Method and device for constructing pharmacokinetic model of targeted alpha radionuclide drug

Abstract

The invention relates to the technical field of dosimetry, in particular to a method for constructing a pharmacokinetic model of a targeted alpha radionuclide drug and a device for predicting the administration dosage of radionuclide.The method comprises the steps that nuclear medicine imaging results of alternative radionuclides are obtained for multiple subjects at multiple time points, and on the basis of the nuclear medicine imaging results, the targeted alpha radionuclide drug is obtained; constructing a parent nuclide pharmacokinetic model for the parent nuclide including a plurality of compartments and transfer coefficients between the compartments, constructing a daughter pharmacokinetic model for the plurality of decay daughters including daughter transfer coefficients between the plurality of compartments and the compartments of the given daughter nuclide, and coupling the parent nuclide pharmacokinetic model with the daughter pharmacokinetic model to obtain a complete pharmacokinetic model of the targeted alpha radionuclide drug. Therefore, the problems that nuclear medicine imaging of the targeted alpha radionuclide medicine is difficult, daughters are distributed in an off-target mode after parent nuclides decay, and the parent nuclides and daughters are different in pharmacokinetic model are solved, and the complete pharmacokinetic model of the targeted alpha radionuclide medicine is constructed. And accurate evaluation of the dosage caused by targeted alpha radionuclide drug treatment is realized.

Description

Technical Field

[0001] This application relates to the field of pharmacokinetic model construction, and in particular to a method for constructing a pharmacokinetic model of a drug targeting alpha-radioactive nuclide, and an apparatus for predicting and evaluating the dose induced by treatment with the drug targeting alpha-radioactive nuclide. Background Technology

[0002] Radionuclides can achieve high selectivity and effective killing of tumor lesions through their own chemical properties or by attaching to ligands such as monoclonal antibodies, peptides, or small molecules. Advanced prostate cancer patients often receive androgen deprivation therapy, but many progress to metastatic castration-resistant prostate cancer (mCRPC). Therefore, methods using prostate-specific membrane antigen (PSMA) as a key target for the diagnosis and treatment of mCRPC have been developed. β-radionuclides (such as...) 177 Lu-labeled PSMA ligands have been used clinically, but beta rays have a long tissue range (1-10 mm), easily damaging surrounding normal tissues, and their low linear energy transfer density (LET) results in limited relative biological effectiveness (RBE) for tumor killing. Therefore, clinical trials are exploring the use of alpha radionuclides to replace beta radionuclides to improve efficacy. Among alpha radionuclides, those with higher relative biological effectiveness and unaffected by oxygen content or cell cycle are... 5 Ac has become an important option for targeted radionuclide therapy due to its suitable half-life (10.0 d) and the multi-stage release characteristics of alpha particles.

[0003] Clinical studies have shown that²² 5 Ac-PSMA-617 can overcome the limitations of¹ 77 Resistance to Lu-PSMA significantly improved patient survival. However, in²² 5 The clinical application of Ac-PSMA-617 still faces many challenges: (1) α-radioisotopes are usually difficult to directly quantify. Existing methods mainly use SPECT tomography or planar imaging by detecting γ photons at 220 keV and 440 keV in their decay chain, but the image quality is not high enough, and even with a significant increase in acquisition time, the improvement is limited, and it increases the burden on patients, making it impossible to implement accurate dose calculation and evaluation. (2) The biodistribution of α-radioisotope decay products is different from that of the parent radionuclide. The actual biodistribution of the parent radionuclide and each product must be fully considered in order to achieve accurate and reliable individualized dose assessment. 5 Ac releases ²²¹Fr and ²¹Fr during its decay process.7 At、²¹³Bi、² 09 Tl,²¹³Po and² 09 Pb has six daughter nuclei. Current research often assumes that the daughter nuclei have the same pharmacokinetic characteristics as the parent nucleus or decay completely in situ. However, studies have shown that the backpressure energy generated by alpha decay can cause the daughter nuclei to detach from the target area and exhibit drastically different biodistributions. Ignoring their unique kinetic properties (such as the nephrotoxicity of ²¹³Bi) would severely overestimate the target dose and underestimate the radiation risk to normal organs. Therefore, establishing pharmacokinetic models for alpha-labeled targeted radiopharmaceuticals and constructing devices for predicting and evaluating radionuclide doses are of significant clinical value for promoting the early clinical application of such drugs, improving tumor response rates, reducing radiation exposure levels in healthy tissues, and minimizing patient toxicity. Summary of the Invention

[0004] This application provides a method for constructing a pharmacokinetic model of a drug targeting alpha-radioactive nuclides, as well as a device, electronic device, and storage medium for predicting and evaluating the dose induced by drug treatment targeting alpha-radioactive nuclides. This addresses the challenges of quantitative imaging of drugs targeting alpha-radioactive nuclides, off-target distribution of daughter nuclides after decay, differences in pharmacokinetic model characteristics between the parent nuclide and daughter nuclides, and the difficulty in predicting and evaluating the dose induced by drug treatment targeting alpha-radioactive nuclides. It enables precise pharmacokinetic fitting and dose assessment of targeted alpha-radioactive nuclides, achieving accurate evaluation of the dose induced by drug treatment targeting alpha-radioactive nuclides.

[0005] In a first aspect, this application provides a method for constructing a pharmacokinetic model of a drug targeting an alpha-radioactive nuclide. According to embodiments of the present invention, the method includes: acquiring nuclear medicine imaging results of an alternative nuclide at multiple time points for multiple subjects; constructing a parent nuclide pharmacokinetic model based on the nuclear medicine imaging results, the parent nuclide pharmacokinetic model including multiple compartments and transfer coefficients between compartments, for determining the activity of the parent nuclide within the multiple compartments at a given time point; constructing a daughter nuclide pharmacokinetic model, the daughter nuclide pharmacokinetic model including multiple compartments for a given daughter nuclide and daughter nuclide transfer coefficients between compartments; and coupling the parent nuclide pharmacokinetic model with the daughter nuclide pharmacokinetic model to determine the activities of the parent nuclide and the given daughter nuclide within the compartments at a given time point.

