JP-2026514220-A - 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 aripiprazole injection of a long-acting injectable formulation (LAI) and a second aripiprazole injection of an aripiprazole once-monthly injectable formulation (AOM), as well as a single oral aripiprazole dose. Maintenance administration is performed approximately two months after the first day of aripiprazole treatment using a maintenance LAI. This method is applicable to both gluteal and deltoid muscle administration sites.

Inventors

• ハルリン，マシュー
• ワン，シャオフェン
• ワン，ヤンリン
• ラウフィニア，アラシュ

Assignees

• 大塚製薬株式会社

Dates

Publication Date

20260507

Application Date

20240426

Priority Date

20230426

Claims (20)

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 hypometabolist or has been concomitantly using 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 in 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 patient's deltoid muscle.
11. The method according to any one of claims 1 to 10, wherein the patient suffers from schizophrenia.
12. The method according to any one of claims 1 to 10, wherein the patient suffers from 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 approximately 10 mg to approximately 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 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.
18. The method according to claim 17, 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 300 mg of aripiprazole, and a single oral dose of aripiprazole 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 of aripiprazole comprises approximately 10 mg or approximately 20 mg of aripiprazole.
20. The method according to claim 19, wherein the first injection contains 960 mg of aripiprazole, the second injection contains 400 mg of aripiprazole, and a single oral dose of aripiprazole contains approximately 20 mg of aripiprazole.

Description

This application claims priority to U.S. Provisional Application No. 63/498,313, filed April 26, 2023, No. 63/506,624, filed June 7, 2023, and No. 63/637,079, filed April 22, 2024, the contents of which are incorporated herein by reference in their entirety. 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. 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). Furthermore, a novel ready-to-use (RTU) LAI formulation of aripiprazole monohydrate, administered once every two months via intramuscular buttock injection, 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. The 960 mg aripiprazole 2-month preparation (Ari 2MRTU 960) was developed to extend the maintenance of therapeutic plasma concentrations of aripiprazole from one month to two months using the AOM 400 mg formulation (AOM 400); this is achieved through several considerations, including increased dosing to maintain a minimum aripiprazole concentration similar to that after multiple doses of AOM, as well as other formulation and administration considerations. Compared to other formulations, Ari 2MRTU 960 requires fewer doses (i.e., 6 injections per year for Ari 2MRTU 960 compared to 12 injections per year for AOM), potentially reducing the medication burden on patients and physicians and improving adherence to antipsychotics in adult patients with schizophrenia or BP-I. 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), the previously developed and validated population pharmacokinetic (popPK) model was expanded to include the novel RTU LAI formulation of aripiprazole (Ari RTU LAI) to characterize aripiprazole plasma concentrations after oral administration or after AOM administration to the gluteal or deltoid muscle. This expansion of popPK modeling provides additional options for initiating aripiprazole treatment in patients. For example, this disclosure relates to a method for initiating aripiprazole treatment in patients requiring treatment, comprising 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 the 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 comparable to that of AOM. In some embodiments, this disclosure relates to a method for initiating administration of aripiprazole for treatment of a patient in need of 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 a first injection containing 960 mg or 720 mg of aripiprazole in a long-acting injectable (LAI) and a second injection containing 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. In some embodiments, this disclosure relates