Methods for initiating aripiprazole treatment

Abstract

The present disclosure is directed to a method of initiating aripiprazole therapy in a patient in need thereof, wherein the patient is administered two separate 100-500 mg injections of an intramuscular (IM) depot formulation of aripiprazole into separate gluteal and / or deltoid muscle injection sites and a single dose of oral aripiprazole, administered on day 1 of treatment.

Description

Technical Field

[0001] This application claims the priority of U.S. Provisional Application No. 63 / 003,544, filed on April 1, 2020, the content of which is incorporated herein by reference in its entirety.

Background Art

[0002] Aripiprazole, a partial agonist at the dopamine (D2) and serotonin 5-HT1A receptors and an antagonist at the serotonin 5-HT2A receptor, is an atypical antipsychotic that has demonstrated efficacy in clinical trials for the treatment of schizophrenia and bipolar disorder type I in adults. Abilify Maintena® is an intramuscular (IM) depot formulation of aripiprazole and is a long-acting release suspension injection. It is approved in many countries for the maintenance treatment of schizophrenia in adult patients stabilized on oral aripiprazole.

Summary of the Invention

Problems to be Solved by the Invention

[0003] Monthly aripiprazole is a long-acting IM injection formulation of aripiprazole indicated for the maintenance treatment of schizophrenia and bipolar disorder type I in adult patients stabilized on oral aripiprazole. In the currently approved pharmaceutical product Abilify Maintena®, the first dose is administered with oral aripiprazole (10 mg to 20 mg) concomitantly for 14 consecutive days to adult patients stabilized on oral aripiprazole. In patient populations where there is a potential risk for recurrence or suboptimal treatment outcomes related to adherence (e.g., the patient population for long-acting injectables (LAIs)), achieving therapeutic plasma concentrations in treatment can provide therapeutic benefits.

Means for Solving the Problems

[0004] To provide additional options for this initiation phase, an initiation regimen is provided, based on population pharmacokinetic (population PK) modeling and simulation, that initiates two separate injections of aripiprazole, once monthly, into separate injection sites in the gluteal muscle and / or deltoid muscle, accompanied by a single oral dose of aripiprazole on day 1 of treatment. For example, this disclosure covers an alternative initiation regimen of two separate injections of an intramuscular (IM) depot formulation of aripiprazole, e.g., Abilify Maintena®, which overlaps with a shorter oral administration period. Simulations of an alternative initiation regimen of two injections of an intramuscular (IM) depot formulation of aripiprazole, e.g., in separate injection sites in the gluteal muscle and / or deltoid muscle, accompanied by a single oral dose of aripiprazole on day 1 of treatment, demonstrate sufficient evidence that the alternative initiation regimen may be an additional option for initiating Abilify Maintena®.

[0005] In some embodiments, the Disclosure relates to a method for initiating aripiprazole therapy in a patient in need thereof, comprising administering two separate injections of an aripiprazole intramuscular (IM) depot formulation, each injection comprising approximately 10 mg to approximately 500 mg of aripiprazole to the patient at separate gluteal and / or deltoid injection sites, and a single dose of oral aripiprazole, wherein the administration step is performed on day 1 of treatment.

[0006] In an additional embodiment, each of the two separate injections contains approximately 400 mg of aripiprazole. Furthermore, the method of the present disclosure further comprises administering a single monthly maintenance injection of aripiprazole IM depot formulation after day 1 of treatment. For example, in another embodiment, the single monthly maintenance injection is selected from approximately 300 mg and approximately 400 mg of aripiprazole in the aripiprazole IM depot formulation. In a further embodiment, if the patient is a CYP2D6 poor metabolizer or if the patient is taking a concurrently administered CYP3A4 inhibitor or CYP2D6 inhibitor for longer than 14 days, the single monthly maintenance injection is selected from 160 mg and 200 mg of aripiprazole in the aripiprazole IM depot formulation.

[0007] In a further embodiment, two separate injections of aripiprazole IM depot formulation are administered to separate injection sites in the patient's gluteal muscle. Furthermore, two separate injections of aripiprazole IM depot formulation are administered to injection sites in the patient's gluteal muscle and deltoid muscle. For example, two separate injections of aripiprazole IM depot formulation are administered to separate injection sites in the patient's deltoid muscle.

[0008] In one aspect of this disclosure, the patient has schizophrenia. In another aspect, the patient has bipolar disorder type 1.

[0009] In some further embodiments, the single dose of oral aripiprazole is in the range of approximately 2 mg to approximately 30 mg. For example, the single dose of oral aripiprazole is in the range of approximately 10 mg to approximately 30 mg. Furthermore, for example, the single dose of oral aripiprazole is 20 mg. Also, in some further embodiments, the single dose of oral aripiprazole is 10 mg.

[0010] In some further embodiments, if the patient is a CY2D6 poor metabolizer, each of the two separate injections contains approximately 300 mg of aripiprazole, and the single dose of oral aripiprazole is approximately 20 mg.

[0011] In some further embodiments, the Disclosure relates to an aripiprazole intramuscular (IM) depot formulation comprising about 10 mg to about 500 mg of aripiprazole, for use in combination with a single dose of oral aripiprazole, to administer two separate injections of the aripiprazole intramuscular (IM) depot formulation to a patient in need, at an injection site selected from the gluteal muscle site, the deltoid muscle site, and combinations thereof, the administration step being performed on day 1 of treatment.

[0012] In some further embodiments, the Disclosure relates to aripiprazole or a salt thereof for use in the treatment of schizophrenia or bipolar disorder type I, wherein aripiprazole or a salt thereof is administered to a patient in need by any of the methods of initiating aripiprazole therapy as described herein. Furthermore, the Disclosure also provides the use of aripiprazole or a salt thereof in the manufacture of a pharmaceutical product, wherein aripiprazole or a salt thereof is administered to a patient in need by any of the methods of initiating aripiprazole therapy as described herein. [Brief explanation of the drawing]

[0013] [Figure 1] Figure 1 is a structural model showing aripiprazole PK after oral administration and IM injection in the gluteal and deltoid muscles.

[0014] [Figure 2] Figures 2A-2D show the visually corrected posterior predictive performance evaluation of the combined final population pharmacokinetic (popPK) model.

[0015] [Figure 3] Figures 3A-3C show the purpose of the simulation and the table containing the information.

[0016] [Figure 4]Figures 4A to 4D are diagrams of simulated median (5th to 95th percentile) aripiprazole concentration-time profiles after current or alternative starting regimens and subsequent 400 mg intramuscular depot drug administrations every 28 days. The shading represents the 5th to 95th percentile.

[0017] [Figure 5] Figures 5A and 5B are diagrams of simulated median, 5th, 25th to 75th, and 95th percentile pharmacokinetic profiles after administration of current or alternative starting regimens to subjects already stabilized on 20 mg oral aripiprazole. The shading and dashed lines represent the 5th, 25th to 75th, and 95th percentiles, respectively.

