Methods for dose initiation of aripiprazole treatment

Abstract

To provide a method of dose initiation for an aripiprazole treatment to a patient in need thereof.SOLUTION: Provided is a method for dose initiation, the method comprising administering two separate injections of an aripiprazole intramuscular (IM) depot formulation, each injection comprising about 10 mg to about 500 mg of aripiprazole at an injection site selected from separate gluteal muscle sites, deltoid muscle sites, and combinations thereof, and comprising administering a single dose of oral aripiprazole, the administering step being carried out on a first day of the treatment.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This application claims priority to U.S. Provisional Application No. 63 / 003,544, filed April 1, 2020, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Aripiprazole, a partial agonist at 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 I disorder in adults. Abilify Maintena®, an intramuscular (IM) depot formulation of aripiprazole, is an extended-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 [Problem to be solved by the invention]

[0003] Once-monthly aripiprazole is a long-acting IM injectable formulation of aripiprazole indicated for the maintenance treatment of schizophrenia and bipolar I disorder in adult patients stabilized on oral aripiprazole. In the currently approved drug, Abilify Maintena®, the first dose is administered with co-administered oral aripiprazole (10 mg to 20 mg) for 14 consecutive days to adult patients stabilized on oral aripiprazole. In patient populations considered to be at potential risk for adherence-related relapse or suboptimal treatment outcomes (e.g., patient populations on long-acting injectables (LAIs)), achieving therapeutic plasma concentrations can provide therapeutic benefit. [Means for solving the problem]

[0004] To provide additional options for this initiation phase, a start-up regimen is provided based on population pharmacokinetic (popPK) modeling and simulation to initiate two injections, including two separate monthly administrations of aripiprazole into separate gluteal and / or deltoid muscle injection sites, with a single oral administration of aripiprazole on Day 1 of treatment. For example, the present disclosure is directed to an alternative start-up regimen of two separate administrations of an intramuscular (IM) depot formulation of aripiprazole, e.g., Abilify Maintena®, overlapping with a shorter period of oral administration. Simulations of the alternative start-up regimen of two injections of an intramuscular (IM) depot formulation of aripiprazole into separate gluteal and / or deltoid muscle injection sites, with a single oral administration of aripiprazole on Day 1 of treatment, have shown sufficiency, and the alternative start-up regimen may be an additional option for initiating Abilify Maintena®.

[0005] In some aspects, the present disclosure is directed to a method of initiating aripiprazole therapy in a patient in need thereof, comprising administering two separate injections of an aripiprazole intramuscular (IM) depot formulation, each injection comprising about 10 mg to about 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 administering steps occur on day 1 of treatment.

[0006] In additional embodiments, each of the two separate injections contains about 400 mg of aripiprazole. Furthermore, the methods of the present disclosure further include administering a single monthly maintenance injection of an aripiprazole IM depot formulation after the first day of treatment. For example, in other embodiments, the single monthly maintenance injection is selected from about 300 mg and about 400 mg of aripiprazole in an aripiprazole IM depot formulation. In further embodiments, if the patient is a CYP2D6 poor metabolizer or has been taking a concomitant CYP3A4 inhibitor or CYP2D6 inhibitor for more than 14 days, the single monthly maintenance injection is selected from 160 mg and 200 mg of aripiprazole in an aripiprazole IM depot formulation.

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

[0008] In embodiments of the disclosure, the patient has schizophrenia. In other embodiments, the patient has bipolar disorder type 1.

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

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

[0011] In some further aspects, the present disclosure is directed to an aripiprazole intramuscular (IM) depot formulation comprising about 10 mg to about 500 mg of aripiprazole for use in administering two separate injections of said aripiprazole intramuscular (IM) depot formulation to a patient in need thereof at an injection site selected from the gluteal muscle site, the deltoid muscle site, and a combination thereof, in combination with a single dose of oral aripiprazole, wherein the administering occurs on day 1 of treatment.

[0012] In some further aspects, the present disclosure is directed to aripiprazole or a salt thereof for use in treating schizophrenia or bipolar disorder Type I, wherein the aripiprazole or a salt thereof is administered to a patient in need thereof by any one of the methods of initiating aripiprazole therapy of the present disclosure. Additionally, the present disclosure also provides the use of aripiprazole or a salt thereof in the manufacture of a medicament, wherein the aripiprazole or a salt thereof is administered to a patient in need thereof by any one of the methods of initiating aripiprazole therapy of the present disclosure. [Brief explanation of the drawings]

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

[0014] [Figure 2A] 2A-2D are plots of the prediction-corrected visual post-hoc predictive performance assessment of the combined final population pharmacokinetic (popPK) model. [Figure 2B] 2A-2D are plots of the prediction-corrected visual post-hoc predictive performance assessment of the combined final population pharmacokinetic (popPK) model. [Figure 2C] 2A-2D are plots of the prediction-corrected visual post-hoc predictive performance assessment of the combined final population pharmacokinetic (popPK) model. [Figure 2D]2A-2D are plots of the prediction-corrected visual post-hoc predictive performance assessment of the combined final population pharmacokinetic (popPK) model.

