Initiation of treatment with aripiprazole for schizophrenia or bipolar disorder type 1

Abstract

This disclosure relates to a method for initiating aripiprazole treatment in patients requiring treatment, comprising two separate aripiprazole injections: a first long-acting injectable (LAI) and a second once-monthly injectable (AOM), as well as a single oral aripiprazole dose, on the first day of aripiprazole treatment. Maintenance doses are administered approximately two months after the first day of aripiprazole treatment using LAI maintenance doses. This method is applicable to both gluteal and deltoid muscle injection sites.

Description

[Technical Field]

[0001] This application claims priority to U.S. Provisional Application No. 63 / 498,313 filed on 26 April 2023, No. 63 / 506,624 filed on 7 June 2023, and No. 63 / 637,079 filed on 22 April 2024, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Schizophrenia and bipolar disorder type 1 (BP-I) are complex chronic mental illnesses in which affected individuals typically experience repeated relapses of symptoms interspersed with periods of remission. While daily oral antipsychotic use has proven effective in achieving and maintaining symptom control in many patients, it relies on continuous and long-term use. However, adherence to oral medications is often poor, with data showing that 30–50% of patients with schizophrenia or bipolar disorder type 1 do not take their medication as prescribed. Various strategies exist to improve treatment adherence, including the use of long-acting injectable (LAI) antipsychotics; LAI formulations offer dosing intervals of two weeks to six months, reducing the need for patient adherence compared to daily administration. Indeed, several real-world global study data 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 that exerts partial agonist effects on dopamine D2 and serotonin 5-HT1A receptors, full agonist effects on dopamine D3 receptors, and antagonistic effects on serotonin 5-HT2A receptors. Aripiprazole is available as an oral formulation administered once daily, and as a sustained-release suspension of aripiprazole monohydrate for intramuscular injection, known as aripiprazole once-monthly formulation (AOM). In addition, a novel ready-to-use (RTU) LAI formulation of aripiprazole monohydrate, administered by intramuscular buttock injection every two months, has recently been approved in the United States for the treatment of schizophrenia or BP-I. The new formulations contain aripiprazole monohydrate in doses of 960 mg or 720 mg. In cases of tolerability concerns, the latter dose is used in patients known to be cytochrome P450 (CYP) 2D6 dysmetabolists, and in patients receiving potent CYP2D6 or CYP3A4 inhibitors concomitantly. [Overview of the project]

[0004] Aripiprazole 2-month ready-to-use 960 mg formulation (Ari 2MRTU 960) was developed to extend the maintenance of therapeutic plasma concentrations of aripiprazole from one month to two months using AOM 400 mg formulation (AOM 400); this is achieved through several considerations, including increased dosing to maintain minimum aripiprazole concentrations similar to those after multiple doses of AOM, as well as other formulation and administration considerations. Compared to other formulations, Ari 2MRTU 960 has fewer dosing cycles (i.e., 6 injections per year for Ari 2MRTU 960 compared to 12 injections per year for AOM), which may reduce the medication burden on patients and physicians and improve adherence to antipsychotics 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 preparations ready for 2 months of use), previously developed and validated population pharmacokinetic (popPK) models were expanded to include novel RTU LAI formulations of aripiprazole (Ari RTU LAI) to characterize aripiprazole plasma concentrations after oral administration of aripiprazole or after AOM administration to the gluteal or deltoid muscle. This expansion of popPK modeling provides additional options for initiating aripiprazole treatment in patients.

[0006] For example, this disclosure relates to a method for initiating aripiprazole treatment in patients requiring treatment, by administering two separate aripiprazole injections on the first day of treatment: a first long-acting aripiprazole injection (LAI) and a second once-monthly aripiprazole injection (AOM), as well as a single oral aripiprazole dose. Simulations of an initiation regimen of two injections of aripiprazole LAI and AOM injections to separate injection sites in the buttocks and / or deltoid muscle on the first day of treatment showed that a longer dosing interval was sufficient to obtain a PK exposure profile equivalent to that of AOM.

[0007] In some embodiments, the present disclosure relates to a method for initiating administration of aripiprazole therapy to a patient in need of treatment, comprising the steps of: administering two separate injections of aripiprazole to an injection site selected from the patient's gluteal region, deltoid region, and combinations thereof, 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, and administering a single dose of oral aripiprazole, wherein the administration steps are performed on the first day of aripiprazole therapy.

[0008] In some embodiments, the present disclosure relates to a method for treating schizophrenia or bipolar disorder type I in a patient requiring treatment, comprising the steps of: administering two separate injections of aripiprazole to an injection site selected from the patient's gluteal site, deltoid site, and combinations thereof, 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 a once-a-month (AOM) injectable, and a single administration of oral aripiprazole, wherein the administration is performed on the first day of aripiprazole treatment and the oral aripiprazole administration is in the range of about 10 mg to about 20 mg of aripiprazole; and continuing the administration of maintenance doses of the LAI containing 960 mg or 720 mg of aripiprazole, wherein the maintenance dose is administered about 2 months after the first day of aripiprazole treatment.

Brief Description of the Drawings

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

[0010] [Figure 2] Figure 2 is a graph showing the simulated pharmacokinetic profiles from the final model according to covariates (gender and CYP2D6 status) retained after 6 repeated administrations of 960 mg of Ari 2MRTU of aripiprazole every 8 weeks.

[0011] [Figure 3] Figures 3A - 3D are graphs of goodness-of-fit plots of the final aripiprazole population pharmacokinetic model.

[0012] [Figure 4] Figures 4A - 4G are graphs of predictive-corrected visual predictive performance evaluations of the final aripiprazole population pharmacokinetic model.

[0013] [Figure 5] Figures 5A–5F are graphs of the simulated median aripiprazole concentration-time profiles after initiation of aripiprazole Ari 2MRTU 960 mg across various pretreatment scenarios.

[0014] [Figure 6] Figure 6 is a graph of the simulated median aripiprazole concentration-time profile after aripiprazole (Ari 2MRTU 960 mg) in patients already stabilized with aripiprazole (Ari 2MRTU 960 mg), either as scheduled or after a delay of 2, 4, 6, or 8 weeks.

[0015] [Figure 7] Figure 7 is a graph of the simulated aripiprazole concentration-time median profile for Ari 2MRTU 960 mg on day 28 after AOM on day 0 (patients who have not previously received oral aripiprazole stabilization receive a duplicate dose of 20 mg of oral aripiprazole).

[0016] [Figure 8] Figures 8A–8D are graphs of simulated median aripiprazole concentration-time profiles after two injection initiations of Ari 2MRTU 960 and AOM 400 across various pretreatment scenarios.

[0017] [Figure 9] Figure 9 is a graph of the simulated steady-state aripiprazole concentration-time median profile after administration of Ari 2MRTU 720 in CYP2D6 dysmetabolists.

[0018] [Figure 10] Figure 10 is a graph of the simulated steady-state aripiprazole concentration-time median profile after administration of Ari 2MRTU 720 in combination with the potent inhibitors CYP3A4 or CYP2D6.

[0019] [Figure 11] Figure 11 is a graph of the simulated median aripiprazole concentration-time profiles for all subjects (solid line) and CYP2D6 hypometabolites (dashed line) who received Ari 2MRTU 960 (day 0), AOM 400 (day 0), and 20 mg of oral aripiprazole (day 0), or for all subjects who were pre-stabilized with 10 mg of oral aripiprazole and were CYP2D6 hypometabolites (dotted line) who received Ari 2MRTU 720 (day 0), AOM 300 (day 0), and 20 mg of oral aripiprazole (day 0).

[0020] [Figure 12] Figure 12 is a graph of the simulated median aripiprazole concentration-time profiles for all subjects (solid line) and CYP2D6 low metabolites (dashed line) who received Ari 2MRTU 960 (day 0), AOM 400 (day 0), and 20 mg of oral aripiprazole (day 0), or for subjects who were not pre-stabilized with oral aripiprazole and were CYP2D6 low metabolites (dotted line) who received Ari 2MRTU 720 (day 0), AOM 300 (day 0), and 20 mg of oral aripiprazole (day 0).

[0021] [Figure 13] Figure 13 is a graph of the mean (SD) plasma concentration-time profiles of aripiprazole after a single administration of 780 mg (N=18) or 1200 mg (N=13) of prepared aripiprazole 2M RTU long-acting injectable into the gluteal muscle of subjects with schizophrenia. [Modes for carrying out the invention]

[0022] As used herein, “a (a)” or “an (an)” entity refers to one or more entities; for example, “a compound” refers to one or more compounds, or at least one compound, unless otherwise specified. Thus, the terms “a (a)” [or “an (an)”], “one or more,” and “at least one” are used interchangeably herein.

[0023] As used herein, the term “approximately” means roughly, within a range, roughly, or around. When the term “approximately” is used in conjunction with a numerical range, it modifies that range by extending the upper and lower boundaries of the stated numerical value. Generally, the term “approximately” is used herein to mean a numerical modification of a value that is 5% above or below the stated value.

[0024] As used herein, the terms “to treat,” “to treat,” or “to cure” include, when used in relation to a disorder or condition, any effect resulting in improvement of the disorder or condition, such as reduction, mitigation, adjustment, improvement, or disappearance. Any improvement or reduction in the severity of any symptom of the disorder or condition can be readily assessed by standard methods and techniques known in the art. In some embodiments, the methods or depot formulations of this disclosure can be used as maintenance monotherapy for the treatment of schizophrenia and bipolar disorder type I.

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

[0026] As used herein, “aripiprazole” refers to aripiprazole or its salts, or crystalline forms of aripiprazole or its salts. Aripiprazole or its salts can exist in monohydrate form (aripiprazole hydrate A) or in various anhydrous forms, and are known to exist in the form of anhydrous crystals B, C, D, E, F, and G. All of these crystalline forms can be used as aripiprazole or its salts in the injectable preparations of this disclosure, and furthermore, for example, aripiprazole is in monohydrate form. As used herein, the terms “aripiprazole” or its salts refer to compounds having the following structure: [ka]

[0027] The empirical formula is C 23 H 27 C l2 The substance is N3O2H2O and has a molecular weight of 466.40. This disclosure relates to a method for initiating aripiprazole treatment in a patient requiring treatment, comprising the steps of administering two separate injections of aripiprazole to an injection site selected from the patient's gluteal region, deltoid region, and a combination thereof, in which a first injection contains 960 mg or 720 mg of aripiprazole in a long-acting injectable (LAI) and a second injection contains 400 mg or 300 mg of aripiprazole in an once-monthly (AOM) injectable, as well as a single dose of oral aripiprazole, wherein the administration steps are performed on the first day of aripiprazole treatment.

