Dose initiation for treatment of schizophrenia or bipolar type I disorder with aripiprazole

Abstract

The present disclosure relates to a dose initiation method of performing an aripiprazole treatment on a patient in need thereof, the method comprising administering two separate aripiprazole injections and a single oral aripiprazole on the first day of aripiprazole treatment wherein the first aripiprazole injection is a long acting injection (LAI) and the second aripiprazole injection is a single dose oral aripiprazole injection. And the second injection of aripiprazole is an injection once a month (AOM). Maintaining administration is performed with a maintained dose of the LAI about two months after the first day of the aripiprazole treatment. The method is suitable for application parts of deltoid muscles and gluteus muscles.

Description

Technical Field

[0001] This application claims priority to U.S. Provisional Application No. 63 / 498313, filed April 26, 2023; No. 63 / 506624, filed June 7, 2023; and No. 63 / 637079, filed April 22, 2024; the contents of each of these applications are incorporated herein by reference in their entirety. Background Technology

[0002] Schizophrenia and bipolar I disorder (BP-I) are complex chronic mental health disorders in which affected individuals typically experience multiple symptom relapses separated by periods of remission. While daily oral antipsychotics have proven effective in achieving and maintaining symptom control in many patients, this depends on consistent and long-term use. However, non-compliance with oral medications is common; data indicate that 30–50% of patients with schizophrenia or BP-I do not take their medication as prescribed. Various strategies for improving treatment adherence are available, including the use of long-acting injectable (LAI) antipsychotics; LAI formulations offer dosing intervals of 2 weeks to 6 months, reducing the adherence requirement for patients compared to daily dosing. Indeed, data from several real-world studies have shown that LAI formulations of antipsychotics are associated with significantly improved treatment adherence compared to oral antipsychotics in patients with schizophrenia or BP-I.

[0003] Aripiprazole is an antipsychotic drug with partial agonist activity against dopamine D2 and serotonin 5-HT1A receptors, full agonist activity against dopamine D3 receptors, and antagonist activity against serotonin 5-HT2A receptors. Aripiprazole is available in once-daily oral formulations or as a delayed-release suspension of aripiprazole monohydrate known as once-monthly aripiprazole (AOM) for intramuscular injection. Additionally, a novel off-the-shelf (RTU) aripiprazole monohydrate LAI formulation, administered every two months as an intramuscular injection into the gluteal muscle, has recently been approved in the United States for the treatment of schizophrenia or BP-I. This novel formulation contains 960 mg or 720 mg of aripiprazole monohydrate, the latter dose being used in cases of any tolerability concerns, in patients known to be poor metabolizers of cytochrome P450 (CYP) 2D6, and in patients concurrently taking strong CYP2D6 or CYP3A4 inhibitors. Summary of the Invention

[0004] The 960 mg aripiprazole two-month ready-to-use formulation (Ari 2MRTU 960) was developed to extend the maintenance of therapeutic plasma concentrations of aripiprazole from one month with AOM 400 mg (AOM 400) to two months. This was achieved through several considerations, such as increasing the dosage while maintaining similar minimum aripiprazole concentrations as after multiple doses of AOM and other formulations, and other administration considerations. In particular, the lower dosing frequency of Ari 2MRTU 960 (i.e., 6 injections per year compared to 12 for AOM) may reduce the medication burden on patients and clinicians and improve adherence to antipsychotic treatment in adult patients with schizophrenia or BP-I.

[0005] As part of the development of Ari 2MRTU 960 and Ari 2MRTU 720 (i.e., 720 mg aripiprazole ready-to-use formulation for two months), previously developed and validated population pharmacokinetic (popPK) models for characterizing plasma aripiprazole concentrations after administration of oral aripiprazole or AOM at the gluteal or deltoid muscle sites have been extended to include the novel aripiprazole RTULAI formulation (Ari RTU LAI). This extended popPK model provides additional options for dose initiation of aripiprazole treatment in patients.

[0006] For example, this disclosure relates to a dose-initiation method for aripiprazole treatment in patients in need, the method comprising administering two separate aripiprazole injections and a single oral dose of aripiprazole on the first day of aripiprazole treatment, wherein the first aripiprazole injection is a long-acting injectable (LAI) and the second aripiprazole injection is a once-monthly injectable (AOM). Simulations of a dose-initiation regimen involving two injections of aripiprazole LAI and AOM at separate gluteal and / or deltoid injection sites on the first day of treatment have shown to be sufficient to obtain PK exposure profiles comparable to AOM, with longer dosing intervals.

[0007] In some embodiments, this disclosure relates to a dose-initiation method for aripiprazole treatment in a patient in need, the method comprising administering to the patient two separate aripiprazole injections and a single oral dose of aripiprazole, wherein the first injection comprises 960 mg or 720 mg of aripiprazole in a long-acting injectable (LAI), and the second injection comprises 400 mg or 300 mg of aripiprazole in an once-monthly (AOM) injectable, the injection site being selected from the gluteal region, the deltoid region, and combinations thereof, wherein the administration step is performed on the first day of the aripiprazole treatment.

[0008] In some embodiments, this disclosure relates to a method of treating schizophrenia or type I bipolar disorder in a patient in need, the method comprising: administering to the patient two separate injections of aripiprazole and a single oral dose of aripiprazole, wherein the first injection comprises 960 mg or 720 mg of aripiprazole in a long-acting injectable (LAI), and the second injection comprises 400 mg or 300 mg of aripiprazole in an once-monthly (AOM) injectable, the injection site being selected from the gluteal region, the deltoid region, and combinations thereof, wherein the administration step is performed on the first day of the aripiprazole treatment, and wherein the oral aripiprazole dose is from about 10 mg to about 20 mg of aripiprazole; and continuing to administer a maintenance dose of the LAI formulation comprising 960 mg or 720 mg of aripiprazole, wherein the maintenance dose is administered for about two months after the first day of the aripiprazole treatment. Attached Figure Description

[0009] [ Figure 1 ] Figure 1 This is a basic model diagram describing the pharmacokinetics of aripiprazole after oral administration, AOM, and Ari RTU LAI.

[0010] [ Figure 2 ] Figure 2 This is a graph showing the simulated pharmacokinetic curves from the final model after six repeated administrations of Ari 2MRTU 960 mg aripiprazole every 8 weeks, based on retained covariates (sex and CYP2D6 status).

[0011] [ Figure 3 ] Figure 3 A-3D is the goodness-of-fit plot of the final aripiprazole population pharmacokinetic model.

[0012] [ Figure 4 ] Figure 4 A-4G is a plot of the visual prediction check of the final aripiprazole population pharmacokinetic model.

[0013] [ Figure 5 ] Figure 5 A-5F is a graph of simulated median aripiprazole concentration-time curves after initiation of Ari 2MRTU 960 mg aripiprazole in various prior treatment scenarios.

[0014] [ Figure 6 ] Figure 6 This is a graph showing the simulated median aripiprazole concentration-time curves in patients who have stabilized after treatment with Ari 2MRTU 960 mg aripiprazole, after scheduled administration of Ari 2MRTU 960 mg aripiprazole or after delays of 2, 4, 6, or 8 weeks.

[0015] [ Figure 7 ] Figure 7 The graph shows the simulated median aripiprazole concentration-time curve for patients who did not have stable oral aripiprazole after day 0 AOM and on day 28 using Ari 2MRTU 960 (adding 20 mg of oral aripiprazole in patients who did not have stable oral aripiprazole).

[0016] [ Figure 8 ] Figure 8 A-8D is a graph of simulated median aripiprazole concentration-time curves after two injections starting with Ari 2MRTU 960 plus AOM 400 in various prior treatment scenarios.

[0017] [ Figure 9 ] Figure 9 This is a graph showing the simulated median steady-state aripiprazole concentration-time curve after administration of Ari 2MRTU 720 in CYP2D6 poor metabolizers.

[0018] [ Figure 10 ] Figure 10 This is a graph of the simulated median steady-state aripiprazole concentration-time curve after administration of Ari 2MRTU 720 and strong inhibitors of CYP3A4 or CYP2D6.

[0019] [ Figure 11 ] Figure 11 The graph shows the simulated median aripiprazole concentration-time curves after administration of Ari2MRTU 960 (day 0) and AOM 400 (day 0) and 20 mg oral aripiprazole (day 0) in all subjects (solid line) and CYP2D6 adverse metabolizers (dashed line), or after administration of Ari2MRTU 720 (day 0) and AOM 300 (day 0) and 20 mg oral aripiprazole (day 0) in CYP2D6 adverse metabolizers who were already stable after 10 mg oral aripiprazole.

[0020] [ Figure 12 ] Figure 12 The graph shows the simulated median aripiprazole concentration-time curves after administration of Ari2MRTU 960 (day 0) and AOM 400 (day 0) and 20 mg oral aripiprazole (day 0) in all subjects (solid line) and CYP2D6 adverse metabolizers (dashed line), or after administration of Ari2MRTU 720 (day 0) and AOM 300 (day 0) and 20 mg oral aripiprazole (day 0) in CYP2D6 adverse metabolizers who did not have a stable condition after prior oral aripiprazole.

[0021] [ Figure 13 ] Figure 13This is a graph of the mean plasma concentration (SD) of aripiprazole as a time curve after administration of a single dose of 780 mg (N=18) or 1200 mg (N=13) of ready-to-use aripiprazole 2M RTU long-acting injection to the gluteal muscles of subjects with schizophrenia. Detailed Implementation

[0022] As used herein, "no specific number" refers to one or more of the stated items; for example, unless otherwise stated, "compound" means one or more compounds or at least one compound. Therefore, "no specific number," "one or more," and "at least one" are used interchangeably herein.

[0023] As used herein, the term "approximately" means approximately, within a certain range, roughly, or about. When the term "approximately" is used in conjunction with a numerical range, it modifies the range by extending the boundaries to be above and below the stated value. Generally, the term "approximately" is used herein to modify numerical values ​​to be above and below a deviation of 5% from the stated value.

[0024] As used herein, the term "treatment," when used in conjunction with a disorder or condition, includes any effect that leads to improvement of said disorder or condition, such as relief, reduction, modulation, improvement, or elimination. Any improvement or reduction in the severity of any symptom of said disorder or condition can be readily assessed using standard methods and techniques known in the art. In some embodiments, the currently disclosed methods or reservoir formulations may be used as maintenance monotherapy for the treatment of schizophrenia and bipolar I disorder.

[0025] As used herein, “mammal” refers to domesticated animals (such as dogs, cats, and horses) and humans. In some embodiments, the mammal is a human.

[0026] When used herein, "aripiperazole" refers to aripiprazole or a salt thereof, or the crystalline form of aripiprazole or a salt thereof. Aripiprazole or a salt thereof may be in monohydrate form (aripiperazole hydrate A) or in various anhydrous forms, known to exist as anhydrous crystals B, C, D, E, F, and G. All of these crystalline forms can be used as aripiprazole or a salt thereof in the injectable formulations disclosed herein; furthermore, aripiprazole is, for example, in monohydrate form. The term "aripiperazole or a salt thereof" as used herein refers to compounds having the following structure: [Chemical Formula 1] .