[0018] [Figure 6] Figures 6A and 6B are diagrams of simulated median aripiprazole concentration-time profiles and box plots of Cmax after the Evlefan (registered trademark) starting regimen for CYP2D6 extensive and poor metabolizers. The box plots show the 5th, 25th, median, 75th, and 95th percentiles of Cmax.

[0019] [Figure 7] Figures 7A and 7B are diagrams of simulated median aripiprazole concentration-time profiles and box plots of Cmax after the Evlefan (registered trademark) starting regimen for extensive and poor metabolizers already stabilized on oral aripiprazole. The box plots show the 5th, 25th, median, 75th, and 95th percentiles of Cmax.

[0020] [Figure 8] Figures 8A to 8D are diagrams of simulated median pharmacokinetic profiles after initiation and re-initiation using current or alternative starting regimens 5 weeks after previous intramuscular depot drug administration.

[0021] [Figure 9] Figures 9A–9D show the simulated median pharmacokinetic profiles 6 weeks after previous intramuscular depot administration, after initiation and reinitiation using the current or alternative initiation regimen.

[0022] [Figure 10] Figure 10 illustrates simulated and observed aripiprazole concentrations after oral and intramuscular depot administration of aripiprazole, supporting the definition of the therapeutic range.

[0023] [Figure 11] Figure 11 shows the plasma concentration-time profiles of the aripiprazole composition after single-dose administration of 780 mg (N=18) or 1200 mg (N=13) of sustained-release aripiprazole injection, and the mean plasma concentrations after single-dose administration of 400 mg Abilify Maintena® into the gluteal muscle of subjects with schizophrenia. The shaded areas represent the 5th to 95th percentiles of the predictive model of the PK profile after the initiation regimen of 20 mg oral + 2 × 400 mg IM Maintena® into the gluteal muscle.

[0024] [Figure 12] Figure 12 shows the mean (SD) aripiprazole plasma concentration-time profiles after administration of a ready-to-use single dose of 780 mg (N=18) or 1200 mg (N=13) of aripiprazole 2M sustained-release injection to the gluteal muscles of subjects with schizophrenia.

[0025] [Figure 13] Figure 13 illustrates the observed weekly aripiprazole plasma concentrations after the first intramuscular depot injection. The boxes represent plasma concentrations above 534 ng / mL during 10–20 overlapping oral doses over two weeks following the first IM injection. [Modes for carrying out the invention]

[0026] As used herein, the entity "a" or "an" refers to one or more such entities; for example, "a compound" refers to one or more compounds or at least one compound unless otherwise stated. Thus, the terms "a" (or "an"), "one or more," and "at least one" are used interchangeably herein.

[0027] As used herein, the term “approximately” means roughly, within the range of, roughly, or around. When the term “approximately” is used in conjunction with a numerical range, it modifies the range by extending above and below the boundaries of the stated numerical value. Generally, the term “approximately” is used herein to modify a numerical value by a 5% variation above or below the stated value.

[0028] As used herein, the terms “to treat,” “treating,” or “to cure” include any effect resulting in improvement of the disorder or condition, such as reducing, decreasing, regulating, restoring, or eliminating the disorder or condition, when used in relation to the disorder or condition. Improvement or reduction in the severity of any symptom of the disorder or condition can be readily assessed according to standard methods and techniques known in the art. In some embodiments, the methods or depot formulations disclosed herein can be used as monotherapy maintenance to treat schizophrenia and bipolar disorder type I. In further embodiments, the methods or depot formulations disclosed herein can be used to treat schizophrenia, the acute treatment of manic and mixed symptom manifestations associated with bipolar disorder type I, major depressive disorder (MDD), irritability associated with autism spectrum disorder, and Tourette syndrome.

[0029] As used herein, “mammal” refers to domestic animals (e.g., dogs, cats, and horses) and humans. In some embodiments, the mammal is a human.

[0030] Embodiments: Without limitation, some embodiments of this disclosure include:

[0031] 1. A method for initiating aripiprazole treatment for patients who require it, A method comprising administering two separate injections of an aripiprazole intramuscular (IM) depot formulation, each injection containing approximately 10 mg to approximately 500 mg of aripiprazole to the patient at separate gluteal muscle and / or deltoid muscle injection sites, and a single dose of oral aripiprazole, wherein the administration step is performed on day 1 of treatment.

[0032] 2. The method according to Embodiment 1, wherein each of 2 separate injections contains 400 mg of aripiprazole.

[0033] 3. The method according to Embodiment 1 or 2, further comprising administering a single monthly maintenance injection of aripiprazole IM depot formulation after day 1 of treatment.

[0034] 4. The method according to Embodiment 3, wherein a single monthly maintenance injection is selected from approximately 300 mg and approximately 400 mg of aripiprazole IM depot formulations.

[0035] 5. The method according to Embodiment 3, wherein if the patient is a CYP2D6 poor metabolizer or has been taking a concurrently administered CYP3A4 inhibitor or CYP2D6 inhibitor for longer than 14 days, a single monthly maintenance injection is selected from 160 mg and 200 mg aripiprazole IM depot formulations.

[0036] 6. The method according to any one of Embodiments 1 to 5, wherein two separate injections of aripiprazole IM depot formulation are administered to separate injection sites in the patient's gluteal muscle.

[0037] 7. The method according to any one of Embodiments 1 to 5, wherein two separate injections of aripiprazole IM depot formulation are administered to the injection sites of the patient's gluteal muscle and deltoid muscle.

[0038] 8. The method according to any one of Embodiments 1 to 5, wherein two separate injections of aripiprazole IM depot formulation are administered to separate injection sites in the patient's deltoid muscle.

[0039] 9. The method according to any one of Embodiments 1 to 8, wherein the patient has schizophrenia.

[0040] 10. The method according to any one of Embodiments 1 to 8, wherein the patient has bipolar disorder type I.

[0041] 11. The method according to any one of Embodiments 1 to 10, wherein the single dose of oral aripiprazole is in the range of approximately 2 mg to approximately 30 mg.

[0042] 12. The method according to Embodiment 11, wherein the single dose of oral aripiprazole is in the range of approximately 10 mg to approximately 30 mg.

[0043] 13. The method according to Embodiment 11, wherein the single dose of oral aripiprazole is 20 mg.

[0044] 14. The method according to Embodiment 11, wherein the single dose of oral aripiprazole is 10 mg.

[0045] 15. The method according to Embodiment 1, wherein, if the patient is a CY2D6 poor metabolizer, each of two separate injections contains approximately 300 mg of aripiprazole, and the single dose of oral aripiprazole is approximately 20 mg.

[0046] This disclosure relates to an alternative initiation regimen of two separate administrations of aripiprazole intramuscular (IM) depot formulations with overlapping shorter-term oral doses. For example, it demonstrates that a simulation of an alternative initiation regimen of two 400 mg injections of aripiprazole intramuscular (IM) depot formulations (e.g., Abilify Maintena®) at separate injection sites in the gluteal muscle and / or deltoid muscle, accompanied by a single dose of 20 mg oral aripiprazole on day 1 of treatment, is sufficient, and that the alternative initiation regimen may be an additional option to initiating Abilify Maintena®, for example.