[0015] [Figure 3A] 3A-3C are tables showing the objectives and descriptions of the simulations. [Figure 3B] 3A-3C are tables showing the objectives and descriptions of the simulations. [Figure 3C] 3A-3C are tables showing the objectives and descriptions of the simulations.

[0016] [Figure 4A] 4A-4D are diagrams of simulated median (5th-95th percentile) aripiprazole concentration-time profiles following current or alternative initiation regimens, followed by 400 mg intramuscular depot dosing every 28 days. Shading represents the 5th-95th percentiles. [Figure 4B] 4A-4D are diagrams of simulated median (5th-95th percentile) aripiprazole concentration-time profiles following current or alternative initiation regimens, followed by 400 mg intramuscular depot dosing every 28 days. Shading represents the 5th-95th percentiles. [Figure 4C] 4A-4D are diagrams of simulated median (5th-95th percentile) aripiprazole concentration-time profiles following current or alternative initiation regimens, followed by 400 mg intramuscular depot dosing every 28 days. Shading represents the 5th-95th percentiles. [Figure 4D] 4A-4D are diagrams of simulated median (5th-95th percentile) aripiprazole concentration-time profiles following current or alternative initiation regimens, followed by 400 mg intramuscular depot dosing every 28 days. Shading represents the 5th-95th percentiles.

[0017] [Figure 5A]5A and 5B are plots of the simulated median, 5th, 25th-75th, and 95th percentiles of pharmacokinetic profiles following administration of the current or alternative starting regimen to subjects already stabilized on 20 mg oral aripiprazole. Shading and dashed lines represent the 5th, 25th-75th, and 95th percentiles, respectively. [Figure 5B] 5A and 5B are plots of the simulated median, 5th, 25th-75th, and 95th percentiles of pharmacokinetic profiles following administration of the current or alternative starting regimen to subjects already stabilized on 20 mg oral aripiprazole. Shading and dashed lines represent the 5th, 25th-75th, and 95th percentiles, respectively.

[0018] [Figure 6A] 6A and 6B are box plots of simulated median aripiprazole concentration-time profiles, C, in CYP2D6 extensive and poor metabolizers following the Abilify Maintena® initiation regimen. The box plots show the 5th, 25th, median, 75th, and 95th percentiles of C. [Figure 6B] 6A and 6B are box plots of simulated median aripiprazole concentration-time profiles, C, in CYP2D6 extensive and poor metabolizers following the Abilify Maintena® initiation regimen. The box plots show the 5th, 25th, median, 75th, and 95th percentiles of C.

[0019] [Figure 7A] 7A and 7B are simulated median aripiprazole concentration-time profiles and box plots of Cmax following Abilify Maintena® initiation regimens in extended and poor metabolizers previously stabilized on oral aripiprazole. Box plots show the 5th, 25th, median, 75th, and 95th percentiles of Cmax. [Figure 7B] 7A and 7B are simulated median aripiprazole concentration-time profiles and box plots of Cmax following Abilify Maintena® initiation regimens in extended and poor metabolizers previously stabilized on oral aripiprazole. Box plots show the 5th, 25th, median, 75th, and 95th percentiles of Cmax.

[0020] [Figure 8A] 8A-8D are simulated median pharmacokinetic profiles after initiation and re-initiation with current or alternative initiation regimens 5 weeks after previous intramuscular depot dosing. [Figure 8B] 8A-8D are simulated median pharmacokinetic profiles after initiation and re-initiation with current or alternative initiation regimens 5 weeks after previous intramuscular depot dosing. [Figure 8C] 8A-8D are simulated median pharmacokinetic profiles after initiation and re-initiation with current or alternative initiation regimens 5 weeks after previous intramuscular depot dosing. [Figure 8D] 8A-8D are simulated median pharmacokinetic profiles after initiation and re-initiation with current or alternative initiation regimens 5 weeks after previous intramuscular depot dosing.

[0021] [Figure 9A] 9A-9D are simulated median pharmacokinetic profiles following initiation and re-initiation with current or alternative initiation regimens 6 weeks after previous intramuscular depot dosing. [Figure 9B] 9A-9D are simulated median pharmacokinetic profiles following initiation and re-initiation with current or alternative initiation regimens 6 weeks after previous intramuscular depot dosing. [Figure 9C]9A-9D are simulated median pharmacokinetic profiles following initiation and re-initiation with current or alternative initiation regimens 6 weeks after previous intramuscular depot dosing. [Figure 9D] 9A-9D are simulated median pharmacokinetic profiles following initiation and re-initiation with current or alternative initiation regimens 6 weeks after previous intramuscular depot dosing.

[0022] [Figure 10] FIG. 10 illustrates simulated and observed aripiprazole concentrations following oral and intramuscular gluteal muscle depot administration of aripiprazole, supporting the definition of a therapeutic window.

[0023] [Figure 11] 11 depicts the plasma concentration-time profile of the aripiprazole composition following administration of a single dose of 780 mg (N=18) or 1200 mg (N=13) aripiprazole sustained-release injection and the mean plasma concentration following administration of a single dose of 400 mg Abilify Maintena® into the gluteal muscle in subjects with schizophrenia. The shaded area represents the 5th to 95th percentiles of a predictive model of the PK profile following an initiation regimen of 20 mg orally plus 2 x 400 mg IM Maintena® into the gluteal muscle.