[0028] Embodiment

[0029] Some embodiments of this disclosure include, but are not limited to, the following:

[0030] 1. A method for initiating aripiprazole treatment in patients requiring treatment, comprising the following steps: administering two separate injections of aripiprazole to the patient's gluteal region, deltoid region, or a combination thereof, each injection comprising 960 mg or 720 mg of aripiprazole in a first long-acting injectable (LAI) formulation and 400 mg or 300 mg of aripiprazole in a second LAI formulation, as well as a single dose of oral aripiprazole, wherein the administration steps are performed on the first day of aripiprazole LAI treatment.

[0031] 2. The method according to Embodiment 1, wherein the first LAI formulation is in a gel-like state when left standing and changes to a sol-like state when subjected to impact.

[0032] 3. The method according to Embodiment 1, wherein the second LAI formulation is a suspension prepared from lyophilized powder and water for injection.

[0033] 4. The method according to any one of Embodiments 1 to 3, wherein the first injection comprises 960 mg of aripiprazole.

[0034] 5. The method according to any one of Embodiments 1 to 4, further comprising the step of administering a maintenance dose of the first LAI formulation approximately once every two months after the first day of aripiprazole LAI treatment.

[0035] 6. The method according to Embodiment 5, wherein the maintenance dose of the first LAI preparation is selected from 960 mg and 720 mg of aripiprazole.

[0036] 7. The method according to Embodiment 6, wherein if the patient is a CYP2D6 hypometabolist or has been concomitantly taking a CYP3A4 inhibitor or a CYP2D6 inhibitor for more than 14 days, the maintenance dose of the first LAI preparation is 720 mg of aripiprazole.

[0037] 8. The method according to any one of Embodiments 1 to 7, wherein two separate injections of aripiprazole are administered to separate injection sites on the patient's buttocks.

[0038] 9. The method according to any one of Embodiments 1 to 7, wherein two separate injections of aripiprazole are administered to the injection sites of the patient's buttocks and deltoid muscle.

[0039] 10. The method according to any one of embodiments 1 to 7, wherein two separate injections of aripiprazole are administered to separate injection sites in the patient's deltoid muscle.

[0040] 11. The method according to any one of Embodiments 1 to 10, wherein the patient is suffering from schizophrenia.

[0041] 12. The method according to any one of Embodiments 1 to 10, wherein the patient has bipolar disorder type 1.

[0042] 13. The method according to any one of Embodiments 1 to 12, wherein the oral administration of aripiprazole is in the range of approximately 10 mg to approximately 20 mg of aripiprazole.

[0043] 14. The method according to Embodiment 13, wherein the oral administration of aripiprazole comprises approximately 20 mg of aripiprazole.

[0044] 15. The method according to Embodiment 13, wherein the oral administration of aripiprazole comprises approximately 10 mg of aripiprazole.

[0045] 16. The method according to any one of Embodiments 1 to 15, wherein the patient has not been stabilized with oral aripiprazole prior to treatment.

[0046] 17. The method according to Embodiment 1, wherein the patient is a CYP2D6 hypometabolist or has been concomitantly taking a CYP3A4 inhibitor or a CYP2D6 inhibitor for more than 14 days, and the first injection comprises 720 mg of aripiprazole, the second injection comprises 400 mg or 300 mg of aripiprazole, and the single oral dose comprises approximately 10 mg or approximately 20 mg of aripiprazole.

[0047] 18. The method according to Embodiment 17, wherein the patient is a CYP2D6 hypometabolist or has been concomitantly taking a CYP3A4 inhibitor or a CYP2D6 inhibitor for more than 14 days, and the first injection comprises 720 mg of aripiprazole, the second injection comprises 300 mg of aripiprazole, and the single oral dose comprises approximately 20 mg of aripiprazole.

[0048] 19. The method according to Embodiment 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 comprises approximately 10 mg or approximately 20 mg of aripiprazole.

[0049] 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 approximately 20 mg of aripiprazole.

[0050] 21. A method comprising the following steps for treating schizophrenia or bipolar disorder type I in patients requiring treatment: The procedure involves administering two separate injections of aripiprazole to the patient's gluteal region, deltoid region, or a combination thereof, with the first injection containing 960 mg or 720 mg of aripiprazole in a first long-acting injectable (LAI) formulation and the second injection containing 400 mg or 300 mg of aripiprazole in a second LAI formulation, as well as a single oral aripiprazole dose, the administration of which is performed on the first day of aripiprazole LAI treatment, and the oral aripiprazole dose being in the range of approximately 10 mg to approximately 20 mg of aripiprazole; and, The procedure involves continuing the administration of a maintenance dose of a first LAI formulation containing 960 mg or 720 mg of aripiprazole, wherein the maintenance dose is administered approximately once every two months after the first day of aripiprazole LAI treatment.

[0051] 22. The method according to Embodiment 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 comprises approximately 10 mg or approximately 20 mg of aripiprazole.

[0052] 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 approximately 20 mg of aripiprazole.

[0053] 24. The method according to Embodiment 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 comprises approximately 10 mg or approximately 20 mg of aripiprazole.

[0054] 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 approximately 20 mg of aripiprazole.

[0055] 26. The method according to Embodiment 21, wherein the oral administration of aripiprazole comprises approximately 20 mg of aripiprazole.

[0056] 27. The method according to Embodiment 21, wherein approximately two months is in the range of 54 to 58 days.

[0057] 28. Long-acting injectable formulations (LAIs) containing 960 mg or 720 mg of aripiprazole for use in a method of administration initiation including the following steps for aripiprazole therapy in patients requiring treatment: The procedure involves administering two separate injections of aripiprazole to the patient's gluteal region, deltoid region, or a combination thereof, each injection comprising 960 mg or 720 mg of aripiprazole in a first long-acting injectable (LAI) formulation and 400 mg or 300 mg of aripiprazole in a second LAI formulation, as well as a single dose of oral aripiprazole, the administration procedure being performed on the first day of aripiprazole LAI treatment.

[0058] 29. Use of aripiprazole in the manufacture of a drug for the treatment of schizophrenia or bipolar disorder type I, including the following steps: The procedure involves administering two separate injections of aripiprazole to injection sites selected from the gluteal region, deltoid region, and combinations thereof of a patient requiring treatment, wherein the first injection contains 960 mg or 720 mg of aripiprazole in a first long-acting injectable (LAI) formulation, and the second injection contains 400 mg or 300 mg of aripiprazole in a second LAI formulation, as well as a single dose of oral aripiprazole, the administration procedure being performed on the first day of aripiprazole LAI treatment.

[0059] 30. Use of aripiprazole for the treatment of patients with schizophrenia or bipolar disorder type 1, comprising the steps of administering two separate injections of aripiprazole to injection sites selected from the gluteal region, deltoid region, and combinations thereof of the patient requiring treatment, 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, and a single dose of oral aripiprazole, wherein the administration steps are performed on the first day of aripiprazole LAI treatment.

[0060] 31. A kit comprising a pre-filled syringe containing a long-acting injectable (LAI) formulation containing 960 mg or 720 mg of aripiprazole for use in an initiation of administration method comprising the following steps for aripiprazole therapy in patients requiring treatment: The procedure involves administering two separate injections of aripiprazole to the patient's gluteal region, deltoid region, or a combination thereof, with the first injection comprising 960 mg or 720 mg of aripiprazole in a first long-acting injectable (LAI) formulation and the second injection comprising 400 mg or 300 mg of aripiprazole in a second LAI formulation, as well as a single dose of oral aripiprazole, the administration procedure being performed on the first day of aripiprazole LAI treatment.

[0061] Initiation of aripiprazole treatment

[0062] This disclosure relates to a method for initiating aripiprazole treatment in patients requiring treatment, by administering two separate aripiprazole injections: a first aripiprazole injection from a first long-acting injectable (LAI) formulation and a second aripiprazole injection from a second LAI formulation [monthly injectable (AOM)], in combination with a single oral aripiprazole dose on the first day of aripiprazole LAI treatment. This initiation regimen is also referred to herein as a "two-injection start." This initiation regimen provides an Ari RTU LAI PK exposure profile equivalent to that of AOM with a longer dosing interval. Maintenance doses are administered approximately every two months after the first day of aripiprazole LAI treatment, for example, approximately every two months after administration of a 960 mg or 720 mg aripiprazole first LAI depot formulation. This alternative initiation regimen can be applied to both the deltoid and gluteal muscle administration sites.

[0063] This disclosure utilizes two separate aripiprazole injections, a first injection containing 960 mg or 720 mg of aripiprazole in a long-acting injectable (LAI) formulation, and a second injection containing 400 mg or 300 mg of aripiprazole in a second LAI formulation [Once-Monthly (AOM) injection], as well as a single oral aripiprazole. For example, the method of this disclosure involves administering two separate LAI and AOM aripiprazole injections to separate injection sites in the patient's buttocks and / or deltoid muscle, with the administration performed on the first day of LAI treatment. In some embodiments, the two separate LAI and AOM aripiprazole injections are administered to separate injection sites in the patient's buttocks or separate deltoid muscle sites. In further embodiments, the two separate LAI and AOM aripiprazole injections are administered to injection sites in the patient's buttocks and deltoid muscle.