[0006] Optionally, in some embodiments, the targeted alpha radionuclide includes a target ligand loaded with a target ligand. 225 Ac、 213 Bi、 211 At、 223 Ra、 212 Pb, preferably, in the embodiments of this application, is an α-radioactive nuclide loaded with a target ligand.225 Ac.

[0007] Optionally, in some embodiments, the alternative nuclide includes one loaded with the same targeting ligand. 64 Cu、 134 Ce、 132 La、 68 Ga, preferably, in the embodiments of this application, the alternative nuclide is loaded with the same targeting ligand. 64 Cu. Same targeting ligand 64 Physicochemical properties of Cu-labeled nuclides and chelating groups 225 Ac is similar, ensuring that their biological distribution behavior in the body is consistent, and 64 Cu possesses electron trapping, β-coil... - and β + Three decay modes, of which β + With a decay branching ratio of 0.1749 and a maximum energy of 0.65 MeV, it is suitable for quantitative PET imaging. Furthermore, given that²² 5 Ac has a relatively long physical half-life (about 10 days). 64 Cu has a half-life of 12.7 hours, making it suitable for long-term imaging studies at multiple time points. Therefore, a longer half-life... 64 Cu is an ideal alternative radionuclide for diagnosis.

[0008] Optionally, the targeting ligand includes a prostate-specific membrane antigen.

[0009] Optionally, in some embodiments, the time points are determined based on the targeted α-radioactive nuclide, and the time points include: (1) time points within 0.1 to 1 hour after injection; (2) time points within 1 half-life after injection; (3) time points within 2 to 5 half-lives after injection; and at least one of the following: (4) one-sixth of a half-life after injection; (5) one-third of a half-life after injection; (6) one-half of a half-life after injection. The selection of the time points is premised on (1) not overlapping with other time points. Preferably, in the embodiments of this application, the time points are selected as 1 hour, 2 hours, 4 hours, 12 hours, and 24 hours after injection. The selection of time points that meet the above conditions can effectively obtain the time-activity curve of the target drug and interpret the dynamic distribution and metabolic kinetic parameters of the target drug.

[0010] Optionally, in some embodiments, the plurality of subjects includes at least 15 subjects.

[0011] Optionally, in some embodiments, the transfer coefficient between the parent nuclide compartments is determined by NLME fitting based on nuclear medicine imaging results of the surrogate nuclide. Using NLME for fitting can quantify and analyze sources of variation, including fixed effects reflecting overall population behavior and random effects reflecting inter-individual variability, and accurately model relevant parameter values.

[0012] Optionally, in some embodiments, the multiple compartments of the parent nuclide include: a plasma compartment, a drug-targeting organ compartment, a lesion compartment, an excretion compartment, and other compartments. The multiple compartments of the given daughter nucleus include: a fast-metabolizing soft tissue compartment, a medium-metabolizing soft tissue compartment, a slow-metabolizing soft tissue compartment, a skeletal muscle compartment, a small intestine compartment, a right colon compartment, a left colon compartment, and a rectosigmoid colon compartment, a cortical bone surface compartment, a cortical bone volume compartment, and a cortical bone marrow compartment, a cancellous bone surface compartment, a cancellous bone volume compartment, and a cancellous bone marrow compartment, a red blood cell compartment, a salivary gland compartment, a tumor compartment, a bladder compartment, a urine compartment, a first kidney compartment, a second kidney compartment, a plasma compartment, a first liver compartment, a second liver compartment, an excretion compartment, and a plasma compartment. Meeting the above compartment content enables the establishment of a pharmacokinetic model of the target drug with fine kinetic analysis, achieving accurate prediction in real biological systems.

[0013] Optionally, in some embodiments, the given subbody includes those selected from ²²¹Fr, ²¹ 7 At、²¹³Bi、² 09 Tl,²¹³Po and² 09 Pb, the daughter body transfer coefficient is determined based on ICRP OIR, wherein the compartment model and transfer coefficient of ²²¹Fr adopt the compartment model and transfer coefficient of Cs.

[0014] Optionally, in some embodiments, the activity of the given daughter body in the compartment at a given time point is determined by time integration based on the following formula:

[0015] in, ,nuclide Indicates compartment Medium nuclide nuclide The number of atoms, → ,nuclide Indicates nuclide nuclide From the next room to the next room The transfer rate, → ,nuclide Indicates nuclide nuclide From the next room to the next room The transfer rate, phys,nuclide It is a nuclide nuclide The physical decay constant; It is a previous generation of nuclides The physical decay constant, It is a compartment Middle and upper generation nuclides The number of atoms.

[0016] Secondly, this application provides a method for predicting and evaluating the dose induced by targeted alpha radionuclide drug therapy. According to an embodiment of this application, the method includes: inputting the initial dosage of the targeted alpha radionuclide drug into a pharmacokinetic model of the targeted alpha radionuclide drug to output the activity of the radionuclide in the region of interest at a given time point. The pharmacokinetic model of the targeted alpha radionuclide drug is constructed according to the method described in the first aspect embodiment, and the radionuclide includes the targeted alpha radionuclide parent radionuclide and its multiple decay daughters.

[0017] Thirdly, this application provides an apparatus for predicting and evaluating the dose induced by targeted alpha radionuclide therapy. According to an embodiment of this application, the apparatus includes: an initialization unit for acquiring the activity of the targeted alpha radionuclide at the treatment-induced dose in a target region; and a calculation unit for calculating the dose of the targeted alpha radionuclide at a condition satisfying the treatment-induced dose, according to the method described in the second aspect embodiment.

[0018] Fourthly, this application provides an electronic device. According to an embodiment of this application, the device includes: a processor and a memory; the memory is used to store a computer program; the processor is used to execute the computer program to implement the method for constructing a pharmacokinetic model of a drug targeting alpha-radioactive nuclide or the method for predicting and evaluating the dose induced by treatment with a drug targeting alpha-radioactive nuclide as described in the above embodiments.

[0019] Fifthly, this application provides a computer-readable storage medium having a computer program stored thereon, which is executed by a processor to implement the method for constructing a pharmacokinetic model of a drug targeting alpha-radioactive nuclide and the method for predicting and evaluating the dose induced by treatment with the drug targeting alpha-radioactive nuclide as described in the above embodiments.