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

[0025] [Figure 13] Figure 13 illustrates the observed aripiprazole plasma concentrations by week after the first intramuscular depot injection. Boxes represent plasma concentrations above 534 ng / mL during 10 to 20 overlapping oral doses over the two weeks following the first IM injection. DETAILED DESCRIPTION OF THE INVENTION

[0026] As used herein, "a" or "an" entity refers to one or more of that entity; 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 "about" means approximately, within, roughly, or around. When the term "about" is used in conjunction with a numerical range, it modifies the range by extending the boundaries above and below the stated numerical values. Generally, the term "about" is used herein to modify a numerical value by a variance of 5% above and below the stated value.

[0028] As used herein, the terms "treat," "treating," or "treatment," when used in connection with a disorder or condition, include any effect that results in an improvement of the disorder or condition, such as, for example, alleviating, reducing, modulating, ameliorating, or eliminating. Improvement or reduction in the severity of any symptoms of a disorder or condition can be readily assessed according to standard methods and techniques known in the art. In some embodiments, the methods or pharmaceutical depots disclosed herein can be used to treat schizophrenia and bipolar disorder type I as a sole maintenance therapy. In further embodiments, the methods or pharmaceutical depots disclosed herein can be used to treat the acute treatment of schizophrenia, manic and mixed episodes associated with bipolar disorder type I, major depressive disorder (MDD), irritability associated with autistic disorder, and Tourette's 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 the present disclosure include:

[0031] 1. A method of initiating aripiprazole therapy in a patient in need thereof, comprising: A method comprising administering two separate injections of an aripiprazole intramuscular (IM) depot formulation, each injection comprising about 10 mg to about 500 mg of aripiprazole to a patient at separate gluteal muscle and / or deltoid muscle injection sites, and a single dose of oral aripiprazole, wherein the administering step occurs on day 1 of treatment.

[0032] 2. The method of embodiment 1, wherein each of the two separate injections contains 400 mg of aripiprazole.

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

[0034] 4. The method of embodiment 3, wherein the single monthly maintenance injection is selected from about 300 mg and about 400 mg aripiprazole IM depot formulations.

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

[0036] 6. The method of any one of embodiments 1-5, wherein two separate injections of the aripiprazole IM depot formulation are administered at separate injection sites in the patient's gluteal muscles.

[0037] 7. The method of any one of embodiments 1-5, wherein two separate injections of the aripiprazole IM depot formulation are administered at injection sites in the patient's gluteal and deltoid muscles.

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

[0039] 9. The method of any one of embodiments 1-8, wherein the patient has schizophrenia.

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

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

[0042] 12. The method of embodiment 11, wherein the single dose of oral aripiprazole ranges from about 10 mg to about 30 mg.

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

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

[0045] 15. The method of embodiment 1, wherein if the patient is a CY2D6 poor metabolizer, each of the two separate injections comprises about 300 mg of aripiprazole, and the single dose of oral aripiprazole is about 20 mg.

[0046] The present disclosure is directed to an alternative initiation regimen of two separate administrations of an intramuscular (IM) depot formulation of aripiprazole with a shorter overlap of oral administration. For example, simulations of an alternative initiation regimen of two 400 mg injections of an intramuscular (IM) depot formulation of aripiprazole (e.g., Abilify Maintena®) at separate injection sites in the gluteal and / or deltoid muscles with a single 20 mg oral dose of aripiprazole on day 1 of treatment have shown efficacy, and the alternative initiation regimen may be an additional option for initiating, for example, Abilify Maintena®.

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

[0048] As used herein, a reference to aripiprazole refers to aripiprazole or a salt thereof, or a crystalline form of aripiprazole or a salt thereof. Aripiprazole or a salt thereof may be in the form of a monohydrate (aripiprazole hydrate A) or various anhydrous forms, which are known to exist in the forms of anhydrous crystalline B, anhydrous crystalline C, anhydrous crystalline D, anhydrous crystalline E, anhydrous crystalline F, and anhydrous crystalline G. All of these crystalline forms can be used as aripiprazole or a salt thereof in the injectable preparations of the present disclosure, and further, for example, aripiprazole is in the form of a monohydrate.

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

[0050] Conventional Aripiprazole Dosing Regimen

[0051] The conventional dosing regimen for aripiprazole includes the recommended starting and maintenance doses of Abilify Maintena®, which are 300 mg or 400 mg monthly (at least 26 days after the previous injection). For patients naive to aripiprazole, patients establish tolerability 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] After the first Abilify Maintena® injection, oral aripiprazole (10 mg to 20 mg) is administered for 14 consecutive days to achieve therapeutic aripiprazole concentrations during therapy initiation. For patients already stabilized on another oral antipsychotic (and known to tolerate aripiprazole), antipsychotic treatment is continued for 14 consecutive days after the first Abilify Maintena® injection to maintain therapeutic antipsychotic concentrations during therapy initiation.

[0053] If adverse reactions occur at the 400 mg dose, consideration may be given to reducing the dose to 300 mg once monthly.