[0047] Aripiprazole is 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydrocarbostyryl. The empirical formula is C 23 H 27 It is Cl2N3O2, and its molecular weight is 448.38. Its chemical structure is: [ka] That is the case.

[0048] As used herein, references to aripiprazole refer to aripiprazole or its salts, or to the crystalline forms of aripiprazole or its salts. Aripiprazole or its salts may be in monohydrate form (aripiprazole hydrate A) or various anhydrous forms, which 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, furthermore, for example, aripiprazole is in monohydrate form.

[0049] Pharmaceutical compositions containing aripiprazole are known as useful antipsychotic agents for the treatment of schizophrenia and bipolar disorder type I.

[0050] Conventional dosing regimen for aripiprazole

[0051] The conventional dosing regimen for aripiprazole includes the recommended starting and maintenance doses of Abilify Maintena®, which are 300 mg or 400 mg per month (26 days or more after the previous injection). For patients who have never taken aripiprazole, they should confirm their tolerance to oral aripiprazole before initiating treatment with Abilify Maintena®. Due to the half-life of oral aripiprazole, it may take up to two weeks to fully assess tolerability.

[0052] Following the first Abilify Maintena® injection, oral aripiprazole (10 mg to 20 mg) is administered for 14 consecutive days to achieve a therapeutic aripiprazole concentration during the initiation of therapy. For patients already stable on another oral antipsychotic (and known to tolerate aripiprazole), treatment with the antipsychotic is continued for 14 consecutive days after the first Abilify Maintena® injection to maintain a therapeutic antipsychotic concentration during the initiation of therapy.

[0053] If adverse reactions occur with a 400 mg dose, the dose may be reduced to 300 mg once a month.

[0054] Therefore, the currently approved initiation regimen consists of a single intramuscular injection of aripiprazole depot formulation, followed by 14 consecutive days of daily oral administration of aripiprazole (10-20 mg).

[0055] In this specification, references to aripiprazole intramuscular depot formulations refer to Abilify Maintena® (aripiprazole), and the prescribing information for the sustained-release suspension for intramuscular use is from the initial U.S. approval in 2002, which was revised in June 2020.

[0056] Alternative dosing regimens for aripiprazole

[0057] This disclosure relates to an alternative initiation regimen or treatment initiation that involves administering two separate injections of approximately 100 mg to approximately 500 mg of aripiprazole intramuscular depot formulation (Abilify Maintena®) to separate injection sites in the gluteal muscle and / or deltoid muscle, along with a single oral dose of aripiprazole on day 1 of treatment. The single oral dose of aripiprazole ranges from approximately 2 mg to approximately 30 mg; for example, a single oral dose of aripiprazole ranges from approximately 10 mg to approximately 30 mg. This alternative initiation regimen provides an option for the first dose or initiation dose of aripiprazole intramuscular depot formulation. The maintenance dose remains unchanged; for example, the maintenance dose is followed by a single monthly injection after a 400 mg or 300 mg aripiprazole IM depot formulation. Similar to conventional treatment initiation regimens, the alternative initiation regimen is applicable to both the deltoid and gluteal muscle injection sites.

[0058] This disclosure utilizes two separate aripiprazole intramuscular depot injections at doses ranging from approximately 100 to approximately 500 mg of aripiprazole. For example, the method of this disclosure involves administering two separate 400 mg injections of aripiprazole intramuscular (IM) depot formulation to separate injection sites in the patient's gluteal muscle and / or deltoid muscle, with the administration performed on day 1 of treatment. In some embodiments, the two separate injections of aripiprazole IM depot formulation are administered to separate injection sites in the patient's gluteal muscle or separate sites in the deltoid muscle. In further embodiments, the two separate injections of aripiprazole IM depot formulation are administered to injection sites in the patient's gluteal muscle and deltoid muscle. Furthermore, the patient has schizophrenia, and for example, the patient has bipolar disorder type I.

[0059] The rationale for selecting alternative initiation regimen doses is based on simulations using a population pharmacokinetic (popPK) model. The range of initiation regimens was considered to shorten the length of overlap between oral administration and the first IM depot injection while maintaining the median concentration within the previously defined therapeutic range and similar to that of currently approved initiation regimens (i.e., median concentration, 25th–75th percentile, and 5th–95th percentile). Based on the simulation results, the recommended dose for alternative initiation regimens is in the range of approximately 100 mg to approximately 500 mg, and in some embodiments, two 400 mg injections of aripiprazole intramuscular depot formulation at separate injection sites, e.g., gluteal muscle and / or deltoid muscle, accompanied by a single dose of oral aripiprazole on day 1 of treatment, for example, with a single dose of oral aripiprazole ranging from approximately 2 mg to 30 mg, for example, a single dose of oral aripiprazole ranging from approximately 20 mg.

[0060] Clinical pharmacology experiments

[0061] The objective of the clinical pharmacological experiment was to validate, using PK modeling and simulation techniques, a two-injection regimen of monthly sustained-release injectable aripiprazole to eliminate the need for 14 days of oral aripiprazole supplementation during initial treatment.

[0062] method

[0063] A previously developed popPK model (Food and Drug Administration: Center for Drug Evaluation and Research, Aripiprazole IM Depot Formulation: Clinical Pharmacology and Biopharmaceutical Overview (Application No. 202971s000) 2012)) was able to adequately characterize aripiprazole PK after oral administration and gluteal muscle IM depot injection, but this was extended to include injection at the deltoid muscle site. The final model was developed using PK data obtained from seven clinical trials after oral administration and IM depot injection (both gluteal and deltoid muscles). A total of 8,214 aripiprazole concentrations (16% oral, 65% gluteal muscle, 16% deltoid muscle, and 3% triceps or thigh administration) from 817 subjects were included in the final analysis dataset. The predictive performance of the final model was evaluated by predictively corrected visual post-hoc predictive performance assessment (pcVPC).

[0064] Using the final popPK model, we simulated and evaluated a range of initiation regimens with shorter overlap periods of oral administration after the first IM depot injection, identifying regimens such as: (1) daily administration of 10 mg oral aripiprazole, corresponding to the previously confirmed therapeutic range (94.0 ng / mL) for the lower limit of the simulated median minimum aripiprazole concentration (Cmax, ss) at steady state, and daily administration of the highest approved dose of oral aripiprazole, 30 mg, remaining at the 95th percentile of the maximum aripiprazole concentration (Cmax, ss) at steady state (741 ng / mL); and (2) yielding similar plasma concentrations (i.e., median concentrations, 25th–75th percentile, and 5th–95th percentile) to the currently approved initiation regimen with a single injection (one monthly injection of 400 mg of aripiprazole, accompanied by 14 days of oral aripiprazole [10–20 mg]).