[0027] The empirical formula is C 23 H 27Cl2N3O2H2O has a molecular weight of 466.40. This disclosure relates to a dose-initiation method for aripiprazole treatment in a patient in need, the method comprising administering two separate aripiprazole injections and a single oral dose of aripiprazole to the patient, wherein the first injection comprises 960 mg or 720 mg of aripiprazole in a long-acting injectable (LAI), and the second injection comprises 400 mg or 300 mg of aripiprazole in an once-monthly (AOM) injectable, the injection site being selected from the gluteal region, the deltoid region, and combinations thereof, wherein the administration step is performed on the first day of the aripiprazole treatment.

[0028] Implementation

[0029] In addition to the above, some embodiments of this disclosure include, but are not limited to: 1. A method for dose initiation of aripiprazole treatment in a patient in need, the method comprising: administering to the patient two separate aripiprazole injections and a single oral dose of aripiprazole, wherein the first injection comprises 960 mg or 720 mg of aripiprazole in a first long-acting injectable (LAI) formulation, and the second injection comprises 400 mg or 300 mg of aripiprazole in a second LAI formulation, the injection site being selected from the gluteal region, the deltoid region, and combinations thereof, wherein the administration steps are performed on the first day of aripiprazole LAI treatment.

[0030] 2. The method according to embodiment 1, wherein the first LAI formulation is in gel form when left to stand and becomes a sol when subjected to impact.

[0031] 3. The method according to embodiment 1, wherein the second LAI formulation is a suspension prepared from lyophilized powder and water for injection.

[0032] 4. The method according to any one of embodiments 1 to 3, wherein the first injection comprises 960 mg of aripiprazole.

[0033] 5. The method according to any one of embodiments 1 to 4, further comprising administering a maintenance dose of the first LAI formulation once within approximately two months after the first day of aripiprazole LAI treatment.

[0034] 6. The method according to embodiment 5, wherein the maintenance dose of the first LAI formulation is selected from 960 mg and 720 mg aripiprazole.

[0035] 7. The method according to embodiment 6, wherein when the patient is an adverse metabolizer of CYP2D6 or is concurrently taking a CYP3A4 inhibitor or a CYP2D6 inhibitor for more than 14 days, the maintenance dose of the first LAI preparation is 720 mg aripiprazole.

[0036] 8. The method according to any one of embodiments 1 to 7, wherein the two independent aripiprazole injections are administered at the patient's independent gluteal injection site.

[0037] 9. The method according to any one of embodiments 1 to 7, wherein the two independent aripiprazole injections are administered at the injection sites in the gluteal and deltoid muscles of the patient.

[0038] 10. The method according to any one of embodiments 1 to 7, wherein the two independent aripiprazole injections are administered at the independent deltoid injection site of the patient.

[0039] 11. The method according to any one of embodiments 1 to 10, wherein the patient suffers from schizophrenia.

[0040] 12. The method according to any one of embodiments 1 to 10, wherein the patient suffers from type I bipolar disorder.

[0041] 13. The method according to any one of embodiments 1 to 12, wherein the dose of the oral aripiprazole is about 10 mg to about 20 mg of aripiprazole.

[0042] 14. The method according to embodiment 13, wherein the dose of the oral aripiprazole comprises about 20 mg of aripiprazole.

[0043] 15. The method according to embodiment 13, wherein the dose of the oral aripiprazole comprises about 10 mg of aripiprazole.

[0044] 16. The method according to any one of embodiments 1 to 15, wherein the patient had not been stabilized by oral aripiprazole prior to the treatment.

[0045] 17. The method according to Embodiment 1, wherein the patient is an adverse metabolizer of CYP2D6 or is concurrently taking a CYP3A4 inhibitor or a CYP2D6 inhibitor for more than 14 days, the first injection contains 720 mg of aripiprazole, the second injection contains 400 mg or 300 mg of aripiprazole, and the single oral dose of aripiprazole contains about 10 mg or about 20 mg of aripiprazole.

[0046] 18. The method according to embodiment 17, wherein the patient is an adverse metabolizer of CYP2D6 or is concurrently taking a CYP3A4 inhibitor or a CYP2D6 inhibitor for more than 14 days, the first injection contains 720 mg of aripiprazole, the second injection contains 300 mg of aripiprazole, and the single oral dose of aripiprazole contains approximately 20 mg of aripiprazole.

[0047] 19. The method according to embodiment 1, wherein the first injection contains 960 mg of aripiprazole, the second injection contains 400 mg or 300 mg of aripiprazole, and the single oral dose of aripiprazole contains about 10 mg or about 20 mg of aripiprazole.

[0048] 20. The method according to embodiment 19, wherein the first injection contains 960 mg of aripiprazole, the second injection contains 400 mg of aripiprazole, and the single oral dose of aripiprazole contains about 20 mg of aripiprazole.

[0049] 21. A method for treating schizophrenia or type I bipolar disorder in a patient in need, the method comprising: administering to the patient two separate injections of aripiprazole and a single oral dose of aripiprazole, wherein the first injection comprises 960 mg or 720 mg of aripiprazole in a first long-acting injectable (LAI) formulation, and the second injection comprises 400 mg or 300 mg of aripiprazole in a second LAI formulation, the injection site being selected from the gluteal region, the deltoid region, and combinations thereof, wherein the administration steps are performed on the first day of aripiprazole LAI treatment, and wherein the oral dose of aripiprazole is about 10 mg to about 20 mg of aripiprazole; and continuing to administer a maintenance dose of the first LAI formulation comprising 960 mg or 720 mg of aripiprazole, wherein the maintenance dose is administered once every two months after the first day of aripiprazole LAI treatment.

[0050] 22. The method according to embodiment 21, wherein the first injection contains 960 mg of aripiprazole, the second injection contains 400 mg or 300 mg of aripiprazole, and the single oral dose of aripiprazole contains about 10 mg or about 20 mg of aripiprazole.

[0051] 23. The method according to embodiment 22, wherein the first injection contains 960 mg of aripiprazole, the second injection contains 400 mg of aripiprazole, and the single oral dose of aripiprazole contains about 20 mg of aripiprazole.

[0052] 24. The method according to embodiment 21, wherein the first injection contains 720 mg of aripiprazole, the second injection contains 400 mg or 300 mg of aripiprazole, and the single oral dose of aripiprazole contains about 10 mg or about 20 mg of aripiprazole.

[0053] 25. The method according to embodiment 24, wherein the first injection contains 720 mg of aripiprazole, the second injection contains 300 mg of aripiprazole, and the single oral dose of aripiprazole contains about 20 mg of aripiprazole.

[0054] 26. The method according to embodiment 21, wherein the dose of the oral aripiprazole comprises about 20 mg of aripiprazole.

[0055] 27. The method according to embodiment 21, wherein the approximately two months is 54 to 58 days.

[0056] 28. A long-acting injectable (LAI) comprising 960 mg or 720 mg of aripiprazole, a dose initiation method for treating aripiprazole in a patient in need, the method comprising: The patient was given two separate injections of aripiprazole and a single oral dose of aripiprazole. The first injection contained 960 mg or 720 mg of aripiprazole from a first-acting injectable (LAI) formulation, and the second injection contained 400 mg or 300 mg of aripiprazole from a second LAI formulation. The injection sites were selected from the gluteal, deltoid, or combinations thereof. The administration step is performed on the first day of aripiprazole LAI treatment.

[0057] 29. Use of aripiprazole in the preparation of a medicament for the treatment of schizophrenia or type I bipolar disorder, the treatment comprising: Administer two separate injections and a single oral dose of aripiprazole to patients in need. The first injection contains 960 mg or 720 mg of aripiprazole from a first-line long-acting injectable (LAI) formulation, and the second injection contains 400 mg or 300 mg of aripiprazole from a second-line LAI formulation. Injection sites may be selected from the gluteal, deltoid, or combinations thereof. The administration step is performed on the first day of aripiprazole LAI treatment.

[0058] 30. Use of aripiprazole for the treatment of patients with schizophrenia or type I bipolar disorder, wherein the aripiprazole is used to administer two separate injections and a single oral dose of aripiprazole to a patient in need, wherein the first injection comprises 960 mg or 720 mg of aripiprazole in a first long-acting injectable (LAI) formulation, and the second injection comprises 400 mg or 300 mg of aripiprazole in a second LAI formulation, the injection site being selected from the gluteal region, the deltoid region, or a combination thereof. The administration step is performed on the first day of aripiprazole LAI treatment.

[0059] 31. A medication kit equipped with a pre-filled syringe containing a long-acting injectable (LAI) of 960 mg or 720 mg aripiprazole, for dose initiation of aripiprazole treatment in a patient in need, the method comprising: The patient was given two separate injections of aripiprazole and a single oral dose of aripiprazole. The first injection contained 960 mg or 720 mg of aripiprazole from a first-acting injectable (LAI) formulation, and the second injection contained 400 mg or 300 mg of aripiprazole from a second LAI formulation. The injection sites were selected from the gluteal, deltoid, or combinations thereof. The administration step is performed on the first day of aripiprazole LAI treatment.

[0060] Aripiprazole dose-initiated treatment

[0061] This disclosure relates to a dose-initiation method for aripiprazole treatment in patients in need, the method comprising administering two separate aripiprazole injections and a single oral dose of aripiprazole on the first day of aripiprazole LAI treatment, wherein the first aripiprazole injection is a first long-acting injectable (LAI) formulation, and the second aripiprazole injection is a second LAI formulation (once-monthly injectable (AOM)). In this disclosure, this dose-initiation regimen is also referred to as “two-injection initiation.” This dose-initiation regimen provides comparable Ari RTU LAI PK exposure profiles to AOM, with longer dosing intervals. Maintenance dosing is administered once within approximately two months after the first day of aripiprazole LAI treatment using a maintenance dose of the LAI; for example, the maintenance dose is a single dose of 960 mg or 720 mg of the first aripiprazole LAI reservoir formulation over approximately two months thereafter. The alternative initiation regimen is applicable to both deltoid and gluteal muscle application sites.

[0062] This disclosure utilizes two separate aripiprazole injections and a single oral dose of aripiprazole, wherein the first injection comprises 960 mg or 720 mg of aripiprazole in a long-acting injectable (LAI) formulation, and the second injection comprises 400 mg or 300 mg of aripiprazole in a second LAI formulation (once-monthly (AOM) injection). For example, the method of this disclosure administers two separate LAI and AOM aripiprazole injections to the patient at separate gluteal and / or deltoid muscle injection sites, wherein the administration is performed on the first day of the LAI treatment. In some embodiments, the two separate LAI and AOM aripiprazole injections are administered at either a separate gluteal or deltoid muscle injection site in the patient. In another embodiment, the two separate LAI and AOM aripiprazole injections are administered at both the gluteal and deltoid muscle injection sites in the patient.