[0054] Thus, the currently approved initiation regimen consists of a single IM injection of an intramuscular depot formulation of aripiprazole, followed by daily oral tablets of aripiprazole (10–20 mg) for 14 consecutive days.

[0055] References herein to aripiprazole intramuscular depot formulations refer to Abilify Maintena® (aripiprazole), an extended-release suspension injection, for intramuscular use, first approved in the U.S. in 2002, as updated in June 2020.

[0056] Alternative Dosing Regimens for Aripiprazole

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

[0058] The present disclosure utilizes two separate injections of an aripiprazole intramuscular depot formulation at a dose of aripiprazole ranging from about 100 to about 500 mg. For example, the method of the present disclosure administers two separate 400 mg injections of an aripiprazole intramuscular (IM) depot formulation to separate injection sites in the patient's gluteal muscle and / or deltoid muscle, the administrations occurring on day 1 of treatment. In some embodiments, two separate injections of the aripiprazole IM depot formulation are administered to separate injection sites in the patient's gluteal muscle or separate injection sites in the deltoid muscle. In further embodiments, two separate injections of the aripiprazole IM depot formulation are administered to the patient's gluteal muscle and deltoid muscle injection sites. Additionally, the patient has schizophrenia, for example, the patient has bipolar disorder type I.

[0059] The rationale for the selection of the alternative initiation regimen dose was based on simulations using population pharmacokinetic(s) (popPK) models. The range of the initiation regimen was considered to shorten the length of overlap of oral dosing with the first IM depot injection while maintaining median concentrations within the previously defined therapeutic range and similar to those of currently approved initiation regimens (i.e., median, 25th-75th, and 5th-95th percentile concentrations). Based on the results of the simulation, the recommended dose for the alternative initiation regimen is in the range of about 100 mg to about 500 mg, and in some embodiments, two 400 mg injections of an intramuscular depot formulation of aripiprazole, e.g., at separate injection sites in the gluteal and / or deltoid muscles, accompanied by a single dose of oral aripiprazole on day 1 of treatment, e.g., the single dose of oral aripiprazole is in the range of about 2 mg to 30 mg of aripiprazole, e.g., a single 20 mg dose of oral aripiprazole.

[0060] Clinical pharmacology experiments

[0061] The objective of the clinical pharmacology study was to validate, using PK modeling and simulation methods, a two-injection starting regimen for once-monthly depot 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 Formulations: Clinical Pharmacology and Biopharmaceutical Overview (Application No. 202971s000) 2012) was able to adequately characterize aripiprazole PK after oral administration and IM depot injection into the gluteal muscle, and this was extended to include injections at the deltoid muscle site. PK data from seven clinical trials after oral administration and IM depot injection (both gluteal muscle and deltoid muscle) were used to develop the final model. A total of 8,214 aripiprazole concentrations (16% oral, 65% gluteal muscle, 16% deltoid, and 3% triceps or thigh) from 817 subjects were included in the final analysis dataset. The predictive performance of the final model was assessed using 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 that: (1) remained within the previously established therapeutic range, corresponding to the lower end of the simulated median minimum aripiprazole concentration at steady state (Cmax,ss) after daily administration of 10 mg oral aripiprazole (94.0 ng / mL), and the 95th percentile of maximum steady-state aripiprazole concentration (Cmax,ss) after daily administration of the highest approved oral aripiprazole dose of 30 mg; and (2) resulted in plasma concentrations (i.e., median, 25th-75th, and 5th-95th percentiles) similar to the currently approved single-injection initiation regimen (one monthly 400 mg injection of aripiprazole with 14 days of oral aripiprazole [10-20 mg]).

[0065] An overview of popPK modeling and simulations supporting alternative initiation regimens is provided below under the section heading "PopPK Modeling." Simulations of aripiprazole plasma concentration-time profiles following administration of alternative initiation regimens to cytochrome P450 2D6 (CYP2D6) extensive or poor metabolizers (below under the section heading "Subjects who are CYP2D6 poor metabolizers") in subjects without and with prior stabilization with oral aripiprazole (below under the section headings "Alternative Initiation Regimens Without Prior Oral Aripiprazole Stabilization" and "Alternative Initiation Regimens With Prior Oral Aripiprazole Stabilization") are also presented in this module in the scenario of after no maintenance dose (below under the section heading "No Maintenance IM Depot Dose Administered").

[0066] Aripiprazole oral formulation

[0067] Aripiprazole is a psychotropic drug available as oral (aripiprazole) tablets. In some embodiments, aripiprazole oral tablets are available in active ingredient strengths of, for example, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg. Inactive ingredients in oral tablets include, for example, corn starch, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. Coloring agents can 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 within 3 to 5 hours; the absolute oral bioavailability of the tablet formulation is approximately 87%. Aripiprazole oral tablets can be administered with or without food. For example, administration of a 15 mg oral tablet of aripiprazole with a standard high-fat meal did not significantly affect 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 by three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. In vitro studies have shown that CYP3A4 and CYP2D6 enzymes are involved in the dehydrogenation and hydroxylation of aripiprazole, with N-dealkylation being catalyzed by CYP3A4. Aripiprazole is the major drug moiety in the systemic circulation. At steady state, the active metabolite, dehydroaripiprazole, accounts for approximately 40% of the aripiprazole AUC in plasma.