[0020] Sixthly, this application provides a computer program product comprising computer instructions that, when some or all of the computer instructions are executed on a computer, cause the method for constructing a pharmacokinetic model of a drug targeting alpha-radioactive nuclide and the method for predicting and evaluating the dose induced by treatment with the drug targeting alpha-radioactive nuclide, as described in the above embodiments, to be performed.

[0021] Therefore, this application has the following beneficial effects: (1) This application addresses the need for precise quantitative imaging of alpha radionuclides by selecting those with the same ligands, similar biological spatial distribution, and ease of nuclear medicine imaging. 64 Cu-PSMA as a diagnostic alternative nuclide, based on pre-treatment... 64 Nuclear medicine image data from Cu-PSMA were used to fit the model's transfer coefficients. An NLME model was employed, balancing fixed effects of overall population behavior with random effects reflecting inter-individual variability, to fit the pharmacokinetic parameters of the parent radionuclide to at least 15 subjects. All transfer coefficients were obtained, establishing a complete pharmacokinetic model of the parent radionuclide, providing a novel model construction method for image-based quantitative dose calculation.

[0022] (2) In the pharmacokinetic model of the α-radioactive nuclide drug constructed in this application, each nuclide compartment model is modeled separately and coupled into a complete pharmacokinetic model according to the decay chain. This model reflects the relationship between different organs on the distribution, uptake and clearance of different nuclides, and can simulate the change of nuclide activity over time.

[0023] (3) The pharmacokinetic model of the drug targeting α-radioactive nuclide constructed in this application can be used to predict the activity of a specific nuclide drug in the source organ at any time point after administration and to calculate the time integral activity. The dose evaluation of the drug targeting α-radioactive nuclide can be completed by using the organ S value or direct Monte Carlo and other dose calculation methods, which provides theoretical support for the dose evaluation of targeted therapy of the drug targeting α-radioactive nuclide and fills the technical gap in the field.

[0024] Additional aspects and advantages of this application will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of this application. Attached Figure Description

[0025] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood from the description of the embodiments taken in conjunction with the following drawings, in which: Figure 1 This is a flowchart illustrating the construction of a pharmacokinetic model for a drug targeting an alpha radionuclide according to an embodiment of this application. Figure 2 Provided according to one embodiment of this application225 Structure of the parent nucleoside pharmacokinetics model of Ac-PSMA; Figure 3 Provided according to one embodiment of this application 225 Structure of Ac-PSMA daughter product pharmacokinetic model; Figure 4 A schematic block diagram of a device for predicting and evaluating the dose caused by targeted alpha radionuclide drug therapy according to an embodiment of this application; Figure 5 This is a schematic block diagram of an electronic device according to an embodiment of this application; Figure 6 To target alpha radionuclides 225 Under the conditions of Ac pharmacokinetic model and in-situ decay of daughter products... 225 Differences in time-integrated activity of various nuclides in the Ac pharmacokinetic model. Detailed Implementation

[0026] The embodiments of this application are described in detail below, with examples of the embodiments illustrated in the accompanying drawings. Those skilled in the art will understand that the embodiments described below with reference to the accompanying drawings are exemplary and intended to explain this application, and should not be construed as limiting this application.

[0027] In the embodiments of this application, the terms "module" and "unit" refer to a computer program or part of a computer program that has a predetermined function and works with other related parts to achieve a predetermined goal, and can be implemented wholly or partially using software, hardware (such as processing circuitry or memory), or a combination thereof. Similarly, a processor (or multiple processors or memory) can be used to implement one or more modules or units. Furthermore, each module or unit can be part of an overall module or unit that includes the functionality of that module or unit.

[0028] Before introducing the technical solution of this application, the relevant knowledge of this application will be introduced below: In the embodiments of this application, "alpha radionuclide" refers to a class of unstable atomic nuclei (nuclides) with alpha decay characteristics, which spontaneously emit alpha particles (i.e., helium nuclei composed of 2 protons and 2 neutrons) from the atomic nucleus, and at the same time transform into another nuclide (daughter nucleus).

[0029] In the embodiments of this application, "pharmacokinetics" refers to the branch of pharmacology that studies the dynamic changes in the absorption, distribution, metabolism and excretion of drugs in the body after they enter the body, as well as the quantitative relationship between drug concentration and time. It can provide a scientific basis for rational drug use in clinical practice and drug development.

[0030] In the embodiments of this application, "parent nuclide" refers to a primitive, unstable nuclide that spontaneously transforms into another nuclide (daughter nuclide) and releases radiation (such as alpha particles or beta particles) during radioactive decay.

[0031] In the embodiments of this application, "daughter" refers to a new nuclide formed spontaneously from an original unstable nuclide through radioactive decay.

[0032] In the embodiments of this application, "compartment" refers to a virtual physiological space in a pharmacokinetic model, which is imagined as a body with the same drug concentration variation pattern, and is used to simplify the distribution and elimination process of drugs in the body.

[0033] In the embodiments of this application, the "transfer coefficient" refers to the rate constant of drug transfer from one compartment to another in the compartment model, which is used to quantify the transfer speed of drug between different virtual spaces.

[0034] In the embodiments of this application, "treatment-induced dose" refers to the radiation absorbed dose (or effective dose) received by the patient's target tissue / organ (such as tumor) and surrounding normal tissue / organ during radiotherapy. It is a quantitative indicator for assessing the effectiveness of radiotherapy and the risk of radiation damage.

[0035] In the embodiments of this application, "activity" refers to the number of times a radionuclide undergoes spontaneous nuclear decay per unit time. It is a physical quantity that quantifies the intensity of radionuclide decay and determines the degree to which the nuclide contributes to the radiation dose to the human body or the environment.

[0036] In the embodiments of this application, "coupling" refers to integrating two or more independent models into a collaborative whole by setting specific association rules (such as parameter passing, variable sharing, and feedback linkage), so that the output of one model can be used as the input condition of another model, or to jointly simulate more complex system behaviors through data interaction between models.

[0037] In the embodiments of this application, "NLME fitting" refers to the process of estimating parameters of experimental data with nonlinear characteristics and multi-level variation by using a nonlinear mixed-effects model (NLME) and statistical algorithms. Its core is to simultaneously quantify the fixed effects (common patterns of the population) and random effects (individual / group differences) of the data to achieve accurate modeling of complex data.