[0063] This disclosure also relates to a method of treating schizophrenia or type I bipolar disorder in patients in need, the method comprising: administering to the patient two separate injections of aripiprazole and a single oral dose of aripiprazole, wherein the first injection comprises 960 mg or 720 mg of aripiprazole in a first long-acting injectable (LAI) formulation, and the second injection comprises 400 mg or 300 mg of aripiprazole in a second LAI formulation (once-monthly (AOM) injection), the injection site being selected from the gluteal region, the deltoid region, and combinations thereof, wherein the administration steps are performed on the first day of aripiprazole LAI treatment; and continuing to administer a maintenance dose of the first LAI formulation comprising 960 mg or 720 mg of aripiprazole, wherein the maintenance dose is administered once every two months after the first day of aripiprazole treatment.

[0064] In this disclosure, aripiprazole treatment may exclude administration of oral aripiprazole to establish tolerance prior to the initiation of LAI treatment using an injection of 960 mg or 720 mg aripiprazole in a first long-acting injectable (LAI) formulation.

[0065] In some embodiments, the method of this disclosure includes administering the two separate aripiprazole injections at separate gluteal injection sites in the patient. In some embodiments, the method of this invention includes administering the two separate aripiprazole injections at both the gluteal and deltoid muscle injection sites in the patient. In some embodiments, the method of this disclosure includes administering the two separate aripiprazole injections at separate deltoid muscle injection sites in the patient.

[0066] In some embodiments, the method of this disclosure includes the patient having schizophrenia or bipolar I disorder. In some embodiments, the method of this disclosure includes the patient having schizophrenia. In some embodiments, the method of this disclosure includes the patient having bipolar I disorder.

[0067] In some implementations, on the day of initiation, two separate aripiprazole injections are administered at two different injection sites along with a 20 mg dose of oral aripiprazole. The first injection contains 960 mg or 720 mg of aripiprazole from a first long-acting injectable (LAI) formulation, and the second injection contains 400 mg or 300 mg of aripiprazole from a second LAI formulation (once-monthly (AOM) injection).

[0068] In some embodiments, when using the two-injection initiation method, it is preferable to inject into two different sites in two different muscles. It is preferable not to inject the two injections simultaneously into the same deltoid or gluteal muscle. For known aberrant CYP2D6 metabolizers, it is preferable to administer to two separate deltoid muscles or one deltoid and one gluteal muscle. It is preferable not to inject into both gluteal muscles.

[0069] In some embodiments, preferably, on the first day of treatment, a single injection of 960 mg or 720 mg of aripiprazole in a first long-acting injectable (LAI) formulation is administered to the gluteal muscle, a single injection of 400 mg or 300 mg of aripiprazole in a second LAI formulation (once-monthly (AOM) injection) is administered to the gluteal or deltoid muscle, and a single dose of 10 mg or 20 mg of aripiprazole is administered orally.

[0070] In some implementations, oral aripiprazole is not administered for 1 to 13 days after the first day of aripiprazole LAI treatment.

[0071] The rationale for selecting the dosage of the alternative initiation regimen is based on simulations from population pharmacokinetic (popPK) models. For example, previously developed and validated population pharmacokinetic (popPK) models characterizing plasma concentrations of aripiprazole after administration of oral aripiprazole or monthly intramuscular injection of aripiprazole (AOM) were extended to include the RTU LAI formulation of aripiprazole (Ari RTU LAI). Overall, 8899 aripiprazole pharmacokinetic (PK) samples from 1191 adults across 10 clinical trials were included in the final co-analysis dataset. Aripiprazole plasma concentration-time curves were simulated in 1000 virtual patients for various Ari RTU LAI initiation and maintenance scenarios. The final popPK model, incorporating data from oral aripiprazole, AOM, and Ari RTU LAI, was found to be well-fitting, with Ari RTU LAI absorption modeled via parallel zero-order and lag-first-order processes. Simulations were conducted across multiple scenarios to inform dosing recommendations, including various treatment initiation regimens for the Ari RTULAI formulation every two months in patients who were previously stable or unstable after oral aripiprazole and in patients switching from AOM. Other simulations considered missed / delayed dosing, CYP2D6 metabolic status, and concomitant use of CYP2D6 or CYP3A4 inhibitors. Overall, simulations across various scenarios indicated that the PK exposure profile of Ari RTU LAI was comparable to that of AOM, with longer dosing intervals.

[0072] The first long-acting injectable (LAI) formulation (Aripiprazole Long-Acting Injection (LAI))

[0073] In the method of this disclosure, the first injection comprises 960 mg or 720 mg of aripiprazole in a first long-acting injectable (LAI) formulation. In some embodiments, the first injection comprises 960 mg of aripiprazole in the first LAI formulation. In some embodiments, the first injection comprises 720 mg of aripiprazole in the first LAI formulation. Furthermore, the method of this disclosure includes administering a maintenance dose of the first LAI formulation. In some embodiments, the maintenance dose of the first LAI formulation comprises 960 mg or 720 mg of aripiprazole. In some embodiments, the maintenance dose comprises 960 mg of aripiprazole in the first LAI formulation. In some embodiments, the maintenance dose comprises 720 mg of aripiprazole in the first LAI formulation.

[0074] In some embodiments, the first LAI formulation comprises a composition containing aripiprazole, a specific suspending agent (suspending agent (A)), and a dispersion medium. For example, the injectable formulations of this disclosure contain at least water as a dispersion medium. Water or an aqueous solvent containing water and an organic solvent can be used as a dispersion medium containing at least water. In some embodiments, the dispersion medium is water, further for example, sterile water for injection.

[0075] The specific suspending agent (suspending agent A) contained in the first LAI formulation includes at least one suspending agent selected from (i) and (ii): (i) polyvinylpyrrolidone, and (ii) polyethylene glycol and carboxymethyl cellulose or salts thereof.

[0076] In some embodiments, the first LAI formulation comprises aripiprazole or a salt thereof, water, and at least one suspending agent selected from (i) and (ii): (i) polyvinylpyrrolidone, and (ii) polyethylene glycol and carboxymethyl cellulose or a salt thereof, wherein the aripiprazole or the salt thereof has an average primary particle size in the range of about 0.5 μm to about 30 μm, and the concentration of the aripiprazole or the salt thereof is in the range of about 200 mg / mL to about 600 mg / mL. The currently disclosed first LAI formulation, i.e., a two-month ready-to-use (RTU) or long-acting injectable (LAI) formulation, is described in U.S. Patent No. 10,517,951, the entirety of which is incorporated herein by reference. The injectable formulation of the LAI is, for example, a 720 mg sustained-release injectable suspension in a pre-filled Abilify Asimtufii®, Abilify Maintena®, or a 960 mg sustained-release injectable suspension in a pre-filled Abilify Maintena®.

[0077] For example, when the injectable formulation of this disclosure contains aripiprazole or a salt thereof (which may be referred to hereinafter as "the aripiprazole injectable formulation of this disclosure"), the concentration of aripiprazole or a salt thereof is in the range of about 200 mg / mL to about 600 mg / mL. (α) The first LAI formulation of said aripiprazole gels upon standing, which inhibits the precipitation and clumping of aripiprazole particles, thereby providing excellent storage stability. Furthermore, since (β) the injectable formulation readily acquires fluidity upon exposure to slight impact, even in gel form, the formulation can be easily injected at the time of use (injection). Moreover, since the gelled injectable formulation (gel composition) acquires fluidity (forms a sol state) by simply pressing the plunger of the syringe and ejecting the formulation through the injection needle, the formulation can be smoothly ejected through the needle as is. Therefore, the formulation can be thixotropic and can be well dispersed in muscles or subcutaneously with relatively little local disturbance and pain at the time of injection.

[0078] In other words, when the concentration of aripiprazole or its salts is 100 mg / mL or lower, even with the use of suspension A (or further aging treatment), an injectable formulation capable of forming a gel may not be produced. Therefore, the first LAI formulation of this disclosure comprises aripiprazole or its salts, using a specific suspension (suspension A) and a specific concentration of aripiprazole or its salts (about 200 mg / mL to about 600 mg / mL, for example, about 250 mg / mL to about 450 mg / mL and about 300 mg / mL to about 400 mg / mL). When the first LAI formulation of this disclosure comprises a salt of aripiprazole, the above concentrations are based on aripiprazole.

[0079] In some embodiments, the first LAI formulation comprises aripiprazole at a concentration of about 200 mg / mL to about 600 mg / mL, for example about 200 mg / mL to about 500 mg / mL, for example about 250 mg / mL to about 450 mg / mL, for example about 300 mg / mL to about 400 mg / mL, for example about 300 mg / mL.

[0080] In some embodiments, in the first LAI formulation of this disclosure, when polyvinylpyrrolidone is contained as suspending agent A, the concentration of polyvinylpyrrolidone is in the range of about 0.1 mg / mL to about 100 mg / mL, for example about 1 mg / mL to about 50 mg / mL, for example about 2 mg / mL to about 20 mg / mL.

[0081] In some embodiments, when the first LAI formulation of this disclosure comprises (i) polyvinylpyrrolidone as suspending agent A and further comprises one or more other suspending agents, at least one member selected from polyethylene glycol and carboxymethyl cellulose or salts thereof is included as one or more other suspending agents. For example, these injectable formulations of this disclosure comprise (i) polyvinylpyrrolidone as suspending agent A, and when they further comprise one or more other suspending agents, they comprise any combination of suspending agents shown below (i-1) to (i-3).

[0082] (i-1) Polyvinylpyrrolidone and polyethylene glycol; (i-2) Polyvinylpyrrolidone and carboxymethyl cellulose or their salts; and (i-3) Polyvinylpyrrolidone, polyethylene glycol and carboxymethyl cellulose or their salts.

[0083] Regardless of which combination of (i-1) to (i-3) is included in these injectable formulations of this disclosure, as described above, the concentration of polyvinylpyrrolidone is from about 0.1 mg / mL to about 100 mg / mL, for example from about 1 mg / mL to about 50 mg / mL, for example from about 2 mg / mL to about 20 mg / mL. In (i-1) or (i-3), the concentration of polyethylene glycol is from about 0.05 mg / mL to about 100 mg / mL, for example from about 0.1 mg / mL to about 50 mg / mL. In (i-2) or (i-3), the concentration of carboxymethyl cellulose or a salt thereof is from about 0.5 mg / mL to about 50 mg / mL, for example from about 1 mg / mL to about 30 mg / mL, for example from about 2 mg / mL to about 20 mg / mL.

[0084] By including carboxymethyl cellulose or its salts, the increase in viscosity during the production process can be suppressed. This allows aripiprazole or its salts to be efficiently pulverized to the desired particle size. In some embodiments, the molecular weight of carboxymethyl cellulose or its salts is in the range of 49,000 to 300,000. Furthermore, by including polyethylene glycol, dehydration shrinkage can be prevented even during long-term storage of the resulting injectable formulation. In some embodiments, the molecular weight of polyethylene glycol is in the range of 400 to 4,000. In some embodiments, (i-3) is present in the injectable formulation.

[0085] In some embodiments, the average molecular weight of carboxymethyl cellulose or its salts is, for example, 5,000 or greater, preferably 10,000 or greater, more preferably 20,000 or greater, more preferably 30,000 or greater, more preferably 40,000 or greater, and even more preferably 50,000 or greater. In other embodiments, the average molecular weight of carboxymethyl cellulose or its salts is, for example, 300,000 or less, preferably 250,000 or less, more preferably 200,000 or less, and even more preferably 150,000 or less. In other embodiments, the average molecular weight of carboxymethyl cellulose or its salts is, for example, 5,000 to 300,000, preferably 10,000 to 250,000, preferably 20,000 to 200,000, and even more preferably 50,000 to 150,000.