[0070] After a single oral dose of [14C]-labeled aripiprazole, approximately 25% and 55% of the administered radioactivity was recovered in the 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] The present disclosure utilizes oral tablets containing aripiprazole in a single oral dose selected from 2 mg to 30 mg, e.g., 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg. In some embodiments, the single oral dose ranges from about 10 mg to about 30 mg, e.g., 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; the aripiprazole monohydrate is 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4 dihydrocarbostyril monohydrate. The empirical formula is C 23 H 27 It is Cl2N3O2·H2O and has a molecular weight of 466.40. Its chemical structure is: [ka] is.

[0074] For example, in some embodiments, aripiprazole intramuscular (IM) depot formulations are sustained-release suspension injections in prefilled dual-chamber syringes with 400 mg or 300 mg active ingredient strengths and vials with 400 mg or 300 mg active ingredient strengths. The labeled active ingredient strengths are calculated based on the anhydrous form (aripiprazole). In some embodiments, the inactive ingredients (depending on the administered dose) for the 400 mg and 300 mg active ingredient strength products, respectively, 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 (a pH adjuster). In a further embodiment, dose adjustments can be made using pre-filled dual-chamber syringes with 400 mg or 300 mg active ingredient strength and extended-release suspension injections in vials with 400 mg or 300 mg active ingredient strength; i.e., dose adjustments can be made in patients taking a CYP2D6 poor metabolizer and a concomitant CYP3A4 inhibitor or CYP2D6 inhibitor. Dose adjustments to 200 mg and 160 mg can be made by using 300 mg or 400 mg active ingredient strength vials for intramuscular injection into the deltoid or gluteal muscles for patients taking a CYP2D6 inhibitor, CYP3A4 inhibitor, or CYP3A4 inhibitor for more than 14 days. The presently disclosed aripiprazole IM depot formulation, Abilify Maintena®, for a sustained release suspension form is described in U.S. Patent Nos. 7,807,680, 8,030,313, 8,338,427, 8,338,428, 8,399,469, 8,722,679, 8,759,351, 8,993,761, 9,089,567, and 10,525,057; all of which are incorporated by reference in their entireties.

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

[0076] Due to the low solubility of aripiprazole particles, absorption of aripiprazole into the systemic circulation is slow and prolonged after intramuscular injection. After single-dose administration of aripiprazole intramuscular depot formulations in the deltoid and gluteal muscles, the extent of aripiprazole absorption (AUCt, AUC∞) was similar for both injection sites, but the rate of absorption (Cmax) was 31% higher after administration into the deltoid compared with the gluteal muscle. However, at steady state, AUC and Cmax were similar for both injection sites. After multiple intramuscular doses, aripiprazole plasma concentrations 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 in the gluteal muscle, the mean apparent terminal elimination half-life of aripiprazole was approximately 29.9 days, and after multiple injections, the mean apparent terminal elimination half-life of aripiprazole was approximately 46.5 days for 300 mg and 400 mg intramuscular depot aripiprazole administered every 4 weeks. Steady-state concentrations for typical subjects were achieved by the fourth dose at both administration sites. Approximately dose-proportional increases in aripiprazole and dehydroaripiprazole exposure were observed after 300 mg and 400 mg intramuscular depot aripiprazole injections every 4 weeks.

[0077] Aripiprazole elimination occurs primarily via hepatic metabolism involving two P450 isoenzymes, CYP2D6 and CYP3A4. Aripiprazole is not a substrate for CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2E1 enzymes. Aripiprazole also does not undergo direct glucuronidation.

[0078] The present disclosure utilizes two separate intramuscular depot injections of aripiprazole with a dose of aripiprazole ranging from about 100 mg to about 500 mg, and further, for example, each of the two intramuscular depot injections of aripiprazole contains a dose of 300 mg or 400 mg of aripiprazole. For example, the method of the present disclosure administers two separate 300 mg or 400 mg injections of an intramuscular (IM) depot of aripiprazole to separate injection sites in the patient's gluteal muscle and / or deltoid muscle, with administration occurring on day 1 of treatment. In some embodiments, two separate injections of the IM depot are administered to separate injection sites in the patient's gluteal muscle or deltoid muscle. In further embodiments, two separate injections of the IM depot are administered to the patient's gluteal muscle and deltoid muscle. Further, the patient has schizophrenia, for example, the patient has bipolar disorder type I. [Example]

[0079] Therapeutic Range and Aripiprazole Plasma Concentrations During Medication Initiation Using Alternative Initiation Regimens

[0080] A previously proposed therapeutic range 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 maximum aripiprazole concentration (Cmax,ss) at steady state after daily administration of 30 mg, the highest approved oral aripiprazole dose, is provided in Figure 10. Statistics related to the simulations in this disclosure are presented by median, 25th-75th, and 5th-95th percentiles of concentration. Therefore, for direct comparison of these simulations with the previously proposed therapeutic range (Figure 10), a horizontal reference line representing the 95th percentile of previously simulated Cmax,ss concentrations (741 ng / mL) after daily administration of 30 mg oral aripiprazole has been added to the simulations provided in this disclosure.