[0038] In the embodiments of this application, "ICRP OIR" refers to the Occupational Intakes of Radionuclides report series published by the International Commission on Radiological Protection (ICRP). This series is a core technical document in the field of nuclear radiation protection used to assess the internal radiation dose of radionuclides to occupational populations, and was developed to solve the problem of internal radiation dose assessment in occupational scenarios.

[0039] In the embodiments of this application, "cumulative activity" refers to the integral value of the activity of a radionuclide over time within a specific time period, that is, the total cumulative activity over time, which is used to quantify the total decay contribution of the radionuclide within that time period.

[0040] In the embodiments of this application, "SPECT imaging" refers to single-photon emission computed tomography, a non-invasive molecular imaging examination method based on radionuclide tracing technology. It detects single photons emitted by radioactive tracers in the body and reconstructs three-dimensional tomographic images by computer, which are used to visualize organ function, metabolic activity and the distribution of pathological tissues.

[0041] In the embodiments of this application, "PET imaging" refers to positron emission tomography, a molecular imaging examination method based on positive tracer technology. It detects positrons generated by the decay of tracers in vivo and gamma photons after electron annihilation, and then reconstructs three-dimensional tomographic images by computer to reflect functional information such as organ metabolism, cell proliferation and biomolecular interactions.

[0042] In the embodiments of this application, the "Akaike Information Content Criterion" refers to a statistical method of quantitative indicators used for model selection and evaluation. Its core is to seek a balance between model goodness of fit and model complexity. By quantifying the model's ability to interpret data and avoiding overfitting penalties, it selects a concise model with the best fit.

[0043] In the embodiments of this application, the "time activity curve" refers to a curve plotted with time as the horizontal axis and radioactivity or normalized activity as the vertical axis. It is used to intuitively reflect the dynamic distribution, uptake and clearance of radioactive tracers (or nuclides) in a specific region of the body over time. The area under the curve can quantify the total number of decays (TIA, Time integral activity) of the radioactive tracer (or nuclide) in the target region within a specific time period.

[0044] In the embodiments of this application, "organ S-value" refers to the organ dose conversion coefficient per unit intake activity, which is used to quantify the average radiation dose level caused by a unit of radioactivity to a target organ.

[0045] In the embodiments of this application, "direct Monte Carlo" refers to a numerical simulation technique that uses the Monte Carlo method to directly calculate the target physical quantity by simulating the transport processes of radioactive particles in matter, including attenuation, absorption, and scattering. Its core is to approximate the real physical process through a large number of random samples without relying on simplified analytical models or empirical coefficients.

[0046] Before introducing the method for constructing the pharmacokinetic model of the targeted alpha radionuclide drug according to the embodiments of this application, let's briefly introduce the relevant current technology.

[0047] In current clinical research, radiotherapy regimens for prostate cancer target beta radionuclides (such as...). 177 The tumor-killing efficiency of alpha radionuclides (such as α-radioactive nuclides) is relatively limited. Therefore, clinical trials are exploring the use of alpha radionuclides (such as α-radioactive nuclides) with relatively higher biological effects and the potential to overcome tumor radiation tolerance. 5 Ac, Pb, etc.) can be used as alternatives to β-radioactive nuclides for treatment. 5 Ac has become an important option for targeted radionuclide therapy due to its suitable half-life (10.0 d) and the multi-stage release characteristics of alpha particles.

[0048] In targeted radionuclide therapy, accurately assessing the absorbed dose to target tissues and normal organs is crucial for efficacy and safety. However, dosimetric calculation paradigms suitable for obtaining patient anatomy and source term spatial distribution are difficult to directly apply.²² 5 Ac-PSMA therapy is limited by several factors, including: First, it is often difficult to directly quantify alpha-targeting radionuclides. Current methods primarily rely on SPECT tomography or planar imaging to detect 220 keV and 440 keV gamma photons in their decay chains. However, due to low therapeutic activity, significantly extended acquisition times result in limited improvement in image quality and increase patient burden, hindering precise dose calculation and evaluation. Second, the biodistribution of the decay products of alpha-targeting radionuclides differs from that of the parent radionuclide. 225 Of the four alpha particles released during Ac decay, three originate from the daughter nuclide. The back impulse generated by alpha decay is sufficient to break chemical bonds, causing the daughter nuclide to detach from the target area and exhibit a distinct biological distribution, which may cause toxic damage to other healthy tissues. Therefore, accurately quantifying the actual biological distribution of the parent nuclide and each decay daughter nuclide is crucial for dose assessment.

[0049] In summary, the relevant technologies have the following problems: (1) The spatial distribution of the source terms of the α-radionucleus in the drug treatment regimen targeting α-radionucleus needs to be accurately imaged.

[0050] (2) The decay daughters of the α-radioactive nuclide will be off-target, and the pharmacokinetic models of the parent nuclide and each decay daughter need to be constructed differently.

[0051] (3) The need to improve the prediction and evaluation of effective treatment doses in targeted alpha radionuclide therapy regimens.

[0052] To address the aforementioned issues, this application provides a method for constructing a pharmacokinetic model of a drug targeting alpha-radioactive nuclides. In this method, nuclear medicine imaging results of the alternative nuclide are obtained at multiple time points for multiple subjects. Based on the nuclear medicine imaging results, a parent nuclide pharmacokinetic model is constructed, including multiple compartments and transfer coefficients between compartments, to determine the activity of the parent nuclide in multiple compartments at a given time point. Based on ICRP OIR series publications, a daughter nuclide pharmacokinetic model is constructed, including multiple compartments of a given daughter nuclide and daughter nuclide transfer coefficients between compartments, to determine the activity of each decayed daughter nuclide in a compartment at a given time point. The parent nuclide pharmacokinetic model and the daughter nuclide pharmacokinetic model are coupled to obtain a pharmacokinetic model of the drug targeting alpha-radioactive nuclides. Based on the constructed pharmacokinetic model of the drug targeting alpha-radioactive nuclides, the predicted and evaluated dose of the drug targeting alpha-radioactive nuclides is obtained. This addresses the challenges of direct quantitative imaging in nuclear medicine for alpha-based radionuclide-targeted therapies, off-target effects from decay daughter bodies, differences in pharmacokinetic models between parent and daughter nuclides, and the need for improved prediction and evaluation of treatment-induced doses. It enables precise pharmacokinetic fitting and dose assessment of targeted alpha-based radionuclide-targeted therapies, achieving accurate evaluation of the dose induced by these treatments. This provides theoretical support for dose assessment in alpha-based radionuclide-targeted therapy, filling a technological gap in the field.