[0064] The Disclosure further relates to a treatment method for a patient with schizophrenia or bipolar disorder type 1 requiring treatment, comprising the following steps: administering two separate injections of aripiprazole to the patient's gluteal region, deltoid region, and a combination thereof, each injection comprising 960 mg or 720 mg of aripiprazole in a first long-acting injectable (LAI) formulation and 400 mg or 300 mg of aripiprazole in a second LAI formulation [Once Monthly (AOM) Injectable], and administering a single dose of oral aripiprazole, the administration step being performed on the first day of aripiprazole LAI treatment; and continuing administration of a maintenance dose of the first LAI formulation containing 960 mg or 720 mg of aripiprazole, the maintenance dose being administered approximately once every two months after the first day of aripiprazole treatment.

[0065] In this disclosure, aripiprazole therapy may exclude tolerability-establishing administration of oral aripiprazole before initiating LAI therapy with an injection containing 960 mg or 720 mg of aripiprazole in the first long-acting injectable (LAI) formulation.

[0066] In some embodiments, the method of the present disclosure includes administering two separate injections of aripiprazole to separate injection sites in the patient's buttocks. In some embodiments, the method of the present invention includes administering two separate injections of aripiprazole to injection sites in the patient's buttocks and deltoid muscle. In some embodiments, the method of the present disclosure includes administering two separate injections of aripiprazole to separate injection sites in the patient's deltoid muscle.

[0067] In some embodiments, the methods of the present disclosure include the patient having schizophrenia or bipolar disorder type I.

[0068] In some embodiments, on the initiation day, a single oral 20 mg of aripiprazole is administered, and two separate injections of aripiprazole are administered to two different injection sites: the first injection contains 960 mg or 720 mg of aripiprazole in a first long-acting injectable (LAI) formulation, and the second injection contains 400 mg or 300 mg of aripiprazole in a second LAI formulation [once-monthly (AOM) injection].

[0069] In some embodiments, when initiating with a two-injection start, it is preferable to inject into two different sites in two different muscles. It is preferable not to inject both injections simultaneously into the same deltoid or gluteal muscle. If known to be a CYP2D6 low metabolizer, it is preferable to administer to two separate deltoid muscles, or one deltoid muscle and one gluteal muscle. It is preferable not to inject into two gluteal muscles.

[0070] In some embodiments, it is preferable to administer a single dose of 10 mg or 20 mg of oral aripiprazole on the first day of treatment, administer one injection containing 960 mg or 720 mg of aripiprazole in a first long-acting injectable (LAI) formulation to the buttocks, and administer one injection containing 400 mg or 300 mg of aripiprazole in a second LAI formulation [Once-Monthly (AOM) Injectable] to the buttocks or deltoid muscle area.

[0071] In some embodiments, oral aripiprazole is not administered for days 1-13 after the first day of aripiprazole LAI treatment.

[0072] The rationale for the alternative initiation regimen selection is based on simulations using a population pharmacokinetic (popPK) model. For example, to characterize aripiprazole plasma concentrations after oral aripiprazole administration or once-monthly (AOM) intramuscular injection of aripiprazole, a previously developed and validated population pharmacokinetic (popPK) model was extended to include the aripiprazole RTU LAI formulation (Ari RTU LAI). Overall, the final combined analysis dataset included 8,899 aripiprazole pharmacokinetic (PK) samples from 1,191 adults across 10 clinical trials. In 1,000 hypothetical patients, aripiprazole plasma concentration-time profiles were simulated for various Ari RTU LAI initiation and maintenance scenarios. The final popPK model incorporating data for oral aripiprazole, AOM, and Ari RTU LAI found good fit for the absorption of Ari RTU LAI modeled by parallel zero-order processes and delayed first-order processes. Simulations across multiple scenarios provided dosing recommendations, including various initiation regimens, for a 2-month formulation of Ari RTU LAI in patients pre-stabilized with oral aripiprazole or unstabilized, and for patients switching from AOM. Additional simulations considered missed / delayed doses, CYP2D6 metabolic status, and concomitant use with CYP2D6 or CYP3A4 inhibitors. Overall, simulations across various scenarios demonstrated a PK exposure profile for Ari RTU LAI that is comparable to AOM with longer dosing intervals.

[0073] The first long-acting injectable (LAI) formulation: Aripiprazole long-acting injectable (LAI)

[0074] In the method of the present disclosure, the first injection comprises 960 mg or 720 mg of aripiprazole in the 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 the present disclosure comprises the step of 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.

[0075] In some embodiments, the first LAI formulation comprises a composition comprising aripiprazole, a specific suspension [suspension (A)], and a dispersion medium. For example, the injectable preparations of the present disclosure include at least water as the dispersion medium. As the dispersion medium comprising at least water, water or an aqueous solvent comprising water and an organic solvent can be used. In some embodiments, the dispersion medium is water, and furthermore, for example, sterile water for injection.

[0076] A specific suspending agent (suspending agent A) contained in the first LAI formulation comprises at least one suspending agent selected from (i) and (ii): (i) polyvinylpyrrolidone, and (ii) polyethylene glycol and carboxymethylcellulose or a salt thereof.

[0077] In some embodiments, the first LAI formulation comprises aripiprazole or a salt thereof, water, and at least one suspension selected from (i) and (ii): (i) polyvinylpyrrolidone, (ii) polyethylene glycol and carboxymethylcellulose or a salt thereof. Here, the aripiprazole or 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 salt thereof is in the range of about 200 mg / mL to about 600 mg / mL. The first LAI formulations disclosed herein, two-month ready-to-use (RTU) or long-acting injectable formulations (LAIs), injectable preparations are described in U.S. Patent No. 10,517,951, which is incorporated herein by reference in its entirety. Examples of LAI preparations for injection include Abilify Asimtufii®, Abilify Maintena® 720 mg sustained-release suspension for injection in pre-filled syringes, or Abilify Maintena® 960 mg sustained-release suspension for injection in pre-filled syringes.

[0078] For example, if the injectable preparation of this disclosure contains aripiprazole or a salt thereof (hereinafter sometimes referred to as "aripiprazole injectable preparation of this disclosure"), the concentration of aripiprazole or a salt thereof is approximately 200 mg / mL to approximately 600 mg / mL. (α) The first LAI formulation of aripiprazole becomes gel-like upon standing, suppressing the precipitation and caking of aripiprazole particles, thereby providing excellent storage stability. Furthermore, (β) even in gel form, this injectable preparation easily gains fluidity upon slight impact, making it easy to inject at the time of use (injection). Moreover, the gelled injectable preparation (gel composition) gains fluidity (sol state) simply by pushing the plunger of the syringe and dispensing the preparation through the syringe needle, allowing it to be smoothly dispensed through the needle. Therefore, the preparation has thixotropic properties, resulting in relatively little local discomfort and pain at the time of injection, and can be well dispersed intramuscularly or subcutaneously.

[0079] In other words, if the concentration of aripiprazole or a salt thereof is 100 mg / mL or less, it may not be possible to prepare an injectable preparation capable of forming a gel, even with the use of suspension A (or further maturation treatment). Therefore, the first LAI formulation of this disclosure contains aripiprazole or a salt thereof, and uses a combination of a specific suspension (suspension A) and a specific concentration of aripiprazole or a salt thereof (approximately 200 mg / mL to approximately 600 mg / mL, e.g., approximately 250 mg / mL to approximately 450 mg / mL, and approximately 300 mg / mL to approximately 400 mg / mL, etc.). If the first LAI formulation of this disclosure contains a salt of aripiprazole, the above concentrations are converted to aripiprazole equivalents.

[0080] In some embodiments, the first LAI formulation contains aripiprazole in concentrations of approximately 200 mg / mL to approximately 600 mg / mL, for example, approximately 200 mg / mL to approximately 500 mg / mL, for example, approximately 250 mg / mL to approximately 450 mg / mL, and further, for example, approximately 300 mg / mL to approximately 400 mg / mL, and even further, for example, approximately 300 mg / mL.

[0081] In some embodiments, if the first LAI formulation of the present disclosure contains (i) polyvinylpyrrolidone as suspension 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, and further, for example, about 2 mg / mL to about 20 mg / mL.

[0082] In some embodiments, if the first LAI formulation of the present disclosure comprises (i) polyvinylpyrrolidone as suspension A and further comprises one or more other suspensions, at least one of which is selected from polyethylene glycol and carboxymethylcellulose or a salt thereof, which are included as one or more other suspensions. For example, if these injectable preparations of the present disclosure comprise (i) polyvinylpyrrolidone as suspension A and further comprises one or more other suspensions, they may include any combination of suspensions from (i-1) to (i-3) shown below.

[0083] (i-1) Polyvinylpyrrolidone and polyethylene glycol

[0084] (i-2) Polyvinylpyrrolidone and carboxymethylcellulose or its salts, and

[0085] (i-3) Polyvinylpyrrolidone, polyethylene glycol, and carboxymethylcellulose or salts thereof.

[0086] Regardless of the combination of (i-1) to (i-3) in these injectable preparations of this disclosure, the concentration of polyvinylpyrrolidone is, as described above, about 0.1 mg / mL to about 100 mg / mL, for example, about 1 mg / mL to about 50 mg / mL, and further for example, about 2 mg / mL to about 20 mg / mL. In (i-1) or (i-3), the concentration of polyethylene glycol is about 0.05 mg / mL to about 100 mg / mL, and for example, about 0.1 mg / mL to about 50 mg / mL. In (i-2) or (i-3), the concentration of carboxymethylcellulose or a salt thereof is about 0.5 mg / mL to about 50 mg / mL, for example, about 1 mg / mL to about 30 mg / mL, and further for example, about 2 mg / mL to about 20 mg / mL.

[0087] The inclusion of carboxymethylcellulose or a salt thereof can suppress viscosity increase during manufacturing. This allows aripiprazole or a salt thereof to be efficiently pulverized to the desired particle size. In some embodiments, the molecular weight of carboxymethylcellulose or a salt thereof is in the range of 49,000 to 300,000. Furthermore, the inclusion of polyethylene glycol can prevent syneresis even when the resulting injectable preparation is stored for a long period of time. 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 preparation.