[0086] In some embodiments, a 2% (by weight / volume) aqueous solution of carboxymethyl cellulose or its salt has a viscosity of, for example, 1000. Or lower, preferably 800 Or lower. In other embodiments, the viscosity is, for example, 10. Or higher, preferably 50 Or higher. In other embodiments, the viscosity is, for example, 10 to 1000. Between 50 and 800 The viscosity can be measured according to the method described in USP-NF (e.g., USP42-NF37, 2019 edition).

[0087] In some embodiments, when the first LAI formulation of this disclosure comprises (ii) polyethylene glycol and carboxymethyl cellulose or a salt thereof as suspending agent A, the concentration of polyethylene glycol is from about 0.05 mg / mL to about 2 mg / mL, for example from about 0.1 mg / mL to about 1 mg / mL. In other embodiments, the concentration of carboxymethyl cellulose or a salt thereof is from about 0.5 mg / mL to about 50 mg / mL, for example from about 1 mg / mL to about 30 mg / mL, for example from about 2 mg / mL to about 20 mg / mL.

[0088] In some embodiments, when the first LAI formulation of this disclosure comprises (ii) polyethylene glycol and carboxymethyl cellulose or a salt thereof as suspending agent A, and further comprises one or more other suspending agents, polyvinylpyrrolidone may be included as said one or more other suspending agents. For example, the injectable formulation of this disclosure comprises (ii) polyethylene glycol and carboxymethyl cellulose or a salt thereof as suspending agent A, and when it further comprises one or more other suspending agents, it contains the suspending agent (i-3). In this case, the concentrations of polyethylene glycol, carboxymethyl cellulose or a salt thereof, and polyvinylpyrrolidone are the same as described in (i-3) above.

[0089] In some embodiments, in the first LAI formulation of this disclosure, when using the suspension of (i-3), the composition comprises about 0.5 mg / mL to about 20 mg / mL of polyvinylpyrrolidone, about 0.1 mg / mL to about 100 mg / mL of polyethylene glycol, about 0.5 mg / mL to about 50 mg / mL of carboxymethyl cellulose or a salt thereof, and about 250 mg / mL to about 450 mg / mL (e.g., about 300 mg / mL to about 400 mg / mL) of aripiprazole or a salt thereof. In this case, the polyethylene glycol may be polyethylene glycol 400 or polyethylene glycol 4000. In some embodiments, the polyvinylpyrrolidone has a K value of about 12 to about 20. In other aspects, the aripiprazole or a salt thereof has an average primary particle size of about 1 μm to 10 μm.

[0090] Because an excessively large average primary particle size of the aripiprazole or its salts may lead to precipitation, the average primary particle size is in the range of about 0.5 μm to about 30 μm, for example, about 1 μm to about 20 μm. When the injectable formulation of this disclosure is taken in a dosage form administered every two months, the aripiprazole or its salts have an average primary particle size of about 1 μm to about 50 μm, for example, about 1 μm to about 10 μm, for example, about 2 μm to about 5 μm. The average secondary particle size is up to but does not exceed three times the average primary particle size, for example, up to but does not exceed twice it.

[0091] In some embodiments, the first LAI formulation of this disclosure is suitably formulated into a dosage form that can be administered once every two months. For example, the concentration of aripiprazole or a salt thereof in the first LAI formulation of this disclosure administered once every two months is from about 200 mg / mL to about 600 mg / mL, for example from about 250 mg / mL to about 500 mg / mL, for example from about 300 mg / mL to 400 mg / mL, for example from about 300 mg / mL. When the injectable formulation is administered once every two months, the dose volume is from about 2 mL to about 4 mL, for example from about 2.2 mL to about 3.5 mL, for example from about 2.3 mL to about 3.4 mL, for example from about 3.2 mL.

[0092] In some embodiments, the first LAI formulation of this disclosure achieves the aforementioned effects (α) and (β). They may be in gel form or may have fluidity (i.e., they may be in sol form). As stated above, the achievement of effects (α) and (β) can be objectively verified using a rotational rheometer. The first LAI formulation can be formulated as a pre-filled sol-gel forming injection (also referred to herein as a "pre-filled sol-gel forming injection"). This injection formulation is thixotropic. Furthermore, the formulation may be in gel form when at rest and may transform into a sol upon impact.

[0093] In some embodiments, the method of preparing the first LAI formulation includes preparing a liquid mixture of the starting materials and pulverizing the aripiprazole or its salt contained in the liquid mixture to a desired average primary particle size, optionally followed by aging.

[0094] In some aspects, a method for preparing a gel-based first LAI formulation according to the invention comprises allowing a liquid mixture to stand at 5 to 70°C for 5 minutes or longer, said liquid mixture comprising aripiprazole or a salt thereof at a concentration of about 200 mg / mL to about 600 mg / mL and an average primary particle size of about 0.5 μm to about 30 μm, water, and at least one suspending agent selected from (i) and (ii): (i) polyvinylpyrrolidone and (ii) polyethylene glycol and carboxymethyl cellulose or a salt thereof.

[0095] For example, in some other embodiments, a preparation method comprising the steps of: pulverizing aripiprazole or its salt to an average primary particle size of about 0.5 μm to about 30 μm in a liquid mixture comprising aripiprazole or its salt at a concentration of about 200 mg / mL to about 600 mg / mL, water, and at least one suspending agent selected from (i) and (ii): (i) polyvinylpyrrolidone and (ii) polyethylene glycol and carboxymethyl cellulose or its salt; and allowing the pulverized liquid mixture to stand at 5°C to 70°C for 5 minutes or longer.

[0096] In some embodiments, this disclosure includes administering the first LAI formulation resulting in a total dose of aripiprazole administered to the patient of 960 mg or 720 mg, for example 960 mg, further for example 720 mg, wherein the injectable formulation may optionally be administered in one or more fractions. In some other embodiments, administering the first LAI formulation results in a total dose of aripiprazole administered to the patient of about 960 mg, wherein the injectable formulation may be administered in one or more fractions. For example, to obtain a total dose of 960 mg of aripiprazole to be administered to the patient, one (1) injection of the first LAI formulation comprising 960 mg / mL aripiprazole is administered. The 960 mg dose may optionally be administered in separate injections at short intervals. In some embodiments, the first injection comprises 960 mg of aripiprazole. In some embodiments, administering the first LAI formulation results in a total dose of aripiprazole administered to the patient of about 720 mg, wherein the injectable formulation may be administered in one or more fractions. For example, to obtain a total dose of 720 mg aripiprazole to be administered to the patient, one (1) injection of a first LAI formulation containing 720 mg / mL aripiprazole is administered. In some embodiments, the first injection contains 720 mg aripiprazole. The 720 mg dose may optionally be administered in separate injections at short intervals. As described above, the number of aripiprazole injections and the concentration vary depending on the total dose of aripiprazole to be administered and the concentration of aripiprazole contained in each injectable formulation.

[0097] In some embodiments, the administration of the first LAI formulation to the subject is by intramuscular injection. In some embodiments, intramuscular administration is performed at a site selected from the deltoid, gluteal, and combinations thereof. In some embodiments, the site is the gluteal muscle. For example, depending on the number of injections used for administration, the injection sites may cover various locations in the deltoid and / or gluteal muscles.

[0098] In some embodiments, maintenance dosing is administered once with a maintenance dose of the first LAI formulation approximately two months after the first day of aripiprazole LAI treatment; for example, a maintenance dose of 960 mg or 720 mg of the first LAI formulation is administered once within approximately two months thereafter. Similar to conventional dose-initiation protocols, these alternative initiation protocols apply to both deltoid and gluteal muscle application sites. For example, the method of administering the first LAI formulation of aripiprazole disclosed herein is performed approximately every two months. In some embodiments, the first LAI formulation is administered approximately every 42 to 70 days or at any integer between these and including the endpoints, such as every 49 to 63 days, for example every 50 to 60 days, i.e., every 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, or 62 days. In other aspects, the first LAI formulation is administered approximately every 56 days, for example, every 54 to 58 days. In other respects, the first LAI formulation is administered approximately every 8 weeks, for example, every 6 to 10 weeks. In some embodiments, the maintenance dose is 960 mg of the first LAI formulation. In some embodiments, the maintenance dose is 720 mg of the first LAI formulation.

[0099] In some embodiments, this disclosure further specifies that when the patient is an adverse metabolizer of CYP2D6 or is concurrently taking a CYP3A4 inhibitor or a CYP2D6 inhibitor for more than 14 days, the maintenance dose of the first LAI formulation is 720 mg aripiprazole.

[0100] In some embodiments, the first LAI formulation of this disclosure can be filled into a syringe as is, serving as a pre-filled syringe. This simplifies the syringe's construction and reduces its size and weight. In some embodiments, the first LAI formulation contains 960 mg of aripiprazole in the pre-filled syringe. In some embodiments, the first LAI formulation contains 720 mg of aripiprazole in the pre-filled syringe. In another embodiment, when the first LAI formulation of this disclosure is filled into a syringe, the sol suspension can be administered by simply pressing the plunger rod of the syringe and spraying the first LAI formulation of this disclosure through the injection needle. This provides a pre-filled syringe that offers clinical convenience and operability, and is therefore very useful in medicine and industry. One example of producing such a pre-filled syringe is to produce the first LAI formulation as described above, pre-fill the syringe with the formulation, and then allow it to stand as described above to allow the first LAI formulation to gel.

[0101] In some embodiments, the first LAI formulation comprises a dose strength of 720 mg or 960 mg in a pre-filled syringe, and said strength is calculated based on the anhydrous form (aripiperazole). The concentration of aripiprazole is from 200 mg / mL to 600 mg / mL. In some embodiments, the inactive ingredients are sodium carboxymethyl cellulose (0.5 mg / mL to 50 mg / mL), polyethylene glycol 400 (0.05 mg / mL to 2 mg / mL), povidone (0.1 mg / mL to 100 mg / mL), sodium chloride (0.1 mg / mL to 50 mg / mL), sodium dihydrogen phosphate monohydrate (0.1 mg / mL to 10 mg / mL), sodium hydroxide (for pH adjustment), and water for injection (qs).

[0102] In some embodiments, the first LAI formulation comprises a dose strength of 720 mg or 960 mg in a pre-filled syringe, and said dose strength is calculated based on the anhydrous form (aripiperazole). The inactive ingredients are sodium carboxymethyl cellulose (5 mg / mL), polyethylene glycol 400 (1 mg / mL), povidone (4 mg / mL), sodium chloride (6.1 mg / mL), sodium dihydrogen phosphate monohydrate (0.74 mg / mL), sodium hydroxide (for pH adjustment), and water for injection (qs). In some embodiments, the first LAI formulation comprises a dose strength of 960 mg of aripiprazole in a pre-filled syringe with a volume of approximately 3.2 mL. In some embodiments, the first LAI formulation comprises a dose strength of 720 mg of aripiprazole in a pre-filled syringe with a volume of approximately 2.4 mL.