[0053] Specifically, Figure 1 This is a flowchart illustrating a method for constructing a pharmacokinetic model of a drug targeting an alpha radionuclide, as provided in an embodiment of this application.

[0054] refer to Figure 1 As shown, the method for constructing the pharmacokinetic model of the targeted α-radionoid includes the following steps: Nuclear medicine imaging results of alternative radionuclides were obtained at multiple time points for multiple subjects.

[0055] Optionally, in some embodiments, the alpha radionuclide includes 225 Ac、 213 Bi、 211 At、 223 Ra、212 Pb, preferably, in the embodiments of this application, the targeted α-radionium is a ligand loaded with a targeting ligand. 225 Ac-PMSA.

[0056] In this application embodiment, multiple time points are set at 1 hour, 2 hours, 4 hours, 12 hours, and 24 hours after injection. Optionally, in some embodiments, 1-2 additional data collections may be performed at a time point ≥48 hours after injection. The multiple subjects in this application embodiment include at least 15 subjects.

[0057] Optionally, in some embodiments, the alternative nuclide is 64 Cu、 134 Ce、 132 La、 68 Ga, preferably, in the embodiments of this application, the alternative nuclide is loaded with the same targeting ligand. 64 Cu-PMSA.

[0058] Optionally, the targeting ligand in the embodiments of this application is a prostate-specific membrane antigen.

[0059] Optionally, in some embodiments, the nuclear medicine imaging results include SPECT imaging and / or PET imaging. This application uses PET imaging in its embodiments. It should be noted that, in terms of image processing, open-source tools such as TotalSegmentator and 3DSlicer are used to automatically segment CT images, extracting masks of structures such as the kidneys, liver, spleen, prostate, and blood vessels. Tumors and structures with significant automatic segmentation errors (such as salivary glands) are manually delineated in the PET images. The masks of the aforementioned organs are mapped to the PET images at the corresponding time points, and the total count rate of each region of interest is calculated. Based on whether scattering correction and attenuation correction have been completed during PET image reconstruction, appropriate quantitative correction is performed on the count to accurately reflect the distribution of radioactivity.

[0060] Based on nuclear medicine imaging results, construct such as Figure 2 The pharmacokinetic model of the parent nucleus shown includes multiple compartments and transfer coefficients between the compartments, used to determine the activity of the parent nucleus in the multiple compartments at a given time point. In this embodiment, the parent nucleus is... 225 Ac-PMSA.

[0061] Optionally, in some embodiments, the multiple compartments include: a plasma compartment, a drug-targeted organ compartment, a lesion compartment, an excretion compartment, and other compartments (rest).

[0062] Optionally, in some embodiments, the drug-targeting organ compartments in the parent nucleoside compartment include organ compartments that highly express PMSA, including: kidney compartments, liver compartments, salivary gland compartments, prostate compartments, and spleen compartments.

[0063] Specifically, in the embodiments of this application, the transfer coefficient of the parent nuclide is based on the substituted nuclide. 64 The nuclear medicine imaging results of Cu were determined by NLME fitting. It should be noted that the NLME model is a statistical method integrating fixed and random effects, widely used for population pharmacokinetic parameter estimation. Within the NLME model framework, fixed effects... Characterizing population-average pharmacokinetic behavior; random effects Describing individual deviations typically assumes a zero-mean multivariate normal distribution. Based on the NLME model definition, the transfer coefficients of the pharmacokinetic model in this application embodiment are... Calculate according to formula (1): (1) Optionally, in some embodiments, the model parameter estimation process can be implemented using the Maximum Likelihood Estimation (MLE) method or a Bayesian method. In this embodiment, the NLME model parameters are iteratively optimized by maximizing the likelihood function, which is described by equation (2): (2) In formula (2) It is the response value. It is the error variance. It is the covariance matrix of random effects. yes The marginal probability density, Given random effects hour The conditional probability density is calculated according to equation (3), where The model is for the first Prediction of individual observations. ( | )yes The prior probability distribution is calculated according to equation (4), where It is the dimension of random effects.

[0064] (3) (4) Optionally, in some embodiments, the selection of the error model can be accomplished by comparing the goodness of fit. In this embodiment, the Akaike information criterion (AIC) is used to evaluate the quality of the selected model. The calculation method of AIC is shown in equation (5): AIC = -2 + 2numParam(5) in, The maximum likelihood value represents the model, and numParam is the total number of model parameters, including the fixed effects and uncertainties of the 15 transition coefficients to be fitted, as well as the parameters of the error model itself. In the model comparison, the model with the smallest AIC value is selected as the optimal model based on the AIC results.

[0065] Based on ICRP OIR series publications, such as Figure 3 The pharmacokinetic model of the progeny shown includes multiple compartments of multiple progeny units and progeny transfer coefficients between compartments for a given progeny unit. This is used to determine the activity of each given progeny unit within a compartment at a given time point. In the embodiments of this application, the progeny units include ²²¹Fr, ²¹ 7 At、²¹³Bi、² 09 Tl,²¹³Po and² 09 Pb. In this embodiment, the compartmental model and transfer coefficient of ²²¹Fr are replaced by the compartmental model and transfer coefficient of Cs, an alkali metal element with similar chemical properties.