[0088] In some embodiments, the average molecular weight of carboxymethylcellulose or its salt is, for example, 5,000 or more, preferably 10,000 or more, more preferably 20,000 or more, more preferably 30,000 or more, more preferably 40,000 or more, and more preferably 50,000 or more. In other embodiments, the average molecular weight of carboxymethylcellulose or its salt is, for example, 300,000 or less, preferably 250,000 or less, more preferably 200,000 or less, and more preferably 150,000 or less. In yet another embodiment, the average molecular weight of carboxymethylcellulose or its salt is, for example, between 5,000 and 300,000, preferably between 10,000 and 250,000, preferably between 20,000 and 200,000, and preferably between 50,000 and 150,000.

[0089] In some embodiments, the viscosity of a 2% (weight / volume) aqueous solution of carboxymethylcellulose or a salt thereof is, for example, 1,000 mPa·s or less, preferably 800 mPa·s or less. In other embodiments, the viscosity is, for example, 10 mPa·s or more, preferably 50 mPa·s or more. In yet another embodiment, the viscosity is, for example, between 10 and 1,000 mPa·s, preferably between 50 and 800 mPa·s. Viscosity can be measured according to the method described in USP-NF (e.g., USP42-NF37, 2019 edition).

[0090] In some embodiments, when the first LAI formulation of the present disclosure comprises (ii) polyethylene glycol and carboxymethylcellulose or a salt thereof as suspension A, the concentration of polyethylene glycol is about 0.05 mg / mL to about 2 mg / mL, and more specifically, about 0.1 mg / mL to about 1 mg / mL. In other embodiments, the concentration of carboxymethylcellulose or a salt thereof is about 0.5 mg / mL to about 50 mg / mL, for example, about 1 mg / mL to about 30 mg / mL, about 2 mg / mL to about 20 mg / mL, etc.

[0091] In some embodiments, if the first LAI formulation of the present disclosure comprises (ii) polyethylene glycol and carboxymethylcellulose or a salt thereof as suspension A, and further comprises one or more other suspensions, then polyvinylpyrrolidone may be included as one or more other suspensions. For example, if the injectable preparation of the present disclosure comprises (ii) polyethylene glycol and carboxymethylcellulose or a salt thereof as suspension A, and further comprises one or more other suspensions, then the suspension of (i-3) is included. In this case, the concentrations of polyethylene glycol, carboxymethylcellulose or a salt thereof, and polyvinylpyrrolidone are the same as those described in (i-3) above.

[0092] In some embodiments, when the suspension of (i-3) is used in the first LAI formulation of the present disclosure, 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 carboxymethylcellulose 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 is polyethylene glycol 400 or polyethylene glycol 4000. In some embodiments, the polyvinylpyrrolidone has a K value of about 12 to about 20. In further embodiments, the aripiprazole or a salt thereof has an average primary particle diameter of about 1 μm to 10 μm.

[0093] Because precipitation may occur if the average primary particle size of aripiprazole or its salts is excessively large, the average primary particle size is in the range of about 0.5 μm to about 30 μm, and for example, about 1 μm to about 20 μm. If the injectable preparation of this disclosure is a dosage form administered once 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, and further for example, about 2 μm to about 5 μm. The average secondary particle size is not more than three times the average primary particle size, and further for example, not more than twice.

[0094] In some embodiments, the first LAI formulation of the present disclosure is appropriately 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 the present disclosure administered once every two months is approximately 200 mg / mL to approximately 600 mg / mL, e.g., approximately 250 mg / mL to approximately 500 mg / mL, and more specifically, approximately 300 mg / mL to approximately 400 mg / mL, and more specifically, approximately 300 mg / mL, in terms of aripiprazole. When the injectable preparation is administered once every two months, the dose is approximately 2 mL to approximately 4 mL, e.g., approximately 2.2 mL to approximately 3.5 mL, and more specifically, approximately 2.3 mL to approximately 3.4 mL, and more specifically, approximately 3.2 mL.

[0095] In some embodiments, the first LAI formulations of this disclosure achieve the effects (α) and (β) described above. These may be gel-like or fluid (i.e., sol-like). As described above, the achievement of effects (α) and (β) can be objectively confirmed using a rotational rheometer. The first LAI formulations may also be formulated into pre-filled sol-gel injection formulations (hereinafter also referred to as "pre-filled sol-gel injection preparations"). These injection formulations exhibit thixotropic properties. Furthermore, the formulations may become gel-like when left standing and change to sol-like when subjected to impact.

[0096] In some embodiments, the method for producing a first LAI formulation includes preparing a liquid mixture of starting materials, grinding the aripiprazole or a salt thereof contained in the liquid mixture to a desired average primary particle size, and then allowing it to mature as appropriate.

[0097] In some embodiments, a method for producing a gel-like first LAI formulation according to the present invention comprises allowing a liquid mixture to stand at 5 to 70°C for 5 minutes or more, the liquid mixture comprising aripiprazole or a salt thereof having an average primary particle size of about 0.5 μm to about 30 μm at a concentration of about 200 mg / mL to about 600 mg / mL, water, and at least one suspension selected from (i) and (ii) below: (i) polyvinylpyrrolidone and (ii) polyethylene glycol and carboxymethylcellulose or a salt thereof.

[0098] For example, in some further embodiments, a manufacturing method comprising the following steps can be used: grinding aripiprazole or a salt thereof to an average primary particle size of about 0.5 μm to about 30 μm in a liquid mixture comprising aripiprazole or a salt thereof at a concentration of about 200 mg / mL to about 600 mg / mL, water, and at least one suspension selected from the group consisting of (i) and (ii) below: (i) polyvinylpyrrolidone, and (ii) polyethylene glycol and carboxymethylcellulose or a salt thereof; and allowing the ground liquid mixture to stand at 5°C to 70°C for 5 minutes or more.

[0099] In some embodiments, the disclosure includes the administration of a first LAI formulation such that the total amount of aripiprazole administered to the patient is 960 mg or 720 mg, for example, 960 mg, and more, for example, 720 mg or more, and the injectable preparation may be administered in one or more divided injections as appropriate. In some further embodiments, the administration of the first LAI formulation results in a total amount of aripiprazole administered to the patient of approximately 960 mg, and one or more injectable formulations are administered. For example, to obtain a total amount of aripiprazole administered to the patient of 960 mg, a single injection of the first LAI formulation containing 960 mg / mL of aripiprazole is administered. The 960 mg dose may be administered in separate injections at short intervals as appropriate. In some embodiments, the first injection contains 960 mg of aripiprazole. In some embodiments, the administration of the first LAI formulation results in a total amount of aripiprazole administered to the patient of approximately 720 mg, and one or more injectable formulations are administered. For example, to obtain a total dose of 720 mg of aripiprazole administered to a patient, a single injection of a first LAI preparation containing 720 mg / mL of aripiprazole is administered. In some embodiments, the first injection contains 720 mg of aripiprazole. The 720 mg dose can be administered in separate injections at short intervals as appropriate. The number of aripiprazole injections and the concentration of aripiprazole vary, as described above, taking into account the total amount of aripiprazole administered and the concentration of aripiprazole contained in each injectable preparation.

[0100] In some embodiments, the administration of the first LAI formulation to the subject is by intramuscular injection. In some embodiments, the intramuscular administration is performed at a site selected from the deltoid muscle, gluteal muscle, and combinations thereof. In some embodiments, the administration site is the gluteal muscle. For example, depending on the number of injections for administration, the injection site may include various parts of the deltoid muscle and / or gluteal muscle.

[0101] In some embodiments, maintenance doses are administered approximately every two months after the first day of aripiprazole LAI treatment, using a maintenance dose of the first LAI formulation; for example, maintenance doses are administered approximately every two months after a 960 mg or 720 mg dose of the first LAI formulation. Similar to conventional initiation regimens, alternative initiation regimens can be applied to both deltoid and gluteal administration sites. For example, the administration method of the first LAI formulation of aripiprazole disclosed herein is performed approximately once every two months. In some embodiments, the first LAI formulation is administered approximately once every 42 to 70 days, or any integer in between including the end of the range, for example, 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 a further embodiment, the first LAI formulation is administered approximately once every 56 days, for example, once every 54 to 58 days. In a further embodiment, the first LAI formulation is administered approximately once every 8 weeks, for example, once 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.

[0102] In some embodiments, the disclosure further relates that if the patient is a CYP2D6 hypometabolist or is concomitantly taking a CYP3A inhibitor or a CYP2D6 inhibitor for more than 14 days, the maintenance dose of the first LAI formulation is 720 mg of aripiprazole.

[0103] In some embodiments, the first LAI formulation of this disclosure can be directly filled into a syringe for use as a pre-filled syringe. This simplifies the syringe structure 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. Once the first LAI formulation of this disclosure is filled into a syringe, in further embodiments, the sol suspension can be administered simply by pushing the plunger rod of the syringe and dispensing the first LAI formulation of this disclosure through the needle of the syringe. This provides a pre-filled syringe with clinical convenience and ease of use, which is highly useful in medical and industrial applications. An example of manufacturing such a pre-filled syringe is to manufacture the first LAI formulation in the manner described above, pre-fill a syringe with this formulation, and then allow it to stand in the manner described above to gel the first LAI formulation.

[0104] In some embodiments, the first LAI formulation is contained in a pre-filled syringe at a dose potency of 720 mg or 960 mg, with these potencies calculated based on the anhydrous form (aripiprazole). The concentration of aripiprazole is 200 mg / mL to 600 mg / mL. In some embodiments, the inactive components are sodium carboxymethylcellulose (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 sterile water for injection (appropriate amount).

[0105] In some embodiments, the first LAI formulation is contained in a pre-filled syringe with a dose potency of 720 mg or 960 mg, the values ​​of which are calculated based on the anhydrous form (aripiprazole). The inactive components are sodium carboxymethylcellulose (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 (appropriate amount). In some embodiments, the first LAI formulation contains aripiprazole with a dose potency of 960 mg in a pre-filled syringe with a volume of approximately 3.2 mL. In some embodiments, the first LAI formulation contains aripiprazole with a dose potency of 720 mg in a pre-filled syringe with a volume of approximately 2.4 mL.

[0106] In some embodiments, the disclosure also includes a kit comprising the pre-filled syringe described above.