[0081] Based on the simulations provided under the heading "Simulation Results" found below, aripiprazole concentrations during dosing initiation can reach the 95th percentile (741 ng / mL) of previously simulated Cmax,ss concentrations following daily administration of 30 mg oral aripiprazole, thus providing the following supporting information in lieu of clinical data:

[0082] - Observed PK and safety data from the subset of subjects in this trial whose aripiprazole plasma concentrations after administration of the proposed alternative starting regimen fell within the 5th to 95th percentiles of simulated concentrations were evaluated and are provided under the heading "Comparison and Analysis of Results Across the Trial." Overall, the safety profile of these subjects was consistent with the known safety profile of Abilify Maintena®.

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

[0084] Summary of individual experiment results

[0085] A population PK analysis was performed to expand the previously submitted popPK model to incorporate deltoid site injections and to conduct simulations examining predicted plasma concentrations following administration of alternative initiation regimens at both the deltoid and gluteal sites. A summary of the combined final popPK model is provided below under the heading "popPK." A summary of the results of a single ascending dose Phase 1 clinical trial to determine the PK, safety, and tolerability of a single high-dose formulation of aripiprazole LAI following 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 8214 aripiprazole concentrations (16% oral, 65% gluteal muscle, 16% deltoid muscle, and 3% triceps or thigh administration) from 817 subjects were included in the final combined analysis dataset. Pharmacokinetic data included in this analysis consisted of aripiprazole concentrations after deltoid or gluteal muscle injections from data included from previous popPK reports as well as 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 sigmoidal absorption for oral administration (Ka) and first-order absorption for IM (primarily gluteal muscle) administration (IMKa).

[0089] The final combined model included the deltoid muscle injection site in the previously developed model by adding a deltoid muscle depot compartment with a separate absorption rate constant (DKa) to the original 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 updates to the original model incorporating the deltoid muscle injection site indicated by the dashed line. The following abbreviations are used in Figure 1: CMT = compartment; DKa = deltoid muscle IM first-order absorption rate constant; Frelative = relative bioavailability; IMKa = gluteal muscle IM first-order absorption rate constant; Ka = oral first-order absorption rate constant; R1 = dose rate into oral absorption compartment; Vc = apparent central volume of distribution; Vp1 = volume of distribution for peripheral compartment 1; Vp2 = volume of distribution for peripheral compartment 2; Q1 = intercompartment clearance 1; Q2 = intercompartment clearance 2. The final popPK model was a linear 3-compartment PK model that utilized sigmoid absorption for oral administration and separate first-order absorption for once-monthly gluteal and deltoid 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, except for DKa, which was predicted using data after deltoid administration. The interindividual variability (IIV) for oral absorption rate constant (Ka) was fixed to the value predicted in the original model, while the IIV for clearance (CL) after IM injection (IMKa and DKa), central volume of distribution (Vc), and first-order absorption rate constant were predicted or re-predicted using the combined final analysis data set.

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

[0092] [Table 1] TIFF2025176037000004.tif93148

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

[0094] The predictive performance of the combined final model was evaluated by prediction-corrected visual posterior predictive performance assessment (pcVPC). The pcVPC of the combined final population PK model for the deltoid and gluteal muscle administration sites after the first and fifth monthly doses is presented in Figures 2A-2D. In Figures 2A-2D, the following abbreviations are used: CI = confidence interval; the visual posterior predictive performance assessment after the first gluteal muscle injection includes PK data from subjects co-administered with oral aripiprazole. Overall, the pcVPC demonstrated good predictive performance of the combined final model for the deltoid and gluteal muscle administration sites, as the distribution of observed data was comparable to the 5th to 95th percentiles of the model-based simulations. Overall, the pcVPC confirmed that the variability seen in the observed PK data could be adequately explained by the final population PK model, as the distribution of observed data was comparable to the 90% prediction intervals of the model-based simulations after single and multiple doses at the deltoid and gluteal muscle sites.

[0095] Simulation results

[0096] The combined final model was utilized to simulate aripiprazole plasma concentration-time profiles after oral, gluteal muscle, and / or deltoid muscle administration of aripiprazole. To compare the simulated PK profiles, a substantial population of 817 subjects (provided as the "popPK model") with demographic characteristics similar to those enrolled in the clinical trials in the final analysis dataset was used to ensure that only the dosing regimen varied throughout the simulation. Individual PK parameters for the subjects in the final analysis dataset (all designated as CYP2D6 extensive metabolizers (EM) except for the simulation of CYP2D6 poor metabolizer (PM) subjects) were generated from the combined final PK model and its final parameter estimates. Individual PK profiles after oral, gluteal muscle, and deltoid muscle administration of aripiprazole were simulated using a 2-hour sampling interval for 24 hours after the previous oral dose and every 24 hours after the previous IM depot dose. A complete listing of all simulations performed is provided in Figures 3A-3C.