[0066] Optionally, in some embodiments, the multiple compartments of a given daughter body include: a fast-metabolizing soft tissue compartment (ST0), a medium-metabolizing soft tissue compartment (ST1), a slow-metabolizing soft tissue compartment (ST2), a skeletal muscle compartment, a small bowel compartment (SIcont), a right colon compartment (RCcont), a left colon compartment (LCcont), and a rectosigmoid colon compartment (RScont), a cortical bone surface compartment (CBS), a cortical bone volume compartment (CBV), and a cortical bone marrow compartment (CBM), a cancellous bone surface compartment (TBS), a cancellous bone volume compartment (TBV), and a cancellous bone marrow compartment (TBM), a red blood cell compartment (RBC), salivary gland compartments, a tumor compartment (Tumeor), a bladder compartment (UBC), a urine compartment (Urine), a first kidney compartment (Other kidney), and a second kidney compartment (Urinary). The liver includes the path, plasma compartment, first liver compartment (Liver1), second liver compartment (Liver2), excretory compartment (Faeces), and plasma compartment (Plasma).

[0067] Optionally, the decay daughter transfer coefficients in some embodiments are shown in Table 1 below. It should be noted that for a specific compartment not included in a certain daughter, its transfer coefficient is uniformly set to 0, while the other transfer coefficients directly adopt the values ​​recommended by ICRP OIR.

[0068] Table 1 225 Ac daughter pharmacokinetic model transfer coefficient

[0069] In this embodiment, the activity of each given sub-sub ... (6) in, ,nuclide Indicates compartment Medium nuclide nuclide The number of atoms, → ,nuclide Indicates nuclide nuclide From the next room to the next room The transfer rate, → ,nuclide Indicates nuclide nuclide From the next room to the next room The transfer rate, phys,nuclide It is a nuclide nuclide The physical decay constant; It is a previous generation of nuclides The physical decay constant, It is a compartment Middle and upper generation nuclides The number of atoms.

[0070] By coupling the constructed parent nuclide pharmacokinetics model with the daughter nuclide pharmacokinetics model, a complete pharmacokinetic model for drugs targeting alpha radionuclides is obtained.

[0071] Therefore, the embodiments of this application solve the problems of high difficulty in quantitative imaging of targeted alpha radionuclide drugs, off-target distribution of daughter bodies after decay of parent nuclide, and differences in the pharmacokinetic model characteristics of parent nuclide and daughter body, and implement accurate pharmacokinetic fitting for targeted alpha radionuclide drugs.

[0072] Secondly, this application provides a method for predicting and evaluating the dose induced by targeted alpha radionuclide drug therapy. Specifically, the initial dosage of the targeted alpha radionuclide drug is input into the pharmacokinetic model of the targeted alpha radionuclide drug to output the activity of the radionuclide in the region of interest at a given time point. Specifically, the transfer coefficients of the fitted pharmacokinetic model are substituted into the pharmacokinetic model of the targeted alpha radionuclide drug, and the corresponding differential equations are solved to obtain the predicted values ​​of the radioactivity of the targeted alpha radionuclide drug and its decay products in the organ at different times, i.e., the time-activity curve. The time-activity curve is then fitted and integrated, and the dose evaluation of the targeted alpha radionuclide drug is completed using organ S-values ​​or direct Monte Carlo dose calculation methods.

[0073] Optionally, the solution of the differential equation system in this embodiment can be applied to the ode15s solver for ill-conditioned differential equations, using automatic step size setting, setting the simulation deadline to 3600h (150 days), and setting absolute tolerance and relative tolerance.

[0074] Therefore, the embodiments of this application solve the problem that the evaluation of the dose caused by targeted alpha radionuclide therapy needs to be improved, and achieve accurate evaluation of the dose caused by targeted alpha radionuclide therapy.

[0075] This application also provides an apparatus for predicting the dose induced by targeted alpha radionuclide drug therapy. (Reference) Figure 4 As shown, the device 400 for predicting the dose induced by radionuclide therapy includes an initialization unit 410 and a calculation unit 420. The initialization unit 410 is used to acquire the activity of the targeted alpha radionuclide drug in the target region at the treatment dose; the calculation unit 420 is used to calculate the treatment dose induced by the targeted alpha radionuclide drug according to the method described in the foregoing embodiments. It should be noted that the foregoing explanation of the embodiments of the method for predicting and evaluating the dose induced by targeted alpha radionuclide therapy also applies to the device for predicting and evaluating the dose induced by targeted alpha radionuclide therapy in this embodiment, and will not be repeated here.

[0076] This application also provides an electronic device. The electronic device 500 can be the training device or execution device described above, but is not limited thereto. (See reference...) Figure 5 As shown, the electronic device 500 may include: The system includes a memory 510 and a processor 520. The memory 510 stores a computer program 530 and transfers the computer program 530 to the processor 520. In other words, the processor 520 can retrieve and run the computer program 530 from the memory 510 to implement the methods described in the embodiments of this application.

[0077] For example, the processor 520 can be used to execute the steps in the above method according to the instructions in the computer program 530.

[0078] In some embodiments of this application, the processor 520 may include, but is not limited to: General-purpose processors, digital signal processors (DSPs), application-specific integrated circuits (ASICs), field-programmable gate arrays (FPGAs), or other programmable logic devices, discrete gate or transistor logic devices, discrete hardware components, etc.

[0079] In some embodiments of this application, the memory 510 includes, but is not limited to: Volatile memory and / or non-volatile memory. Non-volatile memory can be read-only memory (ROM), programmable read-only memory (PROM), erasable programmable read-only memory (EPROM), electrically erasable programmable read-only memory (EEPROM), or flash memory. Volatile memory can be random access memory (RAM), used as an external cache. By way of example, but not limitation, many forms of RAM are available, such as Static RAM (SRAM), Dynamic RAM (DRAM), Synchronous DRAM (SDRAM), Double Data Rate SDRAM (DDR SDRAM), Enhanced SDRAM (ESDRAM), Synchronous Link DRAM (SLDRAM), and Direct Rambus RAM (DR RAM).

[0080] In some embodiments of this application, the computer program 530 may be divided into one or more modules, which are stored in the memory 510 and executed by the processor 520 to perform the method provided in this application. The one or more modules may be a series of computer program instruction segments capable of performing specific functions, which describe the execution process of the computer program 530 in the electronic device.

[0081] refer to Figure 5 As shown, the electronic device 500 may further include: Transceiver 540, which can be connected to processor 520 or memory 510.

[0082] The processor 520 can control the transceiver 540 to communicate with other devices; specifically, it can send information or data to other devices or receive information or data sent by other devices. The transceiver 540 may include a transmitter and a receiver. The transceiver 540 may further include antennas, and the number of antennas may be one or more.