[0107] Second LAI preparation [Aripiprazole once-monthly injection (AOM)]

[0108] In the method of this disclosure, the second injection comprises 400 mg or 300 mg of aripiprazole in the 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).

[0109] In some embodiments, the aripiprazole intramuscular depot formulation comprises aripiprazole monohydrate; the aripiprazole monohydrate is 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydrocarbostyryl monohydrate.

[0110] For example, in some embodiments, the second injection is an aripiprazole intramuscular (IM) depot formulation, which is a sustained-release injectable suspension of 400 mg or 300 mg potency in a pre-filled dual-chamber syringe and 400 mg or 300 mg potency in a vial. In some embodiments, the second injection, which contains 400 mg or 300 mg of aripiprazole in the second LAI formulation [Once Monthly (AOM) Injection], comprises a lyophilized powder or lyophilized cake for the injectable suspension. The indicated potency is calculated based on the anhydrous form (aripiprazole). In some embodiments, the inactive components (per administered dose) for the 400 mg and 300 mg potency products include, respectively, sodium carboxymethylcellulose (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 further embodiments, 400 mg or 300 mg potency sustained-release injectable suspensions in pre-filled dual-chamber syringes and 400 mg or 300 mg potency vials can be used for dose adjustment; i.e., in patients with CYP2D6 dysmetabolism and in patients concomitantly 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 using 300 mg or 400 mg potency vials for deltoid or gluteal intramuscular injection. Abilify Maintena®, the second LAI formulation (aripiprazole IM depot formulation) for sustained-release suspension currently disclosed, is described in U.S. Patents 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 which are incorporated herein by reference in their entirety.

[0111] In some embodiments, the action of aripiprazole intramuscular depot formulations is likely primarily due to the parent drug aripiprazole, and to a lesser extent, to its main metabolite, dehydroaripiprazole, which has been shown to have affinity for D2 receptors similar to the parent drug and accounts for approximately 29% of the parent drug exposure in plasma.

[0112] Due to the low solubility of aripiprazole particles, absorption of aripiprazole into the systemic circulation is slow and prolonged after intramuscular injection. After a single administration of aripiprazole intramuscular depot formulation into the deltoid and gluteal muscles, the absorption rate of aripiprazole (AUCt, AUC∞) was similar at both injection sites, but the absorption rate (Cmax) was 31% higher after administration to the deltoid muscle compared to the gluteal muscle. However, at steady state, AUC and Cmax were similar at both injection sites. After multiple intramuscular administrations, plasma concentrations of aripiprazole gradually increased, reaching peak plasma concentrations at the median Tmax in approximately 5-7 days in the gluteal muscle and approximately 4 days in the deltoid muscle. After buttock administration, the mean apparent terminal elimination half-lives of aripiprazole were approximately 29.9 days and 46.5 days, respectively, after multiple injections of 300 mg and 400 mg aripiprazole intramuscular depot formulations every four weeks. In typical subjects, steady-state concentrations were reached at both injection sites with the fourth dose. Approximately dose-proportional increases in exposure to aripiprazole and dehydroaripiprazole were observed after injections of 300 mg and 400 mg aripiprazole intramuscular depot formulations every four weeks.

[0113] The elimination of aripiprazole occurs primarily through hepatic metabolism involving two P450 isozymes, CYP2D6 and CYP3A4. Aripiprazole is not a substrate of the enzymes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2E1. Aripiprazole also does not undergo direct glucuronidation.

[0114] Aripiprazole oral preparation

[0115] In some embodiments, the method of the present disclosure comprises a single dose of oral aripiprazole. In some embodiments, the dose of oral aripiprazole ranges from about 10 mg to about 20 mg of aripiprazole. 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 whether or not the patient has been pre-stabilized with oral aripiprazole before treatment. In some embodiments, the method is administered if the patient has been pre-stabilized with oral aripiprazole before treatment. In some embodiments, the method is administered if the patient has not been pre-stabilized with oral aripiprazole before treatment.

[0116] In some embodiments, oral tablets of aripiprazole are available in potencies of, for example, 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 include, for example, iron oxide (yellow or red) and FD&C Blue No. 2 aluminum lake.

[0117] Aripiprazole is well absorbed after tablet administration, reaching peak plasma concentrations within, for example, 3 to 5 hours, and the absolute oral bioavailability of the tablet formulation is approximately 87%. Oral tablets of aripiprazole can be administered with or without food. For example, administration of 15 mg oral tablets of aripiprazole with a standard high-fat meal did not significantly affect the Cmax or AUC of aripiprazole or its active metabolite, dehydroaripiprazole, but Tmax was delayed by 3 hours for aripiprazole and 12 hours for dehydroaripiprazole.

[0118] Aripiprazole is metabolized primarily through three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, the enzymes CYP3A4 and CYP2D6 are responsible for the dehydrogenation and hydroxylation of aripiprazole, while N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the major drug portion in the systemic circulation. At steady state, the active metabolite, dehydroaripiprazole, accounts for approximately 40% of the plasma aripiprazole AUC.

[0119] When aripiprazole labeled with [14C] was administered orally as a single dose, approximately 25% and 55% of the administered radioactivity were recovered in urine and feces, respectively. Less than 1% of unchanged aripiprazole was excreted in urine, and approximately 18% of the orally administered dose was recovered unchanged in feces.

[0120] This disclosure describes the use of oral tablets of aripiprazole in a single oral dose selected from approximately 10 mg to approximately 20 mg, for example, 10 mg, 15 mg, and 20 mg of aripiprazole. In some embodiments, the single oral dose is in the range of approximately 10 mg to approximately 20 mg of aripiprazole, for example, approximately 20 mg of aripiprazole. In some embodiments, the single oral dose is selected from 10 mg and 20 mg of aripiprazole. In further embodiments, the single oral dose is 20 mg of aripiprazole. In some embodiments, the single oral dose is 10 mg of aripiprazole.

[0121] In some embodiments, the present disclosure relates to a method for which a patient is a CYP2D6 hypometabolist or is concomitantly taking a CYP3A4 inhibitor or a CYP2D6 inhibitor for more than 14 days, wherein a first injection comprises 720 mg of aripiprazole, a second injection comprises 300 mg of aripiprazole, and a single oral dose comprises approximately 20 mg of aripiprazole.

[0122] In some embodiments, the present disclosure relates to a method in which a first injection comprises 960 mg of aripiprazole, a second injection comprises 400 mg of aripiprazole, and a single oral dose of aripiprazole comprises about 20 mg of aripiprazole. [Examples]

[0123] Development of population pharmacokinetic models

[0124] Source data

[0125] The popPK model was developed using PK data from 10 clinical trials. Data from oral aripiprazole and AOM injected into the gluteal or deltoid region were obtained from a previously developed and validated popPK model reported by Wang et al. [Wang et al. 2021]. The previously developed model 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. The previous model was expanded to include data from aripiprazole RTU LAI formulations obtained from three clinical trials involving 374 patients with schizophrenia or BP-I. Across the three trials, 240 patients received at least one dose of aripiprazole RTU LAI. In total, the final pooled analysis dataset consisted of 8,899 aripiprazole concentration samples from 1,191 individuals.

[0126] Model Development

[0127] As mentioned earlier, the starting point for the development of the popPK model was the previous popPK model for oral aripiprazole and AOM. Briefly, this was a three-compartment model with linear elimination for oral administration, sigmoid absorption (primary absorption following zero-order absorption), and primary absorption of the AOM formulation. Covariate effects included: CYP2D6 metabolic status (CL / F) in apparent clearance; co-administration of potent inhibitors of CYP2D6 or CYP3A4 in clearance; and the influence of sex and body mass index (BMI) on the primary absorption rate constant (Ka) of the AOM formulation. PK data for the Ari RTU LAI formulation was added to the analysis data, and an absorption compartment specific to the Ari RTU LAI formulation was added to the model. Covariate effects from the prior models for oral aripiprazole and AOM were retained, and additional covariates related to the absorption and relative bioavailability of the Ari RTU LAI formulation (i.e., injection site and injection volume) were investigated. Age, sex, and BMI were also evaluated as standard demographic variables. As a first step, potential relationships were visually examined by plotting the individual random effects on covariates (scatter plots for continuous covariates, and parallel box plots for categorical covariates). Next, formal tests of potential covariate effects on the absorption parameters of Ari RTU LAI formulations included a modified stepwise method using progressive selection of all variables statistically significant in univariate analysis (p<0.01 threshold [difference in minimum value of objective function (ΔMVOF) for 1 degree of freedom (df) ≥ 6.63]) and standard stepwise regression elimination (p<0.001 threshold [ΔMVOF for 1 degree of freedom ≥ 10.83]). The relationship between PK parameters and continuous covariates was evaluated using power functions, and the relationship between PK parameters and categorical covariates was evaluated using proportional functions.

[0128] Model Evaluation

[0129] The goodness of fit of the final model was assessed using standard diagnostic plots [e.g., observed concentration vs. population predictive value (PRED), observed concentration vs. individual predictive value, conditionally weighted residuals (CWRES) vs. PRED, and time after first dose]. The predictive performance of the final model was assessed using Visual Post-Hospital Predictive Performance Assessment (VPC) with 500 iterative simulations of the combined dataset. Where significant categorical covariate effects were identified in the final model, simulations were performed to visualize these effects on the concentration-time profile after repeated doses of Ari 2MRTU 960.

[0130] Bioanalysis Methods

[0131] Across all 10 studies, aripiprazole plasma concentrations were measured using validated high-performance liquid chromatography with tandem mass spectrometry. Linear calibration curves were used, and the calibration ranges varied from study to study as follows: 1–250 ng / mL for studies 31-98-206, 31-98-207, and CN138020; 0.5–250 ng / mL for studies 31-05-244 and 31-07-246; and 0.5–500 ng / mL for studies 31-11-290, 31-12-298, 31-201-00104, 31-201-00181, and 31-201-00279.