[0065] An overview of popPK modeling and simulations supporting alternative initiation regimens is provided under the following section heading, “popPK Modeling.” Simulations of aripiprazole plasma concentration-time profiles after administration of alternative initiation regimens to cytochrome P450 2D6 (CYP2D6) extensive or poor metabolizers (under the following section heading, “Subjects as CYP2D6 Poor Metabolizers”) in subjects with and without prior oral aripiprazole stabilization (under the following section headings, “Alternative Initiation Regimens Without Prior Oral Aripiprazole Stabilization” and “Alternative Initiation Regimens with Prior Oral Aripiprazole Stabilization”) are presented in this module, even in a scenario where no maintenance dose was administered (under the following section heading, “No Maintenance IM Depot Dose Administration”).

[0066] Aripiprazole oral preparation

[0067] Aripiprazole is a psychotropic drug available as an oral (aripiprazole) tablet. In some embodiments, oral tablets of aripiprazole are available with active ingredient content 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 may include, for example, iron oxide (yellow or red) and FD&C Blue No. 2 Aluminum Lake.

[0068] Aripiprazole is well absorbed after tablet administration, with peak plasma concentrations occurring, for example, within 3 to 5 hours; the absolute oral bioavailability of the tablet formulation is approximately 87%. Oral tablets of aripiprazole can be administered with or without food. For example, when a 15 mg oral tablet of aripiprazole was administered with a standard high-fat meal, there was no significant effect on the Cmax or AUC of aripiprazole or its active metabolite, dehydroaripiprazole, but the Tmax was delayed by 3 hours for aripiprazole and 12 hours for dehydroaripiprazole.

[0069] Aripiprazole is metabolized primarily through three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. In vitro experiments show that the enzymes CYP3A4 and CYP2D6 are involved in the dehydrogenation and hydroxylation of aripiprazole, while N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the major drug portion in the systemic circulation. Under steady state, the active metabolite, dehydroaripiprazole, accounts for approximately 40% of the aripiprazole AUC in plasma.

[0070] After a single oral administration of [14C]-labeled aripiprazole, approximately 25% and 55% of the administered radioactive material were recovered in urine and feces, respectively. Less than 1% of the aripiprazole was excreted unchanged in the urine, and approximately 18% of the oral dose was recovered unchanged in the feces.

[0071] This disclosure utilizes single oral doses of aripiprazole selected from 2 mg to 30 mg, for example, oral tablets of aripiprazole in single oral doses of 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg. In some embodiments, the single oral dose is in the range of about 10 mg to about 30 mg of aripiprazole, for example, about 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.

[0072] Aripiprazole intramuscular depot formulation

[0073] In some embodiments, the aripiprazole intramuscular depot formulation comprises aripiprazole monohydrate; aripiprazole monohydrate is 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydrocarbostyryl monohydrate. The empirical formula is C 23 H 27 Its chemical structure is Cl2N3O2·H2O, and its molecular weight is 466.40. [ka] That is the case.

[0074] For example, in some embodiments, the aripiprazole intramuscular (IM) depot formulation is a sustained-release suspension injection in a pre-filled dual-chamber syringe containing 400 mg or 300 mg of active ingredient, and in a vial containing 400 mg or 300 mg of active ingredient. The labeled active ingredient content is calculated based on the anhydrous form (aripiprazole). In some embodiments, the inactive components (depending on the dose administered) for each of the 400 mg and 300 mg active ingredient products include sodium carboxymethylcellulose (16.64 mg and 12.48 mg), mannitol (83.2 mg and 62.4 mg), monosodium phosphate monohydrate (1.48 mg and 1.11 mg), and sodium hydroxide (pH adjuster). In further embodiments, dose adjustments can be made using pre-filled dual-chamber syringes containing 400 mg or 300 mg of the active ingredient and sustained-release suspensions in vials containing 400 mg or 300 mg of the active ingredient; that is, dose adjustments can be made in patients taking a CYP2D6 poor metabolizer and a concurrently administered CYP3A4 inhibitor or CYP2D6 inhibitor. Dose adjustments for 200 mg and 160 mg can be made by using vials containing 300 mg or 400 mg of the active ingredient for intramuscular injection into the deltoid or gluteal muscle in patients taking a CYP2D6 inhibitor, CYP3A4 inhibitor, or CYP3A4 for longer than 14 days. The aripiprazole IM depot formulations disclosed herein for sustained-release suspensions, Abilify Maintena®, are 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.

[0075] In some embodiments, the activity of aripiprazole intramuscular depot formulations has been shown to be primarily due to the parent drug, aripiprazole, and to a lesser extent to its abundant metabolite, dehydroaripiprazole, which, like the parent drug, has affinity for the D2 receptor and accounts for approximately 29% of the parent drug exposure in plasma.

[0076] Due to the low solubility of aripiprazole particles, systemic absorption of aripiprazole is slow and prolonged after intramuscular injection. After a single dose of aripiprazole intramuscular depot formulation in the deltoid and gluteal muscles, the absorption range (AUCt, AUC∞) of aripiprazole was similar for 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 for both injection sites. After multiple intramuscular doses, plasma concentrations of aripiprazole gradually increased to maximum plasma concentrations with a median Tmax of approximately 5-7 days for the gluteal muscle and approximately 4 days for the deltoid muscle. After administration via gluteal muscle, the mean apparent terminal elimination half-life of aripiprazole was approximately 29.9 days, while the mean apparent terminal elimination half-life of aripiprazole after multiple injections of 300 mg and 400 mg intramuscular depot formulations administered every four weeks was approximately 46.5 days. Steady-state concentrations for typical subjects were achieved with the fourth dose at both administration sites. Approximate dose-proportional increases in aripiprazole and dehydroaripiprazole exposure were observed after four-weekly injections of 300 mg and 400 mg intramuscular depot formulations of aripiprazole.

[0077] 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 glucuronization.

[0078] This disclosure utilizes two separate aripiprazole intramuscular depot injections with a dose of aripiprazole ranging from approximately 100 mg to approximately 500 mg, and further, for example, each of the two aripiprazole intramuscular depot injections contains a dose of 300 mg or 400 mg of aripiprazole. For example, the method of this disclosure involves administering two separate 300 mg or 400 mg injections of aripiprazole intramuscular (IM) depot formulation to separate injection sites in the patient's gluteal muscle and / or deltoid muscle, with the administration performed on day 1 of treatment. In some embodiments, the two separate injections of aripiprazole IM depot formulation are administered to separate injection sites in the patient's gluteal muscle or to separate sites in the deltoid muscle. In further embodiments, the two separate injections of aripiprazole IM depot formulation are administered to injection sites in the patient's gluteal muscle and deltoid muscle. Furthermore, the patient has schizophrenia, and for example, the patient has bipolar disorder type I. [Examples]

[0079] Therapeutic range and aripiprazole plasma concentration during drug initiation using alternative initiation regimens

[0080] Figure 10 provides previously proposed therapeutic ranges corresponding to the lower limit (94.0 ng / mL) of the simulated median minimum aripiprazole concentration (Cmin,ss) at steady state after daily administration of 10 mg oral aripiprazole, and the conservative upper limit (534 ng / mL) of the simulated 75th percentile of the maximum aripiprazole concentration (Cmax,ss) at steady state after daily administration of the highest approved dose of oral aripiprazole, 30 mg. Statistics related to the simulations in this disclosure are presented by the median concentration, the 25th–75th and 5th–95th percentiles. Therefore, for direct comparison of these simulations with the previously proposed therapeutic ranges (Figure 10), a horizontal baseline representing the 95th percentile (741 ng / mL) of the previously simulated Cmax,ss concentration after daily administration of 30 mg oral aripiprazole has been added to the simulations provided in this disclosure.