[0083] It should be understood that the various components in the electronic device 500 are connected through a bus system, which includes a data bus, a power bus, a control bus, and a status signal bus.

[0084] This application also provides a computer-readable storage medium for storing computer instructions or programs that, when executed on a computer, cause the methods explained in the foregoing embodiments for constructing a pharmacokinetic model of a drug targeting alpha-radioactive nuclide or for predicting and evaluating the dose induced by treatment with a drug targeting alpha-radioactive nuclide to be performed.

[0085] This application also provides a computer program product comprising computer instructions that, when some or all of the computer instructions are executed on a computer, cause the method for constructing a pharmacokinetic model of a drug targeting alpha radionuclide, or the method for predicting and evaluating the dose induced by treatment with a drug targeting alpha radionuclide, as explained in the foregoing embodiments, to be performed.

[0086] The present application's solution will be explained below with reference to embodiments and comparative examples. Those skilled in the art will understand that the following embodiments and comparative examples are for illustrative purposes only and should not be construed as limiting the scope of the application. Where specific techniques or conditions are not specified in the embodiments, they are performed in accordance with the techniques or conditions described in the literature in the art or according to the product manual.

[0087] Example 1 In the embodiments, a pharmacokinetic model for a drug targeting an alpha radionuclide was constructed and applied according to the following method: 1. Alternative radionuclides were obtained from 20 subjects at 1 hour, 2 hours, 4 hours, 12 hours, and 24 hours after injection. 64 Nuclear medicine imaging results of Cu-PSMA.

[0088] 2. Based on alternative nuclides 64 Based on the nuclear medicine imaging results of Cu-PSMA, a pharmacokinetic model of the parent nucleoside, including multiple compartments and the transfer coefficients between compartments, was constructed.

[0089] 3. Construct a daughter pharmacokinetic model based on ICRP OIR, which includes multiple compartments for a given daughter and daughter transfer coefficients between compartments for a given daughter.

[0090] 4. Couple the pharmacokinetic model of the parent nuclide with the pharmacokinetic model of the daughter nuclide to obtain a complete pharmacokinetic model of the drug targeting the α-radioactive nuclide.

[0091] 5. Use the constructed pharmacokinetic model of alpha-targeting radionuclide drugs to predict and evaluate the therapeutic dose of alpha-targeting radionuclide drugs.

[0092] Comparative Example 1 In the embodiments, a pharmacokinetic model of a drug targeting an alpha radionuclide under the assumption of in-situ decay of the daughter nuclide was constructed according to the following method: 1. Alternative radionuclides were obtained from 20 subjects at 1 hour, 2 hours, 4 hours, 12 hours, and 24 hours post-injection.¹ 77 Nuclear medicine imaging results of Lu-PSMA; 2. Based on substitute nuclides¹ 77 Based on the nuclear medicine imaging results of Lu-PSMA, assuming that the daughter nucleus decays at the location of the parent nuclide, a pharmacokinetic model of a targeted alpha radionuclide drug is constructed, including multiple compartments and the transfer coefficients between the compartments.

[0093] 3. Use the constructed pharmacokinetic model of alpha-targeted radionuclide drugs to predict and evaluate the dose induced by alpha-targeted radionuclide drug treatment.

[0094] Results Reference Appendix Figure 6 As shown, compared to the in-situ decay hypothesis, the time-integrated activity of multiple daughter nuclides in salivary glands, blood, tumors, and other compartments is reduced, indicating that the decay-generated daughter nuclides leave the target area, leading to a decrease in radiation dose assessment. The total radiation dose to the liver and kidney compartments is expected to increase when off-target decay daughter nuclides are metabolized into them, with a maximum difference of 188%. 225 The four alpha radionuclides are the most significant contributors to dose in the Ac decay chain: 225 Ac、 221 Fr、217 At and 213 Po. Due to 221 Fr and 217 At has an extremely short half-life and is located at the beginning of the decay chain, making it unlikely to migrate within the body. Therefore, if we assume... 221 Fr and 217 At decays in situ, resulting in relatively small differences in time-integrated activity. Meanwhile... 217 At is a previous generation of nuclide 221 Derived from Fr decay, it has an extremely short half-life and undergoes virtually no migration within organs, decaying rapidly after its formation. Therefore, in practical modeling, for such short-lived nuclides, it is advisable to incorporate them into the model of the previous generation of nuclides to simplify pharmacokinetic modeling, reduce the number of parameters, and improve model stability and computational speed. However, 213 Po is located at the end of the decay chain, and its predecessor nuclide 213 Bi has a significant tendency to accumulate in the kidneys, leading to 213 The distribution of Po changes significantly; if this process is ignored... 213 The time-integrated activity of Po in the kidney would be underestimated by up to 173%. The difference in the time-integrated activities of various nuclides in the two models clearly reveals the potential error caused by neglecting daughter nuclide migration, demonstrating that simply treating daughter nuclides as... 225 Acs having the same distribution or pharmacokinetic behavior can cause systematic errors in organ dose assessment results, further demonstrating the importance of coupled multi-nucleoside pharmacokinetic models in dose assessment.

[0095] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., refer to specific features, structures, materials, or characteristics described in connection with that embodiment or example, which are included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0096] Any process or method described in the flowchart or otherwise herein can be understood as representing a module, segment, or portion of code comprising one or more N executable instructions for implementing custom logic functions or processes, and the scope of the preferred embodiments of this application includes additional implementations in which functions may be performed not in the order shown or discussed, including substantially simultaneously or in reverse order depending on the functions involved, as should be understood by those skilled in the art to which embodiments of this application pertain.

[0097] It should be understood that the various parts of this application can be implemented using hardware, software, firmware, or a combination thereof. In the above embodiments, the N steps or methods can be implemented using software or firmware stored in memory and executed by a suitable instruction execution system. For example, if implemented in hardware, as in another embodiment, it can be implemented using any one or a combination of the following techniques known in the art: discrete logic circuits having logic gates for implementing logical functions on data signals, application-specific integrated circuits (ASICs) having suitable combinational logic gates, programmable gate arrays (FPGAs), field-programmable gate arrays (FPGAs), etc.