[0132] Population pharmacokinetic model simulation

[0133] Following the development of the final PopPK model, multiple simulations were performed to investigate the modes of Ari RTU LAI administration. This included various treatment initiation scenarios, including switching from AOM 400, pre-stabilization with 10 mg, 20 mg, or 30 mg of oral aripiprazole, and no stabilization with oral aripiprazole. For each initiation scenario, two initiation strategies were considered: overlapping use of 10 mg or 20 mg of oral aripiprazole and initial doses of Ari RTU LAI for 14 days, or two-injection initiation (one dose of Ari 2MRTU 960 and one dose of AOM 400 to separate injection sites, combined with a single oral dose of 20 mg of aripiprazole on day 1 of treatment). Additional simulations included: missed / delayed administration (to assess the impact of lack of adherence defined in different scenarios, with Ari 2MRTU 960 administered 2, 4, 6, and 8 weeks late); CYP2D6 metabolizer status (to assess low-dose administration in CYP2D6 low metabolizers); and drug interactions (to assess low-dose administration in combination with potent inhibitors of CYP2D6 or CYP3A4). For comparison, initiation scenarios with Ari RTU LAI 960, Ari RTU LAI 960, and oral aripiprazole were simulated.

[0134] In the simulation, a population of 1,000 virtual patients was created. Individual PK parameters for the virtual patients were derived from patient covariates and random effects using the popPK model and used to simulate individual PK profiles under each dosing scenario. Model covariates (i.e., sex, BMI, and CYP2D6 metabolic status included in the popPK model) were assigned to the virtual patients by resampling from the total patient population (n=1,191) 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 objective parameter. Across almost all simulation scenarios, the virtual patient population remained constant, and the population included a mix of normal and low-metabolizers of CYP2D6, with low-metabolizers accounting for approximately 5% of the population, as obtained through the resampling procedure. The only exception was the scenario where all patients needed to be either normal or CYP2D6 low-metabolizers: in this situation, the status was modified according to the overall virtual patient population. In simulations related to AOM, the administration site was the gluteal muscle to facilitate comparison with Ari RTU LAI, which is administered only to the gluteal muscle.

[0135] The simulation results were graphed by plotting the median over time on a baseline marked to indicate a specific concentration level of interest (i.e., to facilitate interpretation of results and comparison between different plots). This included 95 ng / mL (the plasma concentration identified as the lower effective threshold for preventing immediate relapse): this is based on an exposure response model analysis of AOM 400, which showed that schizophrenia patients with a predicted minimum concentration (Cmin) of aripiprazole ≥ 95 ng / mL were 4.41 times less likely to relapse than patients with Cmin < 95 ng / mL. [Wang et al., 2022] Furthermore, the value of 95 ng / mL is consistent with 94 ng / mL, the median of the minimum steady-state plasma concentration (Cmin,ss) of 10 mg of oral aripiprazole (i.e., the minimum daily dose of oral aripiprazole considered effective for the treatment of adults with schizophrenia), [Salzman et al., 2017; Abilify Prescribing Information, 2020] and is also consistent with therapeutic thresholds of 100–120 ng / mL reported by other researchers. [Hiemke et al., 2018; Meyer & Stahl, 2021; Hart et al., 2022] The baseline of 534 ng / mL (the 75th percentile of the simulated maximum steady-state concentration [Cmax,ss] after administration of 30 mg / day of oral aripiprazole once daily) was also included.

[0136] The rich PK profile was simulated by sampling concentrations every 2 hours for 24 hours after oral administration, and every 24 hours after administration of AOM or Ari RTU LAI.

[0137] Software and Tools

[0138] The popPK model was developed using nonlinear mixed-effects modeling software (NONMEM v7.4.2; Icon Development Solutions, Ellicott City, MD, USA). Estimation was performed using a first-order conditional estimation considering interactions. If satisfactory convergence was not achieved, estimation was performed using stochastic approximate expectation maximization, followed by importance sampling to evaluate MVOF. Data preparation, graph analysis, model diagnostics, and statistical summaries were performed using R (v4.0.5 or later; R Foundation for Statistical Computing, Vienna, Austria) and RStudio (v1.2.5042 or later; RStudio, Inc.). All simulations were performed using Pumas (v2.0; Pumas-AI, Inc., Centreville, VA, USA).

[0139] Results: Development of a population pharmacokinetic model

[0140] Base model

[0141] As a first step, an external validation of the previous model (which characterized aripiprazole plasma concentrations after oral aripiprazole or AOM administration) was performed using new AOM 400 data obtained from study number 031-201-00181. The previous model was able to characterize the new data to some extent, but some overprediction was observed at the start of treatment in the CWRES vs. time panel and the CWRES vs. population prediction panel (data not shown).

[0142] After adding PK data for Ari RTU LAI formulations to the input file, the model that best fit the data was a three-compartment model with linear elimination and various absorption models for oral, AOM, and Ari RTU LAI formulations (Figure 1).

[0143] In Figure 1, *Vc / F shows different values for the Ari RTU LAI formulation. The following abbreviations are used in Figure 1: AOM 400 is once-monthly 400 mg administration of aripiprazole; Ari is aripiprazole; CL / F is apparent clearance; F rel,AOM is the relative bioavailability of the AOM formulation; F rel,LAI is the relative bioavailability of the Ari RTU LAI formulation; K a,deltoid is the absorption rate constant of the AOM formulation at the deltoid site; K a,gluteal is the absorption rate constant of the AOM formulation at the gluteal site; K a,LAI is the absorption rate constant of the Ari RTU LAI formulation; K a,oral is the absorption rate constant of the oral formulation; LAI is long-acting injectable; Q1 / F is apparent inter-compartment clearance 1; Q2 / F is apparent inter-compartment clearance 2; RTU is ready-to-use; Vc / F is apparent central volume; Vp1 / F is the apparent volume of the peripheral compartment 1; Vp2 / F is the apparent volume of the peripheral compartment 2.

[0144] The absorption of the Ari RTU LAI formulation was modeled by parallel zero-order and delayed first-order processes, taking into account the complex absorption process inherent to LAI. The absorption of the Ari RTU LAI formulation was parameterized by the fraction of the total dose absorbed by the zero-order process (FRAC1), the duration of zero-order absorption (DUR0), the start delay time of the first-order process (LAG1), the absorption rate constant of the first-order process (K a RTU), and the bioavailability of the Ari RTU LAI formulation compared to the oral formulation (F relative [[ID=2​​​​​​​In univariate analysis, the K of the injection site a Impact on RTU, gender K a The effects on RTU and the effects of sex on FRAC1 were statistically significant and were carried over to the next analysis. Because injections into the deltoid muscle were few (the intended injection site for Ari 2MRTU 960 or Ari 2MRTU 720 is the buttocks), the K of the injection site was considered. a The impact on RTU was excluded from the final covariate model, and in the sensitivity analysis, the parameter estimates of the base model without deltoid injection data were very similar to those of the base model with all data. Therefore, in the final covariate model, sex was FRAC1 and K a Only the effect on RTU was retained, and neither was removed in the backward removal step.

[0147] Final model

[0148] Table 1 shows the parameter estimates for the final model; parameters that were not fixed were estimated with a relative standard error percentage (% RSE) < 15%.

[0149] Table 1: Pharmacokinetic parameters of the final aripiprazole population pharmacokinetic model [Table 1] TIFF2026514220000003.tif200151 TIFF2026514220000004.tif201151

[0150] AOM, aripiprazole once a month; Ari, aripiprazole; BMI, body mass index; CV, coefficient of variation; CYP, cytochrome P450; K a LAI (First Absorption Rate Constant), NA (None), RSE (Relative Standard Error), RTU (Ready to Use), SD (Standard Deviation).

[0151] According to the final model, in a typical individual, the first peak in concentration occurred 6.75 days (162.1 hours) after administration of the Ari RTU LAI formulation. The fractions absorbed in the primary and zero-order processes were 79.3% and 20.7% in women and 62.7% and 37.3% in men, respectively. Primary absorption began after a delay of 17.5 days (419 hours). In women, K a This corresponds to an absorption half-life of 22.7 days, with a rate of 0.00127 / hour. In men, K a The absorption rate was 0.00242 / hour, corresponding to an absorption half-life of 11.9 days. After the initial dose, a second peak occurred at 41 days post-administration in typical women and 32 days post-administration in typical men. At steady state, a second peak occurred at 33 days post-administration in typical women and 28 days post-administration in typical men. Ari RTU LAI formulation F relative The ratio was 1.58 for oral formulations and 1.06 for AOM formulations.

[0152] Influence of covariates

[0153] Regarding retained covariates, K a The RTU (i.e., absorption rate constant) was 90.7% higher in men than in women, while the FRAC1 (i.e., primary absorption fraction) was 56.0% lower in men than in women.

[0154] For the target covariate combination, typical PK profiles were simulated by fixing all other covariates to baseline values ​​and all random effects to zero. These were then compared across covariate categories in a steady state (C avg,ss ), C max,ss , and C min,ssThe mean concentrations were plotted on the same graph for visual comparison over 48 weeks (i.e., 6 consecutive doses of Ari 2MRTU 960 at 8-week intervals). In previous models, CYP2D6 metabolic status was identified as a covariate of aripiprazole CL / F, and this is maintained in the current analysis; therefore, simulations were performed separately for low-metabolizers and normal-metabolizers of CYP2D6. Depending on the CYP2D6 metabolic status after repeated administration of Ari 2MRTU 960 to a steady state (20 doses), sex was used to determine the aripiprazole exposure parameter (C avg,ss , C max,ss , and C min,ss Table 2 shows the results of simulations demonstrating the effect on ), and Figure 2 shows a graphical evaluation of the retained covariate effects. In Figure 2, the following abbreviations are used, where Ari 2MRTU 960 is aripiprazole 960 mg prepared for 2 months of use; and CYP is cytochrome P450.

[0155] Men had higher peak concentrations of aripiprazole than women (12% higher in normal metabolizers and 6% higher in low metabolizers), but lower trough concentrations (22% lower in normal metabolizers and 10% lower in low metabolizers). avg,ss No gender differences were observed. As expected, simulated aripiprazole concentrations were higher in individuals with low CYP2D6 metabolism compared to those with normal metabolism, and based on the simulated data (Table 2), C in individuals with low CYP2D6 metabolism was higher. avg,ss This was approximately twice as high (97.4%) as that of individuals with normal metabolism.