[0081] Based on the simulations provided below under the heading "Simulation Results," the aripiprazole concentration during the initiation of medication can reach the 95th percentile (741 ng / mL) of the previously simulated Cmax,ss concentration after daily administration of 30 mg oral aripiprazole; therefore, the following supplementary information is provided in lieu of clinical data:

[0082] - Observed pharmacokinetic (PK) and safety data obtained from a subset of subjects in this trial, where aripiprazole plasma concentrations after administration of the proposed alternative initiation regimen fell within the 5th to 95th percentile of simulated concentrations, were evaluated and are provided under the heading "Comparison and Analysis of Results Through the Trial." Overall, the safety profiles of these subjects were consistent with the known safety profiles of Abilify Maintena®.

[0083] - Aripiprazole concentrations above both the 75th and 95th percentiles of the simulated 30 mg oral Cmax, ss were observed and were well tolerated in a previously submitted Phase 3 safety and efficacy trial (clinicaltrials.gov identifier: NCT00705783, title: "Intramuscular Depot Aripiprazole (ASPIRE) as Maintenance Therapy in Patients with Schizophrenia"). Plasma concentrations above these levels during the initiation of treatment are highlighted in Figure 13. In Figure 13, SD is equal to the standard deviation.

[0084] Summary of individual experimental results

[0085] Population PK analysis was performed to expand a previously submitted popPK model to incorporate injection into the deltoid muscle and to conduct simulations to investigate predicted plasma concentrations after administration of alternative initiation regimens in both the deltoid and gluteal muscle regions. A summary of the combined final popPK model is provided below under the heading "popPK". A summary of the results of a single-dose escalation phase 1 trial to determine the PK, safety, and tolerability of a single high-dose formulation of aripiprazole LAI after gluteal muscle administration is provided below under the heading "popPK".

[0086] popPK modeling: Population pharmacokinetic analysis of aripiprazole after oral administration and intramuscular injection into the gluteal or deltoid muscles in adult subjects.

[0087] A total of 8,214 aripiprazole concentrations from 817 subjects (16% oral, 65% gluteal muscle, 16% deltoid muscle, and 3% triceps or thigh administration) were included in the combined final analysis dataset. The pharmacokinetic data included in this analysis consisted of aripiprazole concentrations after deltoid or gluteal muscle injection from data included in previous popPK reports as well as from two additional trials conducted to support the addition of the deltoid muscle as an administration site.

[0088] The model was a three-compartment model with sigmoid absorption for oral administration (Ka) and primary absorption for IM (mainly gluteal muscle) administration (IMKa).

[0089] By adding a deltoid muscle depot compartment with a separate absorption rate constant (DKa) to the original model, the final combined model incorporated the deltoid muscle injection site into the previously developed model. No further structural changes or covariate analyses were performed. A diagram of the structure of the final combined model is presented in Figure 1, along with the update to the original model that incorporates the injection site of the deltoid muscle, indicated by the dashed line. The following abbreviations are used in Figure 1: CMT = compartment; DKa = deltoid muscle IM primary absorption rate constant; Frelative = relative bioavailability; IMKa = gluteal muscle IM primary absorption rate constant; Ka = oral primary absorption rate constant; R1 = drug delivery rate to the oral absorption compartment; Vc = apparent median volume of distribution; Vp1 = volume of distribution of peripheral compartment 1; Vp2 = volume of distribution of peripheral compartment 2; Q1 = intercompartment clearance 1; Q2 = intercompartment clearance 2. The final popPK model is a linear 3-compartment PK model, which utilizes separate primary absorption for sigmoid absorption for oral administration and for monthly gluteal and deltoid muscle IM injections of aripiprazole.

[0090] All population PK parameters were fixed to the values ​​predicted in the original model for oral and gluteal muscle administration, with the exception of DKa, which was predicted to use data after deltoid muscle administration. Inter-individual variability (IIV) for oral absorption rate constant (Ka) was fixed to the predicted value in the original model, while IIV, central volume of distribution (Vc), and first-order absorption rate constant for clearance (CL) after IM injection (IMKa and DKa) were predicted or re-predicted using the combined final analysis dataset.

[0091] The covariate effects remained the same as in the original model, and it was assumed that the effects of sex and body mass index (BMI) on IMKa, which were predicted mainly from data after IM injection into the gluteus maximus muscle, also existed for deltoid injection. No additional covariate analysis was performed. The parameter definitions and values ​​of the combined final model are presented in Table 1 below:

[0092] [Table 1] TIFF2023520004000004.tif93148

[0093] From Table 1, it can be observed that %CV is the percentage coefficient of variation, and RSE is the standard error compared to the mean.

[0094] The predictive performance of the combined final model was evaluated using a predictively corrected visual post-hoc prediction performance assessment (pcVPC). The pcVPC of the combined final population PK model for the deltoid and gluteal muscle injection sites after the first and fifth monthly administrations is shown in Figures 2A-2D. In Figures 2A-2D, the following abbreviations are used: CI = confidence interval; the visual post-hoc prediction performance assessment after the first gluteal muscle injection includes PK data from subjects who received oral aripiprazole concurrently. Overall, the distribution of observed data was equivalent to the 5th to 95th percentiles of concentration in the model-based simulations, indicating that the pcVPC demonstrated good predictive performance of the combined final model for the deltoid and gluteal muscle injection sites. Overall, the distribution of observed data was equivalent to the 90% prediction interval of the model-based simulations after single and multiple administrations in the deltoid and gluteal muscle sites, confirming that the variability observed in the observed PK data could be adequately explained by the final popPK model.

[0095] Simulation results

[0096] Using the combined final model, we simulated the plasma concentration-time profiles of aripiprazole after oral, gluteal muscle, and / or deltoid muscle administration. To compare the simulated PK profiles, we used a substantial population of 817 subjects (provided as the “popPK model”) with similar demographic characteristics to those enrolled in the clinical trials of the final analysis dataset, ensuring that only the dosing regimen changed through the simulation. Individual PK parameters for the subjects in the final analysis dataset (all were designated as CYP2D6 extensive metabolizers (EMs), except for simulations of CYP2D6 poor metabolizer [PM] subjects) were generated from the combined final PK model and its final parameter predictions. Individual PK profiles after oral, gluteal muscle, and deltoid muscle administration of aripiprazole were simulated using a 2-hour sampling interval during the 24 hours following the previous oral administration, and sampling every 24 hours following the previous IM depot administration. A complete enumeration of all simulations performed is provided in Figures 3A–3C.