[0103] In some embodiments, this disclosure also includes a cartridge equipped with the aforementioned pre-filled syringe.

[0104] The second LAI formulation (aripiperazole once-monthly injection (AOM))

[0105] In the method disclosed herein, the second injection comprises 400 mg or 300 mg of aripiprazole in a second LAI formulation (once-monthly (AOM) injection). In some embodiments, the second injection comprises 400 mg of aripiprazole in the second LAI formulation (AOM injection). In some embodiments, the second injection comprises 300 mg of aripiprazole in the second LAI formulation (AOM injection).

[0106] In some embodiments, the intramuscular reservoir formulation of aripiprazole comprises aripiprazole monohydrate; the aripiprazole monohydrate is 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydroquinolinone monohydrate.

[0107] For example, in some embodiments, the second injection is an intramuscular (IM) reservoir formulation of aripiprazole, which is a delayed-release injection suspension in a 400 mg or 300 mg strength pre-filled dual-lumen syringe and a 400 mg or 300 mg strength vial. In some embodiments, the second injection containing 400 mg or 300 mg of aripiprazole in a second LAI formulation (once-monthly (AOM) injection) comprises lyophilized powder or lyophilized cake for the injection suspension. The strength of the label is calculated based on the anhydrous form (ariripiprazole). In some embodiments, the inactive ingredients (per dose) of the 400 mg and 300 mg strength products comprise, respectively, sodium carboxymethyl cellulose (16.64 mg and 12.48 mg), mannitol (83.2 mg and 62.4 mg), sodium dihydrogen phosphate monohydrate (1.48 mg and 1.11 mg), and sodium hydroxide (pH adjuster). In other embodiments, the extended-release injection suspension in the 400 mg or 300 mg strength pre-filled dual-lumen syringe and the 400 mg or 300 mg strength vial can be used for dose adjustment; that is, in patients who are poor metabolizers of CYP2D6 and patients who are concurrently taking CYP3A4 inhibitors or CYP2D6 inhibitors. For patients taking CYP2D6 inhibitors, CYP3A4 inhibitors, or CYP3A4 for more than 14 days, dose adjustments of 200 mg and 160 mg can be obtained by intramuscular injection into the deltoid or gluteal muscles using 300 mg or 400 mg strength vials. Abilify Maintena®, a currently disclosed second LAI formulation (aripiperazole IM reservoir formulation) for suspension in extended-release form, is described in U.S. Patent Nos. 7,807,680, 8,030,313, 8,338,427, 8,338,428, 8,399,469, 8,722,679, 8,759,351, 8,993,761, 9,089,567, and 10,525,057; all of these patents are incorporated herein by reference in their entirety.

[0108] In some embodiments, the activity of the intramuscular reservoir formulation of aripiprazole may be primarily attributed to the parent drug aripiprazole and to a lesser extent to its major metabolite dehydroaripiprazole, which has been shown to have a similar affinity for the D2 receptor to the parent drug and accounts for approximately 29% of the parent drug exposure in plasma.

[0109] Due to the low solubility of aripiprazole particles, absorption into the systemic circulation of aripiprazole after intramuscular injection is slow and prolonged. Following single-dose administration of the intramuscular reservoir formulation of aripiprazole to the deltoid and gluteal muscles, the extent of absorption (AUCt, AUC∞) at both injection sites was similar, but the absorption rate (Cmax) at the deltoid site was 31% higher than that at the gluteal site. However, at steady state, the AUC and Cmax at both injection sites were similar. Following multiple intramuscular administrations, plasma concentrations of aripiprazole gradually increased to maximum plasma concentrations, with a median Tmax of approximately 5–7 days for the gluteal muscle and approximately 4 days for the deltoid muscle. Following intramuscular administration to the gluteal muscle, after multiple injections of 300 mg and 400 mg of the intramuscular reservoir formulation of aripiprazole every 4 weeks, the mean apparent terminal elimination half-life of aripiprazole was approximately 29.9 days and 46.5 days, respectively. For both administration sites, typical subject-level steady-state concentrations were reached by the fourth dose. Following injections of 300 mg and 400 mg aripiprazole intramuscular reservoir formulations every four weeks, an approximately dose-proportional increase in aripiprazole and dehydroaripiprazole exposure was observed.

[0110] Aripiprazole is primarily eliminated through hepatic metabolism, involving two P450 isoenzymes, CYP2D6 and CYP3A4. Aripiprazole is not a substrate of enzymes such as CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2E1. Aripiprazole also does not undergo direct glucuronidation.

[0111] Aripiprazole oral preparations

[0112] In some embodiments, the method of this disclosure includes administering a single dose of oral aripiprazole. In some embodiments, the dose of oral aripiprazole is about 10 mg to about 20 mg. In some embodiments, the dose of oral aripiprazole is 20 mg. In some embodiments, the dose of oral aripiprazole is 10 mg. In some embodiments, the method is administered when the patient is stable, or has not been, with oral aripiprazole prior to the treatment. In some embodiments, the method is administered when the patient is stable with oral aripiprazole prior to the treatment. In some embodiments, the method is administered when the patient has not been stable with oral aripiprazole prior to the treatment.

[0113] In some embodiments, aripiprazole oral tablets may be available in strengths such as 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg. Inactive ingredients in the oral tablets include, for example, corn starch, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. Colorants may include, for example, iron oxide (yellow or red) and FD&C Blue 2 aluminum lake.

[0114] Aripiprazole is well absorbed after tablet administration, with peak plasma concentrations occurring, for example, within 3 to 5 hours; the absolute oral bioavailability of the tablet formulation is approximately 87%. Aripiprazole oral tablets can be administered with or without food. For example, administration of 15 mg aripiprazole oral tablets with a standard high-fat diet does not significantly affect the Cmax or AUC of aripiprazole or its active metabolite dehydroaripiprazole, but delays the Tmax of aripiprazole by 3 hours and that of dehydroaripiprazole by 12 hours.

[0115] Aripiprazole is primarily metabolized via three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for the dehydrogenation and hydroxylation of aripiprazole, while N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the major drug component in systemic circulation. At steady state, the active metabolite dehydroaripiprazole accounts for approximately 40% of the plasma AUC of aripiprazole.

[0116] Following a single oral administration of [14C]-labeled aripiprazole, approximately 25% and 55% of the administered radioactivity were recovered in urine and feces, respectively. Less than 1% of the unchanged aripiprazole was excreted in urine and approximately 18% of the oral dose was recovered unchanged in feces.

[0117] This disclosure utilizes aripiprazole oral tablets, wherein a single oral dose is selected from about 10 mg to about 20 mg, for example, a single oral dose of 10 mg, 15 mg, and 20 mg aripiprazole. In some embodiments, the single oral dose is about 10 mg to about 20 mg aripiprazole, for example, about 20 mg aripiprazole. In some embodiments, the single oral dose is selected from 10 mg and 20 mg aripiprazole. In other embodiments, the single oral dose is 20 mg aripiprazole. In some embodiments, the single oral dose is 10 mg aripiprazole.

[0118] In some embodiments, this disclosure relates to a method comprising the patient being an adverse metabolizer of CYP2D6 or concurrently taking a CYP3A4 inhibitor or a CYP2D6 inhibitor for more than 14 days, wherein the first injection comprises 720 mg of aripiprazole, the second injection comprises 300 mg of aripiprazole, and the single oral dose of aripiprazole comprises about 20 mg of aripiprazole.

[0119] In some embodiments, this disclosure relates to a method comprising the first injection containing 960 mg of aripiprazole, the second injection containing 400 mg of aripiprazole, and the single oral dose of aripiprazole containing about 20 mg of aripiprazole.

[0120] [Example]

[0121] Development of population pharmacokinetic models

[0122] Source data

[0123] PK data from 10 clinical trials were used to develop popPK models. Data on oral aripiprazole and AOM injected at the gluteal or deltoid sites were derived from previously developed and validated popPK models as described by Wang et al. [Wang et al., 2021]. These previously developed models used data from healthy adults (n=52) or adult patients with schizophrenia (n=765) from four phase 1 trials, two phase 1b trials, and one phase 3 trial. These previous models were extended to include data from aripiprazole RTU LAI formulations from three clinical trials involving 374 patients with schizophrenia or BP-I. In these three trials, 240 patients received at least one dose of Ari RTU LAI. In total, the final meta-analysis dataset included 1191 individuals with 8899 aripiprazole concentration samples.

[0124] Model Development

[0125] As mentioned above, the popPK model development started with previous popPK models of oral aripiprazole and AOM. In short, it is a 3-compartment model with linear elimination, S-type absorption (zero order, then first order) after oral administration, and first-order absorption of the AOM formulation. Covariate effects included: the effect of CYP2D6 metabolic status on apparent clearance (CL / F); the effect of co-administration of strong inhibitors of CYP2D6 or CYP3A4 on clearance; and the effects of sex and body mass index (BMI) on the first-order absorption rate constant (Ka) of the AOM formulation. PK data for the Ari RTU LAI formulation were added to the analysis, and the Ari RTU LAI formulation-specific absorption compartment was added to the model. Covariate effects from previous oral aripiprazole and AOM models were retained, while other covariates (i.e., injection site and volume) related to the absorption and relative bioavailability of the Ari RTU LAI formulation were explored. Age, sex, and BMI were assessed as standard demographic variables. As a first step, the potential relationships were investigated graphically by plotting individual random effects against covariates (scatter plots of continuous covariates and side-by-side box plots of categorical covariates). Next, formal testing of the effects of the potential covariates on the absorption parameters of the Ari RTU LAI formulation involved a modified stepwise approach using positive selection of all statistically significant variables in univariate analysis (p < 0.01 threshold [minimum difference of the objective function (ΔMVOF) for 1 degree of freedom (df)). 6.63]) and standard stepwise reverse elimination (p < 0.001 threshold [ΔMVOF for 1 df] [10.83]). The relationship between PK parameters and continuous covariates was evaluated using a power function, while the relationship between PK parameters and categorical covariates was evaluated using a proportional function.

[0126] Model Evaluation

[0127] The goodness of fit of the final model was evaluated using standard diagnostic plots (e.g., observed concentrations relative to population predictions [PRED], observed concentrations relative to individual predictions, conditionally weighted residuals [CWRES] relative to PRED, and time after the first dose). The predictive performance of the final model was evaluated using the Visual Prediction Check (VPC) by simulating 500 replicates of the comprehensive dataset. If significant categorical covariate effects were identified in the final model, simulations were performed to visualize these effects on the concentration-time curves after repeated administrations of Ari 2MRTU 960.

[0128] Bioanalytical methods

[0129] Aripiprazole plasma concentrations were determined using a validated high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS / MS) method in all ten studies. Linear calibration curves were used, with calibration ranges varying across studies as follows: 1–250 ng / mL in studies 31-98-206, 31-98-207, and CN138020; 0.5–250 ng / mL in studies 31-05-244 and 31-07-246; and 0.5–500 ng / mL in studies 31-11-290, 31-12-298, 031-201-00104, 031-201-00181, and 031-201-00279.