[0156] Table 2. Simulated typical aripiprazole exposure parameters at steady state, based on CYP2D6 metabolic status and sex, after repeated administration of Ari 2MRTU 960. [Table 2]

[0157] Ari 2MRTU 960, Aripiprazole 960mg, ready for 2 months of use;C avg,ss , average concentration in a steady state; Cmax,ss , maximum concentration in a steady state; C min,ss , minimum concentration in a steady state; CYP, cytochrome P450.

[0158] The standard goodness-of-fit diagnostic plot of the final model is shown in Figure 3; overall, the final model was able to adequately explain the aripiprazole concentration after administration of the Ari RTU LAI formulation. The slight overprediction at treatment initiation seen in external validation of the previous model with AOM 400 data from study number 031-201-00181 was not present in the fit of the final model.

[0159] In Figure 3, circles represent observed data. The solid black line in the upper panel represents the integrated line. The solid black line in the lower panel represents the zero intercept. The dashed black line with a conditionally weighted residual of ±4 is provided as a baseline for identifying potential outliers. The dashed gray line represents locally estimated scatter plot leveling. The abbreviations AOM stands for aripiprazole once-monthly administration, and Ari RTU LAI stands for aripiprazole ready-to-use long-acting injectable.

[0160] Based on the predictive corrected VPC (pcVPC) and nonparametric VPC, the model's predictive performance was considered adequate. Overall, the pcVPC demonstrated good predictive performance in the final model, as evidenced by the fact that the distribution of observed data was equivalent to the 90% prediction interval of individual predictions (Figure 4).

[0161] In Figure 4, the dashed line represents the observed data (median; 5). th and 95 th The black line represents the percentile. The solid line represents the simulated data (median; 5%). th and 95 th The black area represents the percentile. The shaded area shows the simulated median and 5 percentiles. th and 95 th This represents the 95% confidence interval for the percentile. The abbreviation AOM refers to aripiprazole administered once a month, and Ari RTU LAI refers to aripiprazole ready-to-use long-acting injectable formulation.

[0162] Using the final popPK model, aripiprazole plasma concentration-time profiles were simulated as a means of investigating the manner of Ari 2MRTU administration, reflecting various scenarios that may occur in clinical practice.

[0163] Start of treatment

[0164] Across multiple treatment initiation scenarios, Ari 2MRTU 960 delivered plasma concentrations of aripiprazole equivalent to those of AOM 400. This includes the following cases: initiating administration of Ari 2MRTU 960 after switching from AOM 400 (Figure 5A); initiating administration of Ari 2MRTU 960 and continuing oral aripiprazole for 14 days in patients previously stabilized with oral aripiprazole 10 or 20 mg / day (Figures 5B and 5C); initiating administration of Ari 2MRTU 960 and continuing oral aripiprazole for 14 days in patients not previously stabilized with oral aripiprazole (Figures 5D and 5E); administering AOM 400 on day 0, then initiating administration of Ari 2MRTU 960 on day 28, and continuing oral aripiprazole for 14 days in patients previously stabilized with oral aripiprazole 20 mg / day (Figure 5F); and administering AOM 400 on day 0, then initiating administration of Ari 2MRTU 960 on day 28 in patients not previously stabilized with oral aripiprazole Treatment was initiated with 960, followed by a 14-day overlapping administration of 20 mg / day of oral aripiprazole (Figure 7). Figure 7 is a graph of the simulated median aripiprazole concentration-time profile for Ari 2MRTU 960 on day 28, following administration of AOM on day 0 (overlapping administration of 20 mg of oral aripiprazole to patients not previously stabilized with oral aripiprazole). For comparison, Figure 7 includes solid black lines representing the simulated results for the same patients treated with AOM 400 on days 28 and 56. The baseline is the plasma concentration (95 ng / mL) identified as the lower effective threshold for preventing immediate relapse, and the simulated C after a 1-day administration of 30 mg of oral aripiprazole. max,ss This represents the 75th percentile (534 ng / mL).

[0165] In Figures 5A–5F, for comparison, each figure includes a solid black line representing the simulation results for the same patient treated with AOM 400 (same oral duplicate dosing, where applicable). The baseline is the plasma concentration (95 ng / mL) identified as the lower effective threshold for preventing immediate relapse, and the simulated C after a 1-day dose of 30 mg of oral aripiprazole. max,ss This represents the 75th percentile (534 ng / mL). Regarding abbreviations, AOM 400 means aripiprazole 400 mg once a month; Ari 2MRTU 960 means aripiprazole 960 mg prepared for 2 months of use; C max,ss This represents the maximum concentration in a steady state.

[0166] 2. Scenarios associated with injection initiation (i.e., administration of Ari 2MRTU 960 and AOM 400 to separate injection sites, plus a single dose of oral aripiprazole 20 mg, all administered on the first day of treatment) resulted in more stable plasma concentrations of aripiprazole compared to a single dose of Ari 2MRTU 960 combined with 14 days of oral aripiprazole 10 mg / day or 20 mg / day. This was the case for patients who were previously stabilized with oral aripiprazole 10 mg / day (Figure 8A), 20 mg / day (Figure 8B), and 30 mg / day (Figure 8C), and patients who were not previously stabilized with oral aripiprazole (Figure 8D). For comparison, the red lines in Figures 8A-8D show the simulation results for the same patients treated with Ari 2MRTU 960 on day 0 and double-administered oral aripiprazole 10 mg or 20 mg on days 0-13. Figure 8D includes solid red and dotted green lines showing the simulation results for the same patients treated with Ari 2MRTU 960 on day 0 and given duplicate doses of 10 mg or 20 mg of oral aripiprazole, respectively, from days 0 to 13. The baseline represents the plasma concentration (95 ng / mL) identified as the lower effective threshold for preventing immediate relapse, and the simulated C1 after a 1-day dose of 30 mg of oral aripiprazole. max,ssThis represents the 75th percentile (534 ng / mL). Regarding abbreviations, AOM 400 means aripiprazole 400 mg once monthly; Ari 2MRTU 960 means aripiprazole 960 mg prepared for 2 months; and C max,ss This represents the maximum concentration at steady state. The median simulated aripiprazole concentrations in pre-stabilized or unstabilized CYP2D6 hypometabolized individuals using two injection initiations (i.e., Ari 2MRTU 720 and AOM 300 administered to separate injection sites, followed by a single 20 mg oral aripiprazole dose, all administered on the first day of treatment) are shown in Figures 11 and 12. The baseline is C after a 1-day administration of 10 mg oral aripiprazole. min,ss The median C value (94.0 ng / mL) was the C value after 1 day of oral aripiprazole 30 mg administration. max,ss 75 th Percentile value (534 ng / mL), and C after 1 day administration of oral aripiprazole 30 mg. max,ss 95 th This represents the percentile (741 ng / mL).

[0167] Missed dose / delayed dose

[0168] Missed / delayed doses were simulated to investigate the impact of insufficient adherence to Ari 2MRTU 960 (Figure 6). In scenarios where Ari 2MRTU 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. The median trough plasma concentrations 56 days after delayed administration increased to 231 ng / mL, 217 ng / mL, 205 ng / mL, and 196 ng / mL, respectively (in the last case, administration was a 14-day overlap of oral aripiprazole 10 mg / day).

[0169] In Figure 6, the baseline is the plasma concentration (95 ng / mL) identified as the lower effective threshold for preventing immediate relapse [Wang et al., 2022] and the simulated C after a 1-day administration of oral aripiprazole 30 mg.max,ss 75 th This represents the percentile (534 ng / mL). Regarding abbreviations, Ari 2MRTU 960 means aripiprazole 2-month preparation 960 mg, and C max,ss This represents the maximum concentration in a steady state.

[0170] CYP2D6 metabolic status

[0171] Simulations of Ari 2MRTU 720 in CYP2D6 dymetabolists showed that the steady-state concentration of aripiprazole was non-inferior to AOM 300 (Figure 9). For comparison, Figure 9 includes a solid black line representing the simulation results for the same patients treated with AOM 300. The baseline line represents the plasma concentration (95 ng / mL) identified as the lower effective threshold for preventing immediate relapse, and the simulated C after 1 day of oral aripiprazole 30 mg administration. max,ss This represents the 75th percentile (534 ng / mL). Regarding abbreviations, AOM 300 means aripiprazole 300 mg once a month; 2MRTU 720 means aripiprazole 720 mg prepared for 2 months of use; C max,ss is the maximum concentration in a steady state; CYP is cytochrome P450.

[0172] Long-term combination therapy with CYP2D6 or CYP3A4 inhibitors

[0173] Adding a potent inhibitor, CYP3A4, to Ari 2MRTU 720 resulted in a median steady-state plasma concentration comparable to that of Ari 2MRTU 960 without the addition of either CYP3A4 or CYP2D6. In contrast, adding a potent CYP2D6 inhibitor to Ari 2MRTU 720 resulted in a higher median steady-state plasma concentration compared to Ari 2MRTU 960 without the addition of either CYP3A4 or CYP2D6 (Figure 10). For comparison, Figure 10 includes a solid black line representing the simulated results for the same patients treated with Ari 2MRTU 960. The baseline represents the plasma concentration identified as the lower effective threshold for preventing immediate relapse (95 ng / mL), [Wang et al 2022], and the simulated C after 1 day of oral aripiprazole 30 mg. max,ss 75 th This represents the percentile value (534 ng / mL). Regarding the abbreviations, Ari 2MRTU 720 means 720 mg of aripiprazole prepared for 2 months of use; Ari 2MRTU 960 means 960 mg of aripiprazole prepared for 2 months of use; Cmax,ss means the maximum concentration at steady state; and CYP means cytochrome P450.

[0174] The standard two-injection initiation scenario (i.e., administration of Ari 2MRTU 960 and Ari 2MRTU 960 to separate injection sites, plus a single dose of oral aripiprazole 20 mg, all administered on the first day of treatment) delayed the time to reach therapeutic exposure levels. In this standard two-injection initiation, therapeutic concentrations of aripiprazole were not maintained after the first week of treatment.