[0097] Previous alternative initiation regimens without oral aripiprazole stabilization

[0098] As provided above under the heading "Therapeutic Range and Aripiprazole Plasma Concentrations During Medication Initiation with Alternative Initiation Regimen," several scenarios for medication initiation were simulated to evaluate the time to achieve therapeutic range concentrations. The median and 5th to 95th percentile concentrations of the simulated aripiprazole plasma PK profile for the currently approved initiation regimen (400 mg with 10-20 mg oral doses for 14 days) and an alternative initiation regimen (2 × 400 mg with 20 mg oral doses per day) involving two separate injections administered to the gluteal and / or deltoid muscle sites are shown in Figures 4A–4D. In Figures 4A–4D, the approved initiation regimen was 10-20 mg oral doses (14 days) and 400 mg IM depot (day 1).

[0099] According to the simulation, Figures 4A–4D show that the median and 5th–95th percentile concentrations of the aripiprazole PK profile after administration of the proposed alternative initiation regimen are equivalent to the approved initiation regimen, 400 mg aripiprazole IM on day 1 + 10–20 mg oral aripiprazole for 14 days, for example:

[0100] - The median aripiprazole PK profile after the alternative initiation regimen reached therapeutic levels on day 1 (Cmin,ss: 94.0 ng / mL for 10 mg of aripiprazole daily) and remained above the lower threshold of the therapeutic range thereafter.

[0101] - The 95th percentile of simulated concentrations after the proposed alternative initiation regimen is equivalent to or lower than the 95th percentile of currently approved regimens and is within the upper limit of the therapeutic range as discussed above.

[0102] - Plasma concentrations for all regimens exceed the previously used conservative upper limit of the 75th percentile (741 ng / mL) for simulated Cmax,ss after daily administration, but remain below the 95th percentile (741 ng / mL) for simulated 30 mg oral Cmax,ss.

[0103] - The alternative initiation regimen does not affect the steady-state maintenance concentration.

[0104] Previous oral aripiprazole stabilization alternative initiation regimens

[0105] In the approved brand Abilify Maintena®, the first dose is administered in conjunction with oral aripiprazole (10-20 mg) for 14 consecutive days to adult patients stabilized with oral aripiprazole. Therefore, simulations were performed to predict and compare plasma concentrations over 28 days after administration of the currently approved regimen and alternative initiation regimen to patients stabilized with 20 mg of aripiprazole, which is the highest typical oral dose a patient would receive, prior to initiating treatment with the aripiprazole IM depot. The median, 5th, 25th-75th, and 95th percentiles of the simulated aripiprazole plasma PK profiles for the currently approved regimen and alternative initiation regimen, administered as two separate injections to the gluteal or deltoid muscle site of the target patient previously stabilized with oral aripiprazole dose 20 mg, are presented in Figures 5A and 5B. In Figures 5A and 5B, the approved starting regimens were 10-20 mg orally (for 14 days) and 400 mg IM depot (on day 1). The starting concentration at time zero is the mean steady-state concentration for subjects stabilized with 20 mg oral aripiprazole.

[0106] Simulations show that the median and 5th–95th percentile concentrations of the aripiprazole PK profile after administration of the alternative initiation regimen are equivalent to those of the approved initiation regimen when administered to subjects already stabilized with 20 mg oral aripiprazole:

[0107] - The 95th percentile of the simulated concentration after the alternative initiation regimen is equivalent to or lower than the 95th percentile of the approved regimen.

[0108] - The alternative initiation regimen does not affect the steady-state maintenance concentration.

[0109] Subjects that are CYP2D6 poor metabolizers

[0110] In subjects known to be cytochrome P450 2D6 poor metabolizers (CYP2D6 PM), the currently approved starting dose of IM depot should be reduced from 400 mg to 300 mg due to approximately 50% lower apparent clearance of aripiprazole. Therefore, simulations were performed to predict aripiprazole concentrations after administration of alternative starting regimens for CYP2D6 extensive metabolizer (EM) and PM subjects. Figures 6A and 6B show a comparison of simulated median concentration-time profiles and box plots of aripiprazole maximum plasma concentration (Cmax) after administration of a single dose of 20 mg oral aripiprazole, along with two administrations of 400 mg (CYP2D6 EM and PM subjects) or 300 mg (CYP2D6 PM subjects only) of Abilify Maintena® to the gluteal or deltoid muscle site. In Figures 6A and 6B, the approved starting regimens were 10-20 mg orally (for 14 days) and 400 mg IM depot (on day 1).

[0111] Plasma concentration simulations were performed to allow comparison of simulated median concentration-time profiles and aripiprazole Cmax box plots after a single dose of 20 mg oral aripiprazole, along with two administrations of 400 mg (CYP2D6 EM and PM subjects) or 300 mg (CYP2D6 PM subjects only) IM depot aripiprazole formulations to the gluteal or deltoid muscle site of subjects or patients previously stabilized with 20 mg (EM) or 10 mg (PM) oral aripiprazole. These simulations are presented in Figures 7A and 7B. In Figures 7A and 7B, the approved starting regimen is 10-20 mg oral (14 days) + 400 mg IM depot (day 1). The starting concentration at time zero is the steady-state mean concentration for CYP2D6 EM subjects stabilized with 20 mg oral aripiprazole and PM subjects stabilized with 10 mg oral aripiprazole. For PM, the previous oral dosage was halved (10 mg instead of 20 mg).

[0112] As expected, the simulations showed that when both subjects received two doses of 400 mg IM depot aripiprazole, CYP2D6 PM subjects exhibited higher aripiprazole Cmax and exposure compared to CYP2D6 EM subjects. Therefore, to ensure that concentrations after the alternative initiation regimen are equivalent to and remain within or slightly above the therapeutic range of currently approved regimens, a dose reduction of the proposed regimen—from two doses of 400 mg IM depot aripiprazole to two doses of 300 mg IM depot aripiprazole—with a single dose of 20 mg oral aripiprazole is recommended for subjects or patients known to be CYP2D6 PM.

[0113] No maintenance IM depot dose administered.

[0114] To determine whether an alternative initiation regimen could be applied in situations where currently approved initiation regimens require a single IM depot aripiprazole injection along with a two-week course of concurrent oral administration of aripiprazole, simulations were conducted to evaluate aripiprazole concentrations after the absence of administration of second, third, fourth, or steady-state doses of the IM depot aripiprazole formulation.

[0115] Figures 8A–8D provide a comparison of simulated median aripiprazole plasma concentrations after administration of alternative or currently approved initiation regimens to the gluteal or deltoid muscle sites when a second or third IM depot aripiprazole formulation was administered 5 weeks after a previous injection. In Figures 8A–8D, the approved initiation regimens were 10–20 mg orally (14 days) and 400 mg IM depot (day 1).