[0130] Population pharmacokinetic model simulation

[0131] Multiple simulations were performed after the final PopPK model was developed to explore various aspects of Ari RTU LAI dosing. This included a variety of treatment initiation scenarios, including switching from AOM 400, prior stabilization with oral aripiprazole 10 mg, 20 mg, or 30 mg, and no prior stabilization with oral aripiprazole. For each initiation scenario, two initiation strategies were considered: a first dose of Ari RTU LAI overlapping with 14 days of oral aripiprazole 10 mg or 20 mg, or a two-injection initiation (one dose of Ari 2MRTU 960 and one dose of AOM 400 at separate injection sites on day 1 of treatment, combined with a single oral dose of aripiprazole 20 mg). Other simulations included: missed / delayed dosing (to assess the impact of non-compliance as defined by different scenarios, with Ari 2MRTU 960 dosing delayed by 2, 4, 6, and 8 weeks); CYP2D6 metabolizer status (to assess lower doses in CYP2D6 poor metabolizers); and drug interactions (to assess lower doses when used in combination with strong CYP2D6 or CYP3A4 inhibitors). For comparison, initiation scenarios using Ari RTU LAI 960, Ari RTU LAI 960, and oral aripiprazole were simulated.

[0132] For the simulation, a population of 1000 virtual patients was created. Individual PK parameters for the virtual patients were derived from patient covariates and random effects according to the popPK model and used to simulate individual PK curves for each dosing scenario. Model covariates (i.e., sex, BMI, and CYP2D6 metabolizer status, as included in the popPK model) were assigned to the virtual patients by resampling from the total patient population (n=1191) used to develop the final popPK model. To best reflect the target patient population, random effects and covariates were resampled from individuals with the most relevant and robust information for each parameter of interest. The virtual patient population remained constant in almost all simulation scenarios, including a mixture of normal and poor CYP2D6 metabolizers obtained through the resampling procedure, with poor metabolizers comprising approximately 5% of the population. The only exception was a scenario requiring all patients to be either normal or poor CYP2D6 metabolizers; in this case, the status of the entire virtual patient population changed accordingly. For simulations involving AOM, the administration site was the gluteal muscle to allow for easier comparison with Ari RTU LAI administered only to the gluteal muscle.

[0133] The simulation results were presented graphically by plotting the median over time, with a reference line added to mark certain concentration levels of interest (i.e., for ease of interpretation of the results and comparison between different plots). This included 95 ng / mL (the plasma concentration identified as the lower threshold for efficacy in preventing impending relapse); this was based on an exposure-response model analysis using the AOM 400, which indicated schizophrenia and predicted the lowest aripiprazole concentration (Cmin). Patients with a Cmin < 95 ng / mL were 4.41 times less likely to relapse than those with a Cmin < 95 ng / mL [Wang et al., 2022]. Furthermore, the value of 95 ng / mL was consistent with 94 ng / mL, which is the median of the steady-state lowest oral aripiprazole plasma concentration (Cmin, ss) after 10 mg of oral aripiprazole (i.e., the lowest daily dose considered effective for treating schizophrenia in adults) [Salzman et al., 2017; Abilify Prescription Information, 2020]; it is also roughly similar to treatment thresholds of up to 100–120 ng / mL reported by other researchers [Hiemke et al., 2018; Meyer and Stahl, 2021; Hart et al., 2022]. A reference line indicating a maximum simulated steady-state concentration [Cmax, ss] of 534 ng / mL was also included.

[0134] A rich PK curve was simulated by sampling the concentration every 2 hours within 24 hours after oral administration and every 24 hours after administration of AOM or Ari RTU LAI.

[0135] Software and tools

[0136] The popPK model was developed using nonlinear mixed-effects modeling software (NONMEM v7.4.2; IconDevelopment Solutions, Ellicott City, MD, USA). Estimation was performed using a first-order conditional estimation method with interactions; if satisfactory convergence was not achieved, estimation was performed using stochastic approximation of expectation-maximization, followed by importance sampling to evaluate the mean volatile organic compound (MVOF). Data preparation, graphical analysis, model diagnostics, and statistical summarization were performed using R (v4.0.5 and later; R Foundation for Statistical Computing, Vienna, Austria) and RStudio (v1.2.5042 and later; RStudio, Inc.). All simulations were performed using Pumas (v2.0; Pumas-AI, Inc., Centreville, VA, USA).

[0137] Results: Development of population pharmacokinetic models

[0138] Basic Model

[0139] As a first step, the previous model (characterizing plasma aripiprazole concentrations after oral aripiprazole or AOM) was externally validated using new AOM 400 data from Study 031-201-00181. The previous model was able to characterize the new data well, although slight overprediction was observed in the CWRES vs. time plot and CWRES vs. population prediction plot at treatment initiation (data not shown).

[0140] After adding PK data for the Ari RTU LAI formulation to the input file, the best-fit model for the data was a 3-compartment model with linear elimination, as well as different absorption models for oral, AOM, and Ari RTU LAI formulations. Figure 1 ).

[0141] exist Figure 1 middle, The values ​​differ for the Ari RTU LAI formulation. Figure 1 The following abbreviations are used: AOM 400 is aripiprazole 400 mg once a month; Ari is aripiprazole; CL / F is apparent clearance; Frel,AOM It is the relative bioavailability of the AOM formulation; F rel,LAI This refers to the relative bioavailability of the Ari RTU LAI formulation; K a,三角肌 It is the absorption rate constant of the AOM formulation at the deltoid muscle site; K a,臀肌 K is the absorption rate constant of the AOM formulation at the gluteal muscle site; a,LAI K is the absorption rate constant of the Ari RTU LAI formulation; a,口服 is the absorption rate constant of the oral formulation; LAI is the long-acting injectable formulation; Q1 / F is the apparent intercompartmental clearance 1; Q2 / F is the apparent intercompartmental clearance 2; RTU is the ready-to-use formulation; Vc / F is the apparent central volume; Vp1 / F is the apparent volume 1 in the peripheral compartment; Vp2 / F is the apparent volume 2 in the peripheral compartment.

[0142] The absorption of Ari RTU LAI formulations is modeled using parallel zero-order and lag-based first-order processes, which explain the inherently complex absorption process of LAI. The absorption of Ari RTU LAI formulations is determined by the total dose fraction absorbed via the first-order process rather than the zero-order process (FRAC1), the zero-order absorption duration (DUR0), the lag at the start of the first-order process (LAG1), and the absorption rate constant of the first-order process (K). a RTU) and the bioavailability of Ari RTU LAI formulation relative to oral formulation (F 相对 The RTU was parameterized. Except for the apparent central volume (which differs for the RTU LAI formulation and other formulations of aripiprazole), all other configuration parameters (i.e., apparent clearance and peripheral volume) were shared between the formulations and remained fixed at values ​​from the previous model.

[0143] Covariate analysis (and retained covariates)

[0144] Univariate analysis revealed that the injection site had an effect on K. a RTU, gender pairing K a The effects of RTU and sex on FRAC1 were statistically significant and continued to be used. Injection site effect on K a The effects of RTU were removed from the final covariate model because only a small number of injections were administered at the deltoid site (the intended injection site for Ari 2MRTU 960 or Ari 2MRTU 720 is the gluteal muscle), and in the sensitivity analysis, the parameter estimates of the baseline model without deltoid injection data were very similar to those of the baseline model with all data. Therefore, only the sex-related effects on FRAC1 and K were retained in the final covariate model. a The effects of RTU were not removed during the reverse elimination step.

[0145] Final Model

[0146] The parameter estimates for the final model are shown in Table 1; unfixed parameters are estimated with a relative standard error percentage (% RSE) of <15%.

[0147] Table 1: Pharmacokinetic parameters of the final aripiprazole population pharmacokinetic model

[0148] [Table 1]

[0149] AOM, aripiprazole once a month; Ari, aripiprazole; BMI, body mass index; CV, coefficient of variation; CYP, cytochrome P450; K a , First-order absorption rate constant; LAI, Long-acting injection; NA, Not applicable; RSE, Relative standard error; RTU, Ready-to-use; SD, Standard deviation.

[0150] According to the final model, for a typical individual, the first peak concentration of the Ari RTU LAI formulation occurred 6.75 days (162.1 hours) after administration. The fractions of absorption via first-order and zero-order processes were 79.3% and 20.7% in women, and 62.7% and 37.3% in men, respectively. First-order absorption began after a lag period of 17.5 days (419 hours). In women, K... a The rate is 0.00127 per hour, corresponding to an absorption half-life of 22.7 days. In males, K... a The absorption half-life is 0.00242 per hour, corresponding to an absorption half-life of 11.9 days. Following the first dose, the second peak occurred at day 41 in typical women and day 32 in typical men. At steady state, the second peak occurred at day 33 in typical women and day 28 in typical men. The F of the Ari RTU LAI formulation relative to the oral formulation... 相对 It is 1.58, relative to the F of the AOM formulation. 相对 It is 1.06.

[0151] Effects of covariates

[0152] Regarding the retained covariates, K in males a RTU (Rate of Absorption) was 90.7% higher in men than in women, while FRAC1 (First-Order Fraction of Absorption) was 56.0% lower in men than in women.

[0153] Typical p-value curves for the combination of covariates of interest were simulated, with all other covariates fixed at their reference values ​​and all random effects fixed at zero. These were plotted on the same graph for visual comparison over 48 weeks (i.e., six consecutive administrations of Ari 2MRTU 960 at 8-week intervals), and the steady-state mean concentrations (C0.05) of different covariate classes were compared. avg,ss C max,ss and C min,ss Since CYP2D6 metabolizer status was identified as a covariate of aripiprazole CL / F in previous models and was retained in the current analysis, simulations were performed separately for adverse and normal CYP2D6 metabolizers. The effect of sex on aripiprazole exposure parameters (CL) based on CYP2D6 metabolizer status was confirmed after repeated administration of Ari 2MRTU 960 until steady state (20 doses). avg,ss C max,ss and C min,ss The simulation results of the effects of the retained covariates are shown in Table 2, while the graphical evaluation of the effects of the retained covariates is shown in Table 3. Figure 2 middle. Figure 2 The following abbreviations are used: Ari 2MRTU 960 is aripiprazole ready-to-use for two months, 960 mg; CYP is cytochrome P450.

[0154] Although men had higher peak aripiprazole concentrations (12% higher in normal metabolizers and 6% higher in poor metabolizers) and lower trough aripiprazole concentrations (22% lower in normal metabolizers and 10% lower in poor metabolizers) compared to women, no C was observed between sexes. avg,ss The difference was observed. As expected, simulated aripiprazole concentrations were higher in CYP2D6 adverse metabolizers compared to normal metabolizers; according to the simulated data (Table 2), C in CYP2D6 adverse metabolizers was significantly higher. avg,ss It is approximately twice that of normal metabolizers (97.4%).

[0155] Table 2. Typical aripiprazole exposure parameters under simulated steady-state conditions after repeated administration of Ari 2MRTU 960, based on CYP2D6 metabolizer status and sex.

[0156] [Table 2]

[0157] Ari 2MRTU 960, aripiprazole ready-to-use formula 960 mg; C avg,ss steady-state average concentration; C max,ss Steady-state highest concentration; C min,ss , steady-state minimum concentration; CYP, cytochrome P450.