[0098] Those skilled in the art will understand that all or part of the steps of the methods in the above embodiments can be implemented by a program instructing related hardware. The program can be stored in a computer-readable storage medium, and when executed, the program includes one or a combination of the steps of the method embodiments.

[0099] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. A method for constructing a pharmacokinetic model of a drug targeting an alpha-radioactive nuclide, the model comprising a parent nuclide pharmacokinetic model and a daughter nuclide pharmacokinetic model, characterized in that, include: At multiple time points, nuclear medicine imaging results of alternative radionuclides were obtained for multiple subjects; Based on the nuclear medicine imaging results, a pharmacokinetic model of the parent nucleus is constructed. The pharmacokinetic model of the parent nucleus includes multiple compartments and transfer coefficients between the compartments, which are used to determine the activity of the parent nucleus in the multiple compartments at a given time point. Construct a pharmacokinetic model for a given daughter product, wherein the pharmacokinetic model for a given daughter product includes multiple compartments for a given daughter product and daughter product transfer coefficients between compartments for a given daughter product. and The pharmacokinetic model of the parent nuclide is coupled with the pharmacokinetic model of the daughter nuclide to determine the activity of the parent nuclide and the given daughter nuclide in the compartment at a given time point.

2. The method according to claim 1, characterized in that, The targeted alpha radionuclide includes a target ligand loaded with a target ligand. 225 Ac、 213 Bi、 211 At、 223 Ra、 212 Pb, preferably loaded onto the target ligand 225 Ac, the alternative nuclide includes those loaded with the same target ligand. 64 Cu、 134 Ce、 132 La、 68 Ga, preferably loaded with the same target ligand 64 Cu; Optionally, the targeting ligand includes prostate-specific membrane antigen.

3. The method according to claim 1, characterized in that, The time points are determined based on the targeted alpha radionuclide, and the time points include: (1) Time points within 0.1 to 1 hour after injection; (2) One half-life after injection; (3) Time points within 2-5 half-lives after injection, and Selected from at least one of the following: (4) One-sixth of the half-life after injection; (5) One-third of the half-life after injection; (6) One-half a life after injection, The selection of the time point is based on the premise that (1) it does not overlap with other time points, the multiple subjects include at least 15 subjects, and the transfer coefficient between the parent nuclide compartments is determined by NLME fitting based on the nuclear medicine imaging results of the alternative nuclide.

4. The method according to claim 1, characterized in that, The parent nuclide has multiple compartments including: a plasma compartment, a drug-targeting organ compartment, a lesion compartment, an excretion compartment, and other compartments. The given daughter nucleus has multiple compartments including: a fast-metabolizing soft tissue compartment, a medium-metabolizing soft tissue compartment, a slow-metabolizing soft tissue compartment, a skeletal muscle compartment, a small intestine compartment, a right colon compartment, a left colon compartment, and a rectosigmoid colon compartment, a cortical bone surface compartment, a cortical bone volume compartment, and a cortical bone marrow compartment, a cancellous bone surface compartment, a cancellous bone volume compartment, and a cancellous bone marrow compartment, a red blood cell compartment, a salivary gland compartment, a tumor compartment, a bladder compartment, a urine compartment, a first kidney compartment, a second kidney compartment, a plasma compartment, a first liver compartment, a second liver compartment, an excretion compartment, and a plasma compartment.

5. The method according to claim 1, characterized in that, The given sub-body includes those selected from ²²¹Fr, ²¹ 7 At、²¹³Bi、² 09 Tl,²¹³Po and² 09 Pb, the daughter body transfer coefficient is determined based on ICRP OIR, wherein the compartment model and transfer coefficient of ²²¹Fr adopt the compartment model and transfer coefficient of Cs.

6. The method according to claim 1, characterized in that, The activity of the given sub-body in the compartment at a given time point is determined by time integration based on the following formula: in, ,nuclide Indicates compartment Medium nuclide nuclide The number of atoms, → ,nuclide Represents nuclide nuclide From the next room to the next room The transfer rate, → ,nuclide Represents nuclide nuclide From the next room to the next room The transfer rate, phys,nuclide It is a nuclide nuclide The physical decay constant; It is a previous generation of nuclides The physical decay constant, It is a compartment Middle and upper generation nuclides The number of atoms.

7. A method for predicting and evaluating the dose induced by targeted alpha radionuclide therapy, characterized in that, include: The initial dosage of the α-targeting radionuclide drug is input into the pharmacokinetic model of the α-targeting radionuclide drug to output the activity of the radionuclide in the region of interest at a given time point. The pharmacokinetic model of the α-targeting radionuclide drug is constructed according to the method of any one of claims 1 to 6, wherein the radionuclide includes the α-targeting parent radionuclide and its multiple decay daughters.

8. A device for predicting and evaluating the dose induced by targeted alpha radionuclide therapy, characterized in that, include: An initialization unit is used to obtain the activity of the treatment-induced dose of the targeted alpha radionuclide drug in the target region; and A calculation unit is configured to calculate the dose of the targeted alpha radionuclide drug that satisfies the treatment-induced dose conditions, according to the method of claim 7.

9. An electronic device, characterized in that, include: Processor and memory; The memory is used to store computer programs; The processor is configured to execute the computer program to implement the method for constructing a pharmacokinetic model of a drug targeting alpha radionuclide as described in any one of claims 1 to 6, or the method for predicting and evaluating the dose induced by treatment with a drug targeting alpha radionuclide as described in claim 7.

10. A computer-readable storage medium, characterized in that, The computer-readable storage medium stores computer instructions or programs that, when executed on a computer, cause the method for constructing a pharmacokinetic model of a drug targeting alpha-radioactive nuclide as described in any one of claims 1 to 6, or the method for predicting and evaluating the dose induced by treatment with a drug targeting alpha-radioactive nuclide as described in claim 7.

11. A computer program product, characterized in that, The computer program product includes computer instructions that, when some or all of the computer instructions are executed on a computer, cause the method for constructing a pharmacokinetic model of a drug targeting alpha radionuclide as described in any one of claims 1 to 6, or the method for predicting and evaluating the dose induced by treatment with a drug targeting alpha radionuclide as described in claim 7, to be performed.

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