[0116] Figures 9A–9D provide a comparison of simulated median aripiprazole plasma concentrations after administration of alternative or currently approved initiation regimens to the gluteal or deltoid muscle sites when a fourth or fifth (steady-state) dose was administered 6 weeks after a previous injection. In Figures 9A–9D, the approved initiation regimens were 10–20 mg orally (for 14 days) and 400 mg IM depot (day 1).

[0117] In all simulations, administration of the alternative initiation regimen after the absence of maintenance IM depot administration resulted in median aripiprazole concentrations above the lower threshold of the therapeutic range and similar to the concentrations after the approved initiation regimen.

[0118] Simulation results suggest that if a maintenance IM depot dose is not administered, an alternative initiation regimen may be given instead of oral aripiprazole administered concurrently for 14 days, along with a single IM depot injection of aripiprazole on day 1. Such a treatment strategy after dose absence is consistent with that of the Abilify Maintena® brand.

[0119] Comparison and analysis of results obtained through clinical trials

[0120] An analysis was conducted to evaluate the safety outcomes observed from a subset of 17 subjects from the Phase 1 trial described below, whose plasma concentration-time profiles consistently fell within the 5th to 95th percentile of simulated concentrations after administration of an alternative initiation regimen and were above the mean PK profile after a single intramuscular administration of 400 mg of Abilify Maintena®. A graphical comparison of the overall aripiprazole concentration-time profiles after single-dose administration of 780 mg (N=18) or 1200 mg (N=13) of aripiprazole LAI into the intramuscular region (from previous trials) and the aripiprazole concentration-time profiles from the subset of 17 subjects, highlighted in red, is presented in Figure 11. In Figure 11, N is equal to the number of subjects; a subset of 17 subjects from a clinical trial having plasma concentration-time profiles that fell within the 5th to 95th percentile of simulated concentrations after administration of an alternative initiation regimen and were consistently above the mean PK profile after a single intramuscular dose of 400 mg of Abilify Maintena®; and the lower limit for quantification of aripiprazole was 0.500 ng / mL.

[0121] For reference, the mean (i.e., the dark horizontal line below) aripiprazole plasma concentration-time profile after administration of a single dose of 400 mg Abilify Maintena® to the gluteal muscle, and the simulated concentrations at the 5th to 95th percentiles (combined final model) after administration of an alternative initiation regimen (20 mg oral [Day 1] + 2 × 400 mg aripiprazole IM depot [Day 1]) to the gluteal muscle site (shaded area) are also presented.

[0122] Of the 17 identified subjects, 7 were treated with 1200 mg of aripiprazole LAI and 10 were treated with 780 mg of aripiprazole LAI. A review of safety data from these subjects did not identify any unexpected adverse events, and these safety profiles were concluded to be consistent with the known safety profiles of Abilify Maintena®.

[0123] conclusion

[0124] Simulations have shown that a two-injection initiation regimen, involving a single dose of 20 mg of oral aripiprazole on day 1 of the treatment regimen, along with two monthly injections of aripiprazole into separate gluteal and / or deltoid muscle injection sites, (1) achieves therapeutic aripiprazole plasma concentrations on day 1 of treatment; (2) supports consistent clinical efficacy throughout the entire dosing interval; (3) provides aripiprazole plasma concentrations and thus a safety profile comparable to currently approved (conventional) initiation regimens; and (4) eliminates the need for 14 days of oral tablet supplementation, potentially reducing compliance-related undertreatment during the initiation phase of treatment.

[0125] A Phase 1, open-label, single-dose escalating, parallel-arm clinical trial to determine the pharmacokinetics, safety, and tolerability of aripiprazole administered as a 2-month intramuscular depot to the gluteal muscles in adult patients with schizophrenia.

[0126] This clinical trial was an open-label, single-dose escalation, parallel-arm, multicenter study to determine the pharmacokinetics, safety, and tolerability of single-dose administrations of high-dose aripiprazole LAI formulations of 780 mg (Cohort 1) and 1200 mg (Cohort 2) into the gluteal muscles of adult subjects with schizophrenia. The data from this trial are supplementary information, as they were evaluated against cases where aripiprazole plasma concentrations increased at a similar rate and reached levels predicted in simulations for alternative initiation regimens. Overall, aripiprazole LAI is well-tolerated when administered as a single dose of 780 mg and 1200 mg to adult subjects with schizophrenia. In a subset of 17 subjects, administration of aripiprazole LAI resulted in higher aripiprazole plasma concentrations and faster absorption rates, falling into the 5th–95th percentile of simulated concentrations after administration of the proposed alternative initiation regimen, and resulting in an aripiprazole plasma concentration-time profile that was consistently above the mean PK profile after a single gluteal intramuscular administration of 400 mg of Abilify Maintena® (Figure 1). Safety data from this subset of subjects were evaluated and compared with the known safety profile of Abilify Maintena®. Further details of this analysis are provided in the section titled "Comparison and Analysis of Results Through Clinical Trials."

[0127] Aripiprazole LAI demonstrated sustained-release properties at the evaluated dosing levels, with dosing every two months. Extension of the dosing interval for aripiprazole LAI was primarily achieved through dose increases while maintaining a minimum aripiprazole concentration comparable to that of Abilify Maintena® after multiple dosing. Aripiprazole LAI had a higher aripiprazole concentration in the formulation compared to the currently marketed / approved Abilify Maintena® (300 mg / mL vs. 200 mg / mL), which was manipulated by minor vehicle modifications. The mean particle size distribution and dissolution profile of aripiprazole in the aripiprazole LAI formulation were comparable to those of the Abilify Maintena® formulation, suggesting that this formulation would exhibit a similar sustained-release profile compared to the approved Abilify Maintena® formulation. Figure 12 shows the mean (standard deviation [SD]) aripiprazole plasma concentration-time profiles after single-dose administration of 780 mg or 1200 mg of aripiprazole to the gluteal muscle of subjects with schizophrenia.

[0128] Table 2 below summarizes the aripiprazole PK parameters after a single dose of 780 mg or 1200 mg of aripiprazole administered to the gluteal muscles of subjects with schizophrenia.

[0129] [Table 2]

[0130] From Table 2, AUC∞ is the area under the concentration-time curve calculated from time zero to infinity; AUCt is the area under the concentration-time curve calculated for the last observable concentration at time t; CL / F is the clear clearance of the drug from plasma after extravasation; RTU is the time to immediate availability; tmax is the time to the maximum (peak) plasma concentration; and t1 / 2 is the elimination half-life. Furthermore, a Median (minimum - maximum); b n=14; and c n=11.

[0131] Conclusions from this data include, for example:

[0132] - Aripiprazole LAI was well tolerated when administered as an intramedicinal injection (IM) in single doses of 780 and 1200 mg to adult patients with schizophrenia.

[0133] - A single dose of 780 or 1200 mg of aripiprazole LAI administered to the gluteal muscle resulted in a 100% and 200% increase, respectively, in aripiprazole Cmax and exposure compared to what had been previously observed after a single dose of 400 mg of Abilify Maintena® administered to the gluteal muscle (area under the concentration-time curve [AUC∞] calculated from time zero to infinity and AUC [AUCt] calculated for the last observable concentration at time t).