[0158] Figure 3 The standard goodness-of-fit diagnostic plot of the final model is shown; overall, the final model adequately describes the concentration of aripiprazole after administration of the Ari RTU LAI formulation. The slight overestimation at treatment initiation noted in external validation of previous models using AOM 400 data from Study 031-201-00181 is not present in the fit of the final model.

[0159] exist Figure 3 In the diagram, circles represent observed data. The solid black line in the top plot represents a uniform line. The solid black line in the bottom plot represents a zero intercept. A black dashed line with conditionally weighted residuals equal to ±4 is provided as a reference line to check for potential outliers. The gray dashed line represents a scatter plot smoother for local estimates. The abbreviation AOM stands for aripiprazole once monthly; Ari RTULAI stands for aripiprazole ready-to-use long-acting injectable.

[0160] Based on predictive corrected VPC (pcVPC) and nonparametric VPC, the predictive performance of the model is considered sufficient. Overall, pcVPC demonstrates good predictive performance of the final model. Figure 4 This is evidenced by the fact that the distribution of the observed data is comparable to the 90% prediction range of a single forecast.

[0161] exist Figure 4 In the diagram, dashed lines represent observed data (median; 5th and 95th percentiles, black). Solid lines represent simulated data (median; 5th and 95th percentiles, black). Shaded areas represent the 95% confidence interval for the simulated median and the 5th and 95th percentiles. The abbreviation AOM stands for aripiprazole once monthly, and Ari RTU LAI stands for aripiprazole ready-to-use long-acting injectable.

[0162] The final popPK model was used to simulate the aripiprazole plasma concentration-time curve as a means of exploring various aspects of Ari2MRTU administration, reflecting a variety of scenarios that may occur in clinical practice.

[0163] Treatment initiation

[0164] In various treatment initiation scenarios, Ari 2MRTU 960 resulted in plasma aripiprazole concentrations comparable to AOM 400. This applies to situations where Ari 2MRTU 960 is initiated after switching from AOM 400. Figure 5 A); In patients previously stabilized by oral aripiprazole 10 or 20 mg / day, Ari 2MRTU 960 was initiated with 14 days of overlap oral aripiprazole (A); Figure 5B and 5C); In patients who have not previously been stabilized by oral aripiprazole, initiate Ari 2MRTU 960 plus 14 days of overlap with oral aripiprazole (B and 5C). Figure 5 D and 5E); In patients previously stabilized by oral aripiprazole 20 mg / day, Ari 2MRTU 960 was initiated on day 28 following AOM 400 administration on day 0, followed by 14 days of overlap with oral aripiprazole (D and 5E); Figure 5 F); and in patients who had not previously been stabilized by oral aripiprazole, Ari2MRTU 960 was initiated on day 28 after administration of AOM 400 on day 0, followed by 14 days of overlap with oral aripiprazole 20 mg / day. Figure 7 ). Figure 7 This is a simulated median aripiprazole concentration-time curve plotted on day 28 after AOM administration of Ari 2MRTU 960 (overlapped with oral aripiprazole 20 mg in patients who had not previously been stabilized by oral aripiprazole). For comparative purposes, Figure 7 The solid black line represents the simulated results for the same patients treated with AOM 400 on days 28 and 56. The reference line represents the plasma concentration (95 ng / mL) identified as the threshold of efficacy for preventing impending relapse, and the simulated C-value after daily oral administration of aripiprazole 30 mg. max,ss The 75th percentile (534 ng / mL).

[0165] exist Figure 5 In A-5F, for comparative purposes, each graph includes a solid black line representing the simulated outcome of the same patient treated with AOM 400 (with the same oral overlap in relevant cases). The reference line represents the plasma concentration (95 ng / mL) identified as the threshold of efficacy for preventing impending relapse, and the simulated C after daily oral administration of aripiprazole 30 mg. max,ss The 75th percentile (534 ng / mL). The abbreviation AOM 400 is aripiprazole 400 mg once monthly; Ari 2MRTU 960 is aripiprazole 960 mg ready-to-use for two months; C max,ss It is the highest steady-state concentration.

[0166] Compared to a single dose of Ari 2MRTU 960 plus 14 days of oral aripiprazole 10 mg / day or 20 mg / day, scenarios involving two-injection initiation (i.e., administration of Ari 2MRTU 960 plus AOM 400 plus a single dose of oral aripiprazole 20 mg at separate injection sites, both on day 1 of treatment) produced more stable aripiprazole plasma concentrations. This is suitable for patients who previously received oral aripiprazole 10 mg / day ( Figure 8 A), 20 mg / day ( Figure 8 B) and 30 mg / day ( Figure 8 C) patients who are stable, and patients who have not previously been stable with oral aripiprazole ( Figure 8 D). In Figure 8 In A-8D, for comparative purposes, the red line represents the simulated results of the same patients who were treated with Ari 2MRTU 960 on day 0 and superimposed with oral aripiprazole 10 mg or 20 mg on days 0–13. Figure 8 D, represented by a solid red line and a dotted green line, indicates the simulated outcomes of the same patients treated with Ari 2MRTU 960 on day 0 and subsequently superimposed with oral aripiprazole 10 mg or 20 mg on days 0–13, respectively. The reference line represents the plasma concentration (95 ng / mL) identified as the threshold of efficacy for preventing impending relapse, and the simulated C after daily administration of oral aripiprazole 30 mg. max,ss The 75th percentile (534 ng / mL). Abbreviations: AOM 400 is aripiprazole 400 mg once a month; Ari 2MRTU 960 is a two-month ready-to-use formulation of 960 mg; C max,ss This is the steady-state highest concentration. In previously stable or unstable conditions, the simulated median aripiprazole concentration in CYP2D6 poor metabolizers starting with two injections (i.e., Ari 2MRTU 720 plus AOM 300 at independent injection sites followed by a single oral dose of aripiprazole 20 mg, both on day 1 of treatment) is shown in [data missing]. Figure 11 and Figure 12 The reference line represents the median C value after daily administration of 10 mg of aripiprazole orally. min,ss (94.0 ng / mL), C after daily administration of 30 mg of aripiprazole orally max,ss The 75th percentile (534 ng / mL) and C after daily administration of 30 mg of oral aripiprazole max,ss The 95th percentile (741 ng / mL).

[0167] Missed / Delayed Dosage

[0168] Missed / delayed dosing was simulated to explore the impact of incomplete adherence to Ari 2MRTU 960. Figure 6In scenarios where Ari2MRTU 960 administration was delayed by 2, 4, 6, and 8 weeks, the median trough plasma concentrations at administration were 191 ng / mL, 144 ng / mL, 110 ng / mL, and 80.1 ng / mL, respectively. At 56 days post-administration of the delayed agent, the median trough plasma concentrations had increased to 231 ng / mL, 217 ng / mL, 205 ng / mL, and 196 ng / mL, respectively (in the last case, the agent was administered in conjunction with a 14-day overlap of oral aripiprazole 10 mg / day).

[0169] exist Figure 6 In the figure, the reference line represents the plasma concentration (95 ng / mL) identified as the lower threshold of efficacy for preventing impending relapse [Wang et al., 2022], and the simulated C-value after daily oral administration of aripiprazole 30 mg. max,ss The 75th percentile (534 ng / mL). Abbreviation: Ari 2MRTU 960 is a two-month ready-to-use aripiprazole 960 mg, C max,ss It is the highest steady-state concentration.

[0170] CYP2D6 metabolizer status

[0171] In CYP2D6 adverse metabolizers, Ari 2MRTU 720 was simulated, and the results showed that the steady-state concentration of aripiprazole was comparable to that of AOM 300. Figure 9 ).exist Figure 9 In the figure, for comparative purposes, the graph includes a solid black line representing simulated results in the same patients treated with AOM 300. The reference line represents the plasma concentration (95 ng / mL) identified as the threshold of efficacy for preventing impending relapse, and the simulated C-value after daily oral administration of aripiprazole 30 mg. max,ss The 75th percentile (534 ng / mL). Abbreviations: AOM 300 is aripiprazole 300 mg once a month; Ari 2MRTU 720 is aripiprazole ready-to-use 720 mg for two months; C max,ss It is the highest steady-state concentration; CYP is cytochrome P450.

[0172] Long-term use of CYP2D6 or CYP3A4 inhibitors

[0173] The median steady-state plasma concentrations (MSPs) of Ari 2MRTU 720 with a strong CYP3A4 inhibitor were comparable to those of Ari 2MRTU 960 without a strong CYP3A4 or CYP2D6 inhibitor. In contrast, the administration of Ari 2MRTU 720 with a strong CYP2D6 inhibitor resulted in higher MSPs compared to Ari 2MRTU 960 without a strong CYP3A4 or CYP2D6 inhibitor. Figure 10 ).exist Figure 10 In the figures, for comparative purposes, the figures include a solid black line representing simulated results in the same patients treated with Ari2MRTU 960. The reference line represents the plasma concentration (95 ng / mL) identified as the threshold of efficacy for preventing impending relapse [Wang et al., 2022], and the simulated C-value after daily oral administration of aripiprazole 30 mg. max,ss The 75th percentile (534 ng / mL). Abbreviations: Ari 2MRTU 720 is a two-month ready-to-use aripiprazole 720 mg; Ari 2MRTU 960 is a two-month ready-to-use aripiprazole 960 mg; C max,ss It is the highest steady-state concentration; CYP is cytochrome P450.

[0174] Cases involving a reference two-injection initiation (i.e., administration of Ari 2MRTU 960 plus Ari 2MRTU 960 followed by a single oral dose of aripiprazole 20 mg at separate injection sites, both on day 1 of treatment) resulted in a delay in reaching therapeutic exposure. In this reference two-injection initiation, therapeutic concentrations of aripiprazole were not maintained after the first week of administration.

[0175] discuss

[0176] PopPK analysis is a recognized quantitative method for explaining inter-individual variability in drug concentrations, including results from intrinsic, extrinsic, dose variability, and route of administration. Such analyses are often performed as part of the drug development process to inform dosing regimens to be tested in future clinical trials. PopPK models can also be used to simulate PK curves for scenarios beyond the scope of clinical studies.

[0177] The development and use of a popPK model for characterizing the PK of a novel RTU LAI formulation of aripiprazole administered every two months are described. Based on the current analysis, the PK of aripiprazole after administration of Ari RTU LAI is best characterized by a linear three-compartment model with parallel zero-order and lag-first-order absorption. In the analysis of potential extrinsic and intrinsic covariates affecting the absorption properties of Ari RTU LAI, sex was identified as a statistically significant covariate; specifically, sex was found to affect the fraction of first-order absorption and the first-order K. a Compared to women, faster uptake was observed in men. The finding of sex as a statistically significant covariate in Ari RTU LAI uptake is consistent with AOM uptake in earlier models upon which the current model is based; however, direct comparisons are not possible due to the different structures of the uptake models (i.e., first-order uptake of AOM versus parallel zero-order and first-order uptake of Ari RTU LAI). Although it was found that sex influences the first-order and zero-order uptake scores of Ari RTU LAI as well as the first-order K... a However, as a result of the combination of these effects, it is not expected to be clinically relevant. This was confirmed by simulations of typical p-kJ curves following repeated administration of Ari 2MRTU 960, which showed C in both men and women. avg,ss The values ​​showed no difference. The effect of CYP2D6 metabolizer state, as a covariate from previous models, was retained, where the simulated C... avg,ss It is about twice as common (97.4%) in CYP2D6 adverse metabolizers compared to normal metabolizers.

