBq.

10. 2. The method of claim 1, wherein the average absorbed radiation dose per gram of tissue in the kidney of the human patient is 0.39 Gy / GBq or less.

11. 10. The method of claim 1, wherein the average absorbed radiation dose per gram of tissue in the kidney of the human patient is 0.40 Gy / GBq or less.

12. 10. The method of claim 1, wherein the average absorbed radiation dose per gram of tissue in the kidney of the human patient is 0.41 Gy / GBq or less.

13. 2. The method of claim 1, wherein the average absorbed radiation dose per gram of tissue in the kidney of the human patient is 0.42 Gy / GBq or less.

14. 2. The method of claim 1, wherein the standard deviation of the mean absorbed radiation dose per gram of tissue in the kidney of the human patient is less than or equal to 0.19 Gy / GBq, less than or equal to 0.18 Gy / GBq, less than or equal to 0.17 Gy / GBq, less than or equal to 0.16 Gy / GBq, or less than or equal to 0.15 Gy / GBq.

15. The composition comprises a PSMA I&T ratio of about 4.0:1.0 to about 8.0:1.0, about 4.4:1.0 to about 7.6:1.0, about 4.5:1.0 to about 5.5:1.0, or about 5.0:1.0 to about 6.0:1.

0. １７７ 2. The method of claim 1 , wherein the molar ratio of Lu to Lu is 0.

1.

16. The composition comprises a PSMA I&T ratio of about 3.0:1, about 3.5:1, about 4.0:1.0, about 4.5:1.0, about 5.0:1.0, about 5.5:1.0, about 6.0:1.0, about 6.5:1.0, about 7.0:1.0, about 7.5:1.0, or about 8.0:1.

0. １７７ 2. The method of claim 1 , wherein the molar ratio of Lu to Lu is 0.

1.

17. The composition comprises a PSMA I&T ratio of about 5.1:1.0 to about 5.9:1.0, about 5.2:1.0 to about 5.8:1.0, about 5.3:1.0 to about 5.7:1.0, or about 5.4:1.0 to about 5.6:1.

0. １７７ 2. The method of claim 1 , wherein the molar ratio of Lu to Lu is 0.

1.

18. The composition comprises a PSMA I&T ratio of 4.4:1.0 to 7.6:1.

0. １７７ 2. The method of claim 1 , wherein the molar ratio of Lu to Lu is 0.

1.

19. The composition comprises from about 7.1 GBq to about 7.6 GBq １７７ The method of claim 1, comprising Lu-PSMA I&T.

20. The composition contains 7.4±15% GBq １７７ The method of claim 1, comprising Lu-PSMA I&T.

21. The composition contains 7.4±10% GBq １７７ The method of claim 1, comprising Lu-PSMA I&T.

22. The composition contains 7.4±5% GBq １７７ The method of claim 1, comprising Lu-PSMA I&T.

23. The composition contains about 7.4 GBq １７７ The method of claim 1, comprising Lu-PSMA I&T.

24. The method of claim 1 , wherein the absorbed radiation dose is measured by SPECT imaging, two-dimensional imaging, or a combination thereof.

25. 1. A method comprising: １７７ and administering to a human patient in need thereof a radiopharmaceutical composition comprising the Lu-PSMA I&T, １７７ and wherein the molar ratio of Lu to Lu is 3.0:1.0 to 8.0:1.0, and the composition comprises a radiochemical purity of 95% or greater for at least 72 hours after manufacture, and the absorbed radiation dose per gram of tissue in the kidney of the human patient is 0.60 Gy / GBq or less, 0.55 Gy / GBq or less, 0.50 Gy / GBq or less, 0.45 Gy / GBq or less, 0.40 Gy / GBq or less, 0.35 Gy / GBq or less, 0.30 Gy / GBq or less, 0.25 Gy / GBq or less, 0.20 Gy / GBq or less, or 0.15 Gy / GBq or less.

26. 1. A method comprising: １７７ and administering to a human patient in need thereof a radiopharmaceutical composition comprising the Lu-PSMA I&T, １７７ Lu to 3.0:1.0 to 8.0:1.0 molar ratio, wherein the composition comprises a radiochemical purity of 95% or greater for at least 72 hours after manufacture, and the absorbed radiation dose per gram of tissue in the lacrimal gland of the human patient is from about 0.01 Gy / GBq to about 1.5 Gy / GBq.

27. 1. A method comprising: １７７ and administering to a human patient in need thereof a radiopharmaceutical composition comprising the Lu-PSMA I&T, １７７ and wherein the molar ratio of Lu to Lu is 3.0:1.0 to 8.0:1.0, and the composition comprises a radiochemical purity of 95% or greater for at least 72 hours after manufacture, and the absorbed radiation dose per gram of tissue in the lacrimal gland of the human patient is 1.5 Gy / GBq or less, 1.4 Gy / GBq or less, 1.3 Gy / GBq or less, 1.2 Gy / GBq or less, 1.1 Gy / GBq or less, 1.0 Gy / GBq or less, 0.9 Gy / GBq or less, 0.8 Gy / GBq or less, 0.7 Gy / GBq or less, 0.6 Gy / GBq or less, 0.5 Gy / GBq or less, 0.4 Gy / GBq or less, 0.3 Gy / GBq or less, 0.2 Gy / GBq or less, or 0.1 Gy / GBq or less.

28. The composition comprises a PSMA I&T ratio of about 4.0:1.0 to about 8.0:1.0, about 4.4:1.0 to about 7.6:1.0, about 4.5:1.0 to about 5.5:1.0, or about 5.0:1.0 to about 6.0:1.

0. １７７ 28. The method of claim 27, wherein the molar ratio of Lu to Lu is 0.

1.

29. The composition comprises a PSMA I&T ratio of 4.4:1.0 to 7.6:1.

0. １７７ 28. The method of claim 27, wherein the molar ratio of Lu to Lu is 0.

1.

30. 28. The method of claim 27, wherein the absorbed radiation dose is measured by SPECT imaging, two-dimensional imaging, or a combination thereof.

Images