[0175] Discussion

[0176] PopPK analysis is a well-established quantitative method that explains interpersonal variability in drug concentrations, including intrinsic and extrinsic factors, dose differences, and routes of administration. Such analyses are frequently performed as part of the drug development process to provide dosing regimens to be tested in future clinical trials. PopPK models can also be used to simulate PK profiles in scenarios beyond those studied clinically.

[0177] This paper describes the development and use of a popPK model to characterize the PK of a novel RTU LAI formulation of aripiprazole administered every two months. Based on 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 first-order delayed absorption. In the analysis of exogenous and endogenous covariates that may influence the absorption characteristics of Ari RTU LAI, sex was identified as a statistically significant covariate; specifically, men were observed to absorb more rapidly than women, and sex was associated with first-order absorption and first-order delayed absorption. a It was found that sex affects the fraction. The finding that sex is a statistically significant covariate of Ari RTU LAI absorption was consistent with AOM absorption in the previous model on which the current model is based; however, direct comparison was not possible due to the different structures of the absorption models (i.e., AOM uses first-order absorption, while Ari RTU LAI uses parallel zero-order and first-order absorption). Sex affects the fractions of first-order and zero-order absorption in Ari RTU LAI as well as first-order K a It was found to affect both, but the combination of these effects was not expected to be clinically relevant. This is because, compared to women, C in men avg,ss The typical PK profile after repeated administration of Ari 2MRTU 960, which showed no difference in values, was confirmed by simulation. The effect of CYP2D6 metabolic status was retained as a covariate from previous models and simulated C avg,ss It was found that CYP2D6 levels were approximately twice as high (97.4%) in individuals with low metabolism compared to those with normal metabolism.

[0178] Using the final popPK model, simulations were performed to evaluate the administration of Ari 2MRTU 960 and Ari 2MRTU 720 across multiple realistic clinical situations. Various treatment initiation scenarios were simulated, taking into account different prior treatments (i.e., whether the patient was stabilized with oral aripiprazole or AOM 400). The use of 14 days of overlapping oral aripiprazole, or two-injection initiation of Ari 2MRTU 960 and AOM, as well as a single dose of oral aripiprazole, was also simulated as a means of achieving therapeutic exposure more rapidly, considering the very slow absorption of Ari 2MRTU 960. The simulations also considered Ari 2MRTU 720 mg in CYP2D6 hypometabolists, as well as in long-term users of potent CYP2D6 and CYP3A4 inhibitors. This is important because CYP2D6 hypometabolism is known to affect the pharmacokinetic status of aripiprazole, and the AOM label recommends a 300 mg dose every four weeks for CYP2D6 hypometabolists. Furthermore, both CYP2D6 and CYP3A4 are involved in aripiprazole elimination. Two-injection initiation of Ari 2MRTU 720 and AOM, as well as a single dose of oral aripiprazole, were simulated as means of achieving therapeutic exposure more rapidly, considering the very slow absorption of Ari 2MRTU 720. Simulation data showed that, as shown in Figure 13, it took several days for the aripiprazole concentration to reach 95 ng / mL with a single dose of 780 mg RTU or a single dose of 1200 mg RTU, and that two-injection initiation allowed for rapid attainment of therapeutic exposure, even without a dramatic change in the initiation rate when the dose was increased from 780 mg to 1200 mg. Figure 13 shows the results of a Phase 1, open-label, single-dose escalation, parallel-group study to determine the pharmacokinetics, safety, and tolerability of a 2-month intramuscular depot of aripiprazole administered intrabutrially to adult subjects with schizophrenia, as described in U.S. Patent Application Publication No. 2022 / 0,160,621 A1, which is incorporated herein by reference in its entirety.

[0179] Finally, simulations of missed / delayed administration were performed to evaluate the impact of insufficient adherence at a 2-month dosing interval. Overall, the simulations showed that the PK exposure profile of Ari RTU LAI was comparable to that of AOM with longer dosing intervals.

[0180] The data presented herein provide clinicians with useful information relating to various dosing scenarios of aripiprazole 2-month RTU LAI formulations. While it is impractical / impossible to include all possible dosing scenarios in efficacy and safety studies, popPK modeling and simulation address this by generating PK profiles for scenarios other than those specifically studied, as part of a clinical trial program. In this way, modeling and simulation function as a “virtual” clinical trial, allowing for the exploration of more scenarios than can be performed in an actual clinical trial. Nevertheless, any simulations presented herein must be interpreted in the context of the approved use of Ari 2MRTU 960 and Ari 2MRTU 720, depending on the patient type, prior treatment, and / or country / region.

[0181] The popPK model was developed to characterize the pharmacokinetics (PK) of Ari 2MRTU 960 and subsequently used to conduct model-based simulations investigating various aspects of administration of this novel formulation. The final model was deemed suitable for the purpose of adequately explaining the PK of plasma aripiprazole concentrations after administration of Ari 2MRTU 960; this model established estimates of key popPK parameters and identified sources of drug exposure variability. Simulations across various dosing regimens reasonably occurring in clinical practice demonstrated a PK exposure profile comparable to that of AOM with longer dosing intervals.

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

[0183] Any claim or description containing "or" or "and / or" among at least one member of a group is considered satisfied unless otherwise indicated or is evident from the context, if one, one or more, or all members of the group are present in, used in, or otherwise related to a given product or process. This disclosure includes embodiments in which exactly one member of the group is present in, used in, or otherwise related to a given product or process. This disclosure includes embodiments in which one or more, or all, members of the group are present in, used in, or otherwise related to a given product or process.

[0184] Furthermore, this disclosure includes any modifications, combinations, and rearrangements in which at least one limitation, element, clause, and descriptive term derived from at least one enumerated claim is introduced into another claim. For example, any claim dependent on another claim may be modified to include at least one limitation found in any other claim dependent on the same basic claim. Where elements are presented as a list, for example in Markush group form, each subgroup of the elements is also disclosed, and any element may be removed from a group. Generally, where this disclosure or an aspect thereof is referred to as including a particular element and / or feature, it should be understood that embodiments of this disclosure or an aspect thereof consist of, or essentially consist of, such element and / or feature. For brevity, these embodiments are not described verbatim in this specification. Where a scope is indicated, the endpoint of the scope is also included. Furthermore, unless otherwise indicated, or unless the context and the understanding of those skilled in the art are clear, values ​​expressed as a range may, unless the context clearly indicates otherwise, assume any specific value or subrange within the ranges defined in different embodiments of this disclosure, up to 10 times the unit of the lower limit of the range.

[0185] Those skilled in the art will be able to identify or confirm numerous equivalents of the specific embodiments of the disclosure described herein by means of routine experimentation alone. Such equivalents are intended to be encompassed in the following claims.

Claims

1. A method for initiating aripiprazole treatment in patients requiring treatment, including the following steps: The procedure involves administering two separate injections of aripiprazole to injection sites selected from the patient's buttocks, deltoid muscle, and combinations thereof, 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, as well as a single dose of oral aripiprazole, the administration of which is performed on the first day of aripiprazole LAI treatment.

2. The method according to claim 1, wherein the first LAI formulation is in a gel-like state when left standing and changes to a sol-like state 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 the step of administering a maintenance dose of the first LAI formulation approximately once every two months after the first day of aripiprazole LAI treatment.

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

7. The method according to claim 6, wherein if the patient is a CYP2D6 hypometabolizer or has been concomitantly taking a CYP3A4 inhibitor or a CYP2D6 inhibitor for more than 14 days, the maintenance dose of the first LAI formulation is 720 mg of aripiprazole.

8. The method according to any one of claims 1 to 7, wherein two separate injections of aripiprazole are administered to separate injection sites on the patient's buttocks.

9. The method according to any one of claims 1 to 7, wherein two separate injections of aripiprazole are administered to the injection sites of the patient's buttocks and deltoid muscle.

10. The method according to any one of claims 1 to 7, wherein two separate injections of aripiprazole are administered to separate injection sites in the deltoid muscle of the patient.

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

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

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

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

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

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

17. The method according to claim 1, wherein the patient is a CYP2D6 hypometabolizer or has been concomitantly taking a CYP3A4 inhibitor or a CYP2D6 inhibitor for more than 14 days, and the first injection comprises 720 mg of aripiprazole, the second injection comprises 400 mg or 300 mg of aripiprazole, and the single oral dose comprises about 10 mg or about 20 mg of aripiprazole.

18. The method according to claim 17, wherein the patient is a CYP2D6 hypometabolist or has been concomitantly taking a CYP3A4 inhibitor or a CYP2D6 inhibitor for more than 14 days, and the first injection comprises 720 mg of aripiprazole, the second injection comprises 300 mg of aripiprazole, and the single oral dose comprises approximately 20 mg of aripiprazole.

19. The method according to 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 comprises about 10 mg or about 20 mg of aripiprazole.

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

21. A method comprising the following steps for treating schizophrenia or bipolar disorder type I in patients requiring treatment: The procedure involves administering two separate injections of aripiprazole to the patient's gluteal region, deltoid region, and / or combination thereof, each injection comprising 960 mg or 720 mg of aripiprazole in a first long-acting injectable (LAI) formulation and 400 mg or 300 mg of aripiprazole in a second LAI formulation, as well as a single oral aripiprazole dose, wherein the administration procedure is performed on the first day of aripiprazole LAI treatment, and the oral aripiprazole dose is in the range of approximately 10 mg to approximately 20 mg of aripiprazole; and, The process involves continuing the administration of a maintenance dose of a first LAI formulation containing 960 mg or 720 mg of aripiprazole, wherein the maintenance dose is administered approximately once every two months after the first day of aripiprazole LAI treatment.

22. The method according to 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 comprises about 10 mg or about 20 mg of aripiprazole.

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

24. The method according to 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 comprises about 10 mg or about 20 mg of aripiprazole.

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

26. The method according to claim 21, wherein the oral administration of aripiprazole comprises approximately 20 mg of aripiprazole.

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

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