[0178] The final popPK model was used for simulations to evaluate the dosing of Ari 2MRTU 960 and Ari 2MRTU 720 in a variety of realistic clinical scenarios. Various treatment initiation scenarios were simulated, taking into account different prior treatments (i.e., whether the patient was stable due to oral aripiprazole or AOM 400). Given the very slow absorption of Ari 2MRTU 960, simulations were also performed using overlapping oral aripiprazole for 14 days or starting with two injections of Ari 2MRTU 960 plus AOM followed by a single oral aripiprazole dose as a means of achieving therapeutically within-range exposure more quickly. Simulations of Ari 2MRTU 720 mg in CYP2D6 poor metabolizers and long-term users of strong CYP2D6 and CYP3A4 inhibitors were also considered. This is important because CYP2D6 metabolizer status is known to affect the PK of aripiprazole, and according to the AOM's instructions, a dose of 300 mg every four weeks is recommended in CYP2D6 poor metabolizers. Furthermore, both CYP2D6 and CYP3A4 are involved in the elimination of aripiprazole. Given the very slow absorption of Ari 2MRTU720, a two-injection initiation with Ari 2MRTU 720 plus AOM and a single oral dose of aripiprazole were simulated as a means of achieving therapeutic exposure more quickly. Simulated data showed that a two-injection initiation allowed for rapid achievement of therapeutic exposure, although aripiprazole concentrations took several days to reach 95 ng / mL with a single dose of 780 mg RTU or 1200 mg RTU, and as... Figure 13 As shown, the initiation rate did not change drastically when the dose was increased from 780 mg to 1200 mg. Figure 13 The results of a Phase 1, open-label, single-escalation, parallel-arm study for determining the pharmacokinetics, safety, and tolerability of a two-month intramuscular reservoir of aripiprazole administered to the gluteal muscles in adult subjects with schizophrenia are as described in U.S. Patent Application Publication No. US 2022 / 0160621 A1, the entire patent application of which is incorporated herein by reference.

[0179] Finally, missed / delayed dosing was simulated to assess the impact of incomplete adherence at every two-month dosing interval. Overall, the simulations showed that the PK exposure curve for Ari RTU LAI was comparable to that for AOM, with longer dosing intervals.

[0180] The data presented here provides clinicians with useful information on various dosing scenarios for the two-month RTU LAI formulation of aripiprazole. Including all potential dosing scenarios in efficacy and safety trials is impractical / unfeasible, but popPK modeling and simulation address this by generating PK curves for scenarios beyond those included in specific studies as part of a clinical trial program. In this way, modeling and simulation act as a “virtual” clinical trial, allowing for studies to conduct more scenarios than real-world clinical trials can. Nevertheless, any simulations presented here must be viewed in the context of approved use of Ari 2MRTU 960 and Ari 2MRTU 720, taking into account patient type, prior treatment, and / or country.

[0181] To characterize the pharmacokinetic (PK) of Ari 2MRTU 960, a popPK model was developed and then used for model-based simulations to explore various aspects of the dosing of this novel formulation. The final model was deemed suitable for the purpose, adequately describing the PK of aripiprazole plasma concentrations after administration of Ari 2MRTU 960; the model also established estimates of key popPK parameters and identified sources of variability in drug exposure. Simulations of various dosing regimens that might reasonably be encountered in clinical practice showed PK exposure curves comparable to AOM, with longer dosing intervals.

[0182] All publications and patents mentioned herein are incorporated herein by reference in their entirety, as if each individual publication or patent were specifically and individually indicated to be incorporated herein by reference.

[0183] A claim or description comprising "or" or "and / or" among at least one member of a group is deemed satisfied if one, more than one, or all members of the group are present, used in, or otherwise associated with a given product or process, unless otherwise stated to the contrary or clearly apparent from the context. This disclosure includes embodiments in which only one member of said group is present, used in, or otherwise associated with a given product or process. This disclosure also includes embodiments in which more than one or all members of said groups are present, used in, or otherwise associated with a given product or process.

[0184] Furthermore, this disclosure covers all variations, combinations, and permutations that introduce at least one limitation, element, clause, and descriptive term from at least one of the listed claims into another claim. For example, any claim dependent on another claim may be modified to include at least one limitation present in any other claim dependent on the same basic claim. Where elements are presented in list form, such as in Markush group format, each subgroup of said elements is also disclosed, and any element may be removed from said group. It should be understood that, in general, when this disclosure or an aspect of this disclosure is referred to as containing a particular element and / or feature, embodiments of this disclosure or an aspect of this disclosure consist of, or are substantially composed of, such elements and / or features. For simplicity, those embodiments are not specifically described herein in these terms. Where a range is given, endpoints are included. Furthermore, unless otherwise indicated or clearly apparent from the context and understanding of one of ordinary skill in the art, values ​​expressed as ranges in different embodiments of this disclosure may take any particular value or subrange within the stated range, up to one-tenth of a unit of the lower limit of the range, unless the context clearly indicates otherwise.

[0185] Those skilled in the art will recognize or be able to determine numerous equivalents of the specific embodiments of this disclosure described herein using no more than conventional experiments. These equivalents are intended to be covered by the claims.

Claims

1. A method for initiating aripiprazole treatment in a patient in need, the method comprising: The patient was given two separate injections of aripiprazole and a single oral dose of aripiprazole. The first injection contained 960 mg or 720 mg of aripiprazole from a first-acting injectable (LAI) formulation, and the second injection contained 400 mg or 300 mg of aripiprazole from a second LAI formulation. The injection sites were selected from the gluteal, deltoid, or combinations thereof. The administration procedure is performed on the first day of aripiprazole LAI treatment.

2. The method according to claim 1, wherein the first LAI formulation is in gel form when left to stand and becomes a sol when subjected to impact.

3. The method according to claim 1, wherein the second LAI formulation is a suspension prepared from lyophilized powder and water for injection.

4. The method according to any one of claims 1 to 3, wherein the first injection comprises 960 mg of aripiprazole.

5. The method according to any one of claims 1 to 4, further comprising administering a maintenance dose of the first LAI formulation once within approximately two months after the first day of aripiprazole LAI treatment.

6. The method of claim 5, wherein the maintenance dose of the first LAI formulation is selected from 960 mg and 720 mg aripiprazole.

7. The method of claim 6, wherein when the patient is an adverse metabolizer of CYP2D6 or is concurrently taking a CYP3A4 inhibitor or a CYP2D6 inhibitor for more than 14 days, the maintenance dose of the first LAI preparation is 720 mg aripiprazole.

8. The method according to any one of claims 1 to 7, wherein the two independent aripiprazole injections are administered at the patient's independent gluteal injection site.

9. The method according to any one of claims 1 to 7, wherein the two independent aripiprazole injections are administered at the injection sites in the gluteal and deltoid muscles of the patient.

10. The method according to any one of claims 1 to 7, wherein the two independent aripiprazole injections are administered at the independent deltoid injection site of the patient.

11. The method according to any one of claims 1 to 10, wherein the patient suffers from schizophrenia.

12. The method according to any one of claims 1 to 10, wherein the patient suffers from type I bipolar disorder.

13. The method according to any one of claims 1 to 12, wherein the dose of the oral aripiprazole is about 10 mg to about 20 mg of aripiprazole.

14. The method of claim 13, wherein the dose of the oral aripiprazole comprises about 20 mg of aripiprazole.

15. The method of claim 13, wherein the dose of the oral aripiprazole comprises about 10 mg of aripiprazole.

16. The method according to any one of claims 1 to 15, wherein the patient had not been stabilized by oral aripiprazole prior to the treatment.

17. The method of claim 1, wherein the patient is an adverse metabolizer of CYP2D6 or is concurrently taking a CYP3A4 inhibitor or a CYP2D6 inhibitor for more than 14 days, the first injection comprises 720 mg of aripiprazole, the second injection comprises 400 mg or 300 mg of aripiprazole, and the single oral dose of aripiprazole comprises about 10 mg or about 20 mg of aripiprazole.

18. The method of claim 17, wherein the patient is an adverse metabolizer of CYP2D6 or is concurrently taking a CYP3A4 inhibitor or a CYP2D6 inhibitor for more than 14 days, the first injection contains 720 mg of aripiprazole, the second injection contains 300 mg of aripiprazole, and the single oral dose of aripiprazole contains about 20 mg of aripiprazole.

19. The method of claim 1, wherein the first injection comprises 960 mg of aripiprazole, the second injection comprises 400 mg or 300 mg of aripiprazole, and the single oral dose of aripiprazole comprises about 10 mg or about 20 mg of aripiprazole.

20. The method of claim 19, wherein the first injection comprises 960 mg of aripiprazole, the second injection comprises 400 mg of aripiprazole, and the single oral dose of aripiprazole comprises about 20 mg of aripiprazole.

21. A method for treating schizophrenia or type I bipolar disorder in patients in need, the method comprising: The patient is given two separate injections of aripiprazole and a single oral dose of aripiprazole, wherein the first injection comprises 960 mg or 720 mg of aripiprazole in a first long-acting injectable (LAI) formulation, and the second injection comprises 400 mg or 300 mg of aripiprazole in a second LAI formulation, with the injection site selected from the gluteal region, deltoid region, or a combination thereof, wherein the administration is performed on the first day of aripiprazole LAI treatment, and wherein the oral aripiprazole dose is approximately 10 mg to approximately 20 mg of aripiprazole; and Continue to administer a maintenance dose of the first LAI formulation containing 960 mg or 720 mg of aripiprazole, wherein the maintenance dose is administered once every two months after the first day of aripiprazole LAI treatment.

22. The method of claim 21, wherein the first injection comprises 960 mg of aripiprazole, the second injection comprises 400 mg or 300 mg of aripiprazole, and the single oral dose of aripiprazole comprises about 10 mg or about 20 mg of aripiprazole.

23. The method of claim 22, wherein the first injection comprises 960 mg of aripiprazole, the second injection comprises 400 mg of aripiprazole, and the single oral dose of aripiprazole comprises about 20 mg of aripiprazole.

24. The method of claim 21, wherein the first injection comprises 720 mg of aripiprazole, the second injection comprises 400 mg or 300 mg of aripiprazole, and the single oral dose of aripiprazole comprises about 10 mg or about 20 mg of aripiprazole.

25. The method of claim 24, wherein the first injection comprises 720 mg aripiprazole, the second injection comprises 300 mg aripiprazole, and the single oral dose of aripiprazole comprises about 20 mg aripiprazole.

26. The method of claim 21, wherein the dose of the oral aripiprazole comprises about 20 mg of aripiprazole.

27. The method of claim 21, wherein the approximately two months is 54 to 58 days.

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