[0134] - A single dose of 780 or 1200 mg aripiprazole LAI administered to the gluteal muscle resulted in a slightly less proportional increase in aripiprazole Cmax and a slightly higher dose-proportional increase in exposure (AUCt and AUC∞), based on dose-adjusted mean values.

[0135] - Administration of 780 mg aripiprazole LAI to the gluteal muscle resulted in a shorter median time to peak plasma concentration (tmax) compared to 1200 mg aripiprazole (25.1 days vs. 41.0 days).

[0136] - After administration of 780 or 1200 mg of aripiprazole LAI into the gluteal muscle, the mean terminal elimination half-life (t1 / 2) values ​​for aripiprazole (22.1 and 20.0 days, respectively) were equivalent to and similar to the median t1 / 2 (24.0 days) after a single dose of 400 mg of Abilify Maintena® into the gluteal muscle.

[0137] Based on a thorough examination of mean, median, and individual concentration-time profiles, a consistent increase in aripiprazole concentration, followed by a decrease in concentration and a secondary peak, was observed after administration of 780 or 1200 mg aripiprazole LAI to the gluteal muscle.

[0138] - Furthermore, this Phase I clinical trial supports the use of the present disclosure of a method of initiating treatment for aripiprazole therapy in patients in need, comprising two separate injections of aripiprazole intramuscular (IM) depot formulations of aripiprazole in the range of approximately 10 mg to approximately 500 mg into separate injection sites in the patient's gluteal muscle and / or deltoid muscle, as well as administration of a single dose of oral aripiprazole, with administration taking place on day 1 of treatment. In other words, the use of two injections of aripiprazole in the range of approximately 10 mg to approximately 500 mg resulted in no unexpected adverse events, and the safety profile was consistent with the known safety profile of Abilify Maintena®.

[0139] All publications and patents described 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.

[0140] A claim or specification containing "or" or "and / or" among at least one member of a group is considered satisfied if one, more than one, or all of the group members are present, utilized, or otherwise related to a given product or process, unless otherwise indicated to the contrary or otherwise evident from the context. This disclosure includes embodiments in which exactly one member of the group is present, utilized, or otherwise related to a given product or process. This disclosure includes embodiments in which more than one, or all, of the group members are present, utilized, or otherwise related to a given product or process.

[0141] Furthermore, this disclosure encompasses all variations, combinations, and permutations introduced from at least one of the enumerated claims into another claim, each containing at least one limitation, element, clause, and descriptive term. 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 base claim. Where elements are presented as a list, for example in Markush group format, each subgroup of elements is also disclosed, and any element(s) may be removed from the group. Generally, where this disclosure or aspects of this disclosure are referred to as containing certain elements and / or features, it should be understood that embodiments or aspects of this disclosure consist of, or are essentially, such elements and / or features. Briefly, embodiments are not specifically described herein. Where a scope is given, it includes endpoints. Furthermore, unless otherwise noted or otherwise evident from the context and the understanding of those skilled in the art, values ​​expressed as a range may, unless the context explicitly indicates otherwise, assume any specific value or lower range within the ranges described in the different embodiments of this disclosure, up to one-tenth of the lower limit unit of the range.

[0142] Those skilled in the art can identify or determine many equivalents to the specific embodiments of the disclosure described herein simply by using the prescribed experiments. Such equivalents are intended to be encompassed by the claims.

Claims

1. 1. An aripiprazole intramuscular (IM) depot formulation comprising 300 mg or 400 mg of aripiprazole for initiation of aripiprazole treatment in a patient in need thereof, wherein said patient has schizophrenia or bipolar disorder type I, said initiation comprising two separate injections of said formulation and administration of a single dose of oral aripiprazole, said injections each comprising 300 mg or 400 mg of aripiprazole in said patient at separate injection sites selected from the gluteal muscle site, the deltoid muscle site, and a combination of the gluteal muscle site and the deltoid muscle site, said formulation being used such that said two separate injections and said administration of said single dose of oral aripiprazole occur on day 1 of treatment.

2. 2. The formulation of claim 1, wherein each of the two separate injections contains 400 mg of aripiprazole.

3. 2. The formulation of claim 1, wherein each of the two separate injections contains 300 mg of aripiprazole.

4. 4. The formulation of any one of claims 1 to 3, wherein the aripiprazole treatment further comprises administering a single monthly maintenance injection of an IM depot formulation of aripiprazole after the first day of treatment, the formulation comprising 400 mg of aripiprazole.

5. 4. The formulation of any one of claims 1 to 3, wherein the aripiprazole treatment further comprises administering a single monthly maintenance injection of an IM depot formulation of aripiprazole after the first day of treatment, the formulation comprising 300 mg of aripiprazole.

6. The formulation of any one of claims 1-3, wherein the aripiprazole treatment comprises administering a single monthly maintenance injection selected from aripiprazole 160 mg and 200 mg IM depot formulations of aripiprazole if the patient is a CYP2D6 poor metabolizer or the patient is taking a concomitant CYP3A4 or CYP2D6 inhibitor for more than 14 days.

7. The formulation of any one of claims 4 to 6, wherein each maintenance injection is administered no earlier than 26 days after the previous injection.

8. 2. The formulation of claim 1, wherein two separate injections of the aripiprazole IM depot formulation are administered at separate injection sites in the patient's gluteal muscle.

9. 10. The formulation of claim 1, wherein two separate injections of the aripiprazole IM depot formulation are administered to the patient at injection sites in the gluteal and deltoid muscles.

10. 2. The method of claim 1, wherein two separate injections of the aripiprazole IM depot formulation are administered at separate injection sites in the patient's deltoid muscle.

11. The formulation of any one of claims 1 to 10, wherein the patient has schizophrenia.

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

13. The formulation of any one of claims 1 to 12, wherein the single dose of oral aripiprazole ranges from about 2 mg to about 30 mg of aripiprazole.

14. 14. The formulation of claim 13, wherein the single dose of oral aripiprazole ranges from about 10 mg to about 30 mg.

15. 14. The formulation of claim 13, wherein the single dose of oral aripiprazole is 20 mg.

16. 14. The formulation of claim 13, wherein the single dose of oral aripiprazole is 10 mg.

17. 2. The formulation of claim 1, wherein each of the two separate injections comprises about 300 mg of aripiprazole and the single dose of oral aripiprazole is about 20 mg when the patient is a CYP2D6 poor metabolizer.

18. The formulation of any one of claims 1 to 17, wherein the aripiprazole is in the form of a salt.

19. 2. The formulation of claim 1, wherein the patient is or is not already stabilized with oral aripiprazole, each of the two separate injections contains 400 mg of aripiprazole, and the single dose of oral aripiprazole is about 20 mg.

20. 20. The formulation of claim 19, wherein the patient is already stabilized on oral aripiprazole.

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