[0097] Alternative starting regimen without previous oral aripiprazole stabilization

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

[0099] Simulations show that in Figures 4A-4D, the median and 5th to 95th percentile concentrations of the aripiprazole PK profile after administration of the proposed alternative starting regimen are comparable to the approved starting regimen, 400 mg aripiprazole IM on day 1 + 10 mg to 20 mg oral aripiprazole for 14 days, e.g.:

[0100] - The median aripiprazole PK profile after the alternative initiation regimen reached therapeutic levels on Day 1 (Cmin,ss for 10 mg daily aripiprazole: 94.0 ng / mL) 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 equal to or lower than the 95th percentile of the currently approved regimen and is within the upper limit of the therapeutic range as discussed above.

[0102] - Plasma concentrations for all regimens exceeded the previously used conservative upper limit of the 75th percentile of simulated Cmax,ss, 541 ng / mL after daily dosing, but remained below the 95th percentile of simulated 30 mg oral Cmax,ss (741 ng / mL).

[0103] - Alternative initiation regimens do not affect steady-state maintenance concentrations.

[0104] Alternative starting regimen with prior oral aripiprazole stabilization

[0105] In the approved brand name Abilify Maintena®, the first dose is administered to adult patients stabilized on oral aripiprazole with co-administered oral aripiprazole (10-20 mg) for 14 consecutive days. Therefore, a simulation was performed to predict and compare plasma concentrations over a 28-day period following administration of the currently approved regimen and an alternative starting regimen to patients stabilized on 20 mg of aripiprazole, the highest typical oral dose a patient receives before initiating treatment with IM depot aripiprazole. The median, 5th, 25th-75th, and 95th percentiles of the simulated aripiprazole plasma PK profiles for the currently approved regimen and an alternative starting regimen administered as two separate injections into the gluteal or deltoid muscle sites in subjects previously stabilized on a 20 mg oral aripiprazole dose are presented in Figures 5A and 5B. In Figures 5A and 5B, the approved starting regimen was 10-20 mg oral (for 14 days) and 400 mg IM depot (day 1). The starting concentration at time zero is the mean concentration at steady state for subjects stabilized on 20 mg oral aripiprazole.

[0106] Simulations show that the median and 5th to 95th percentile concentrations of the aripiprazole PK profile following administration of the alternative starting regimen are comparable to the approved starting regimen when administered to subjects already stabilized on 20 mg oral aripiprazole:

[0107] - The 95th percentile of simulated concentrations after the alternative starting regimen is equal to or lower than the 95th percentile of the licensed regimen.

[0108] - Alternative initiation regimens have no effect on steady-state maintenance concentrations.

[0109] Subjects who are CYP2D6 poor metabolizers

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

[0111] Plasma concentration simulations were performed to allow comparison of simulated median concentration-time profiles and box plots of aripiprazole Cmax following administration of a single 20 mg oral dose of aripiprazole, along with two doses of 400 mg (CYP2D6 EM and PM subjects) or 300 mg (CYP2D6 PM subjects only) IM depot aripiprazole formulations into the gluteal or deltoid muscle sites in subjects or patients previously stabilized on 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 concentrations at time zero are the mean concentrations at steady state for CYP2D6 EM subjects stabilized on 20 mg oral aripiprazole and PM subjects stabilized on 10 mg oral aripiprazole. For PM, the previous oral dose was reduced by half (10 mg instead of 20 mg).

[0112] As expected, the simulations resulted in higher aripiprazole Cmax and exposure in CYP2D6 PM subjects compared with CYP2D6 EM subjects when both received two doses of the 400 mg IM depot aripiprazole formulation. Therefore, a dose reduction of the proposed regimen from two doses of the 400 mg IM depot aripiprazole formulation to two doses of the 300 mg IM depot aripiprazole formulation, accompanied by a single 20 mg oral dose of aripiprazole, is recommended for subjects or patients known to be CYP2D6 PMs to ensure that concentrations following the alternative starting regimen are comparable to the currently approved regimen and remain within or slightly above the therapeutic range.

[0113] No maintenance IM depot dose administered

[0114] To determine whether alternative initiation regimens may be applicable in situations where the currently approved initiation regimen requires 2 weeks of concurrent oral administration of aripiprazole with a single injection of an IM depot aripiprazole formulation, a simulation was performed to evaluate aripiprazole concentrations after missing the administration of the second, third, fourth, or steady-state dose of the IM depot aripiprazole formulation.

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

[0116] A comparison of simulated median aripiprazole plasma concentrations after administration of alternative or currently approved initiation regimens into the gluteal or deltoid muscle sites when the fourth or fifth (steady-state) dose was administered 6 weeks after the previous injection is provided in Figures 9A-9D. 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 resulted in median aripiprazole concentrations above the lower threshold of the therapeutic range and similar to concentrations after the approved initiation regimen.

[0118] Simulation results show that if the maintenance IM depot dose is missed, an alternative initiation regimen may be administered in place of co-administered oral aripiprazole for 14 days, along with a single IM depot formulation of aripiprazole injection on day 1. This treatment strategy after a missed dose is consistent with that of the Abilify Maintena® brand.

[0119] Comparison and analysis of results through clinical trials

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

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

[0122] Of the 17 subjects identified, 7 subjects were treated with 1200 mg aripiprazole LAI and 10 subjects were treated with 780 mg aripiprazole LAI. A review of the safety data from these subjects did not identify any unexpected AEs, and it was concluded that the safety profile was consistent with the known safety profile of Abilify Maintena®.

[0123] conclusion

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

[0125] A Phase 1, Open-Label, Single Ascending Dose, Parallel-Arm Study to Determine the Pharmacokinetics, Safety, and Tolerability of a 2-Month Intramuscular Depot of Aripiprazole Administered into the Gluteal Muscle in Adult Subjects with Schizophrenia

[0126] This was an open-label, single-ascending-dose, parallel-arm, multicenter study to determine the PK, safety, and tolerability of single doses of 780 mg (Cohort 1) and 1200 mg (Cohort 2) of a high-dose formulation of aripiprazole LAI administered intramuscularly to adult subjects with schizophrenia. Data from this study are supportive because they were evaluated for cases in which aripiprazole plasma concentrations increased at similar rates and reached levels predicted in simulations for alternative starting regimens. Overall, aripiprazole LAI was well tolerated when administered IM to adult subjects with schizophrenia as single doses of 780 mg and 1200 mg. In a subset of 17 subjects, administration of aripiprazole LAI resulted in higher aripiprazole plasma concentrations and a faster absorption rate, falling within the 5th to 95th percentiles of simulated concentrations after administration of the proposed alternative initiation regimen, resulting in an aripiprazole plasma concentration-time profile that was consistently above the mean PK profile after a single gluteal intramuscular dose of 400 mg Abilify Maintena® (Figure 1). Safety data from this subset of subjects were evaluated and compared to the known safety profile of Abilify Maintena®. Further details of this analysis are provided in the section entitled "Comparison and Analysis of Results Across the Clinical Trial."

[0127] Aripiprazole LAI exhibited sustained release for every-two-month dosing at the dose levels evaluated. The dosing interval extension for aripiprazole LAI was achieved primarily through dose escalation, while maintaining a minimum aripiprazole concentration equivalent to that of Abilify Maintena® after multiple dosing. Aripiprazole LAI has a higher aripiprazole concentration in the drug product compared to the currently marketed / approved Abilify Maintena® (300 mg / mL vs. 200 mg / mL) and was engineered with minor changes to the vehicle. The mean particle size distribution and dissolution profile of aripiprazole for the aripiprazole LAI formulation were comparable to that of the Abilify Maintena® formulation, and this formulation was expected to have a similar sustained-release profile compared to the approved Abilify Maintena® formulation. The mean (standard deviation [SD]) aripiprazole plasma concentration time profiles after administration of a single 780 mg or 1200 mg dose of aripiprazole into the gluteal muscle in subjects with schizophrenia are presented in FIG.

[0128] A summary of aripiprazole PK parameters following single dose administration of 780 mg or 1200 mg of aripiprazole into the gluteal muscle in subjects with schizophrenia is presented in Table 2 below.

[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 apparent clearance of the drug from plasma after extravascular administration; RTU is ready to use; tmax is the time to maximum (peak) plasma concentration; and t1 / 2 is the elimination half-life. Furthermore, a Median(min-max); b n = 14; and cn=11.

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

[0132] - Aripiprazole LAI was well tolerated when administered IM as single doses of 780 and 1200 mg to adult subjects with schizophrenia.

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

[0134] Administration of a single dose of 780 or 1200 mg aripiprazole LAI into the gluteal muscle resulted in a slightly less than proportional increase in aripiprazole Cmax and a slightly greater than dose-proportional increase in exposure (AUCt and AUC∞), based on mean values ​​corrected for dose.

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

[0136] - After administration of 780 or 1200 mg 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 comparable and similar to the median t1 / 2 (24.0 days) after administration of a single dose of 400 mg Abilify Maintena® into the gluteal muscle.

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

[0138] Furthermore, this Phase I clinical trial supports the use of the disclosed method of initiating dosing for aripiprazole treatment in patients in need thereof, comprising administering two separate injections of an intramuscular (IM) depot formulation of aripiprazole in the range of about 10 mg to about 500 mg into separate injection sites in the patient's gluteal and / or deltoid muscles, and a single dose of oral aripiprazole, administered on treatment day 1. That is, the use of two injections of aripiprazole in the range of about 10 mg to about 500 mg did not result in any unexpected AEs, and the safety profile was consistent with the known safety profile of Abilify Maintena®.

[0139] All publications and patents mentioned herein are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference.

[0140] A claim or specification including "or" or "and / or" between 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 relevant to a given product or process, unless specifically indicated to the contrary or otherwise clear from the context. The present disclosure includes embodiments in which exactly one member of the group is present, utilized, or otherwise relevant to a given product or process. The present disclosure includes embodiments in which more than one, or all of the group members are present, utilized, or otherwise relevant to a given product or process.

[0141] Furthermore, the present disclosure encompasses all variations, combinations, and permutations of at least one limitation, element, clause, and descriptive term introduced from at least one of the enumerated claims into another claim. For example, any claim that depends on another claim can be amended to include at least one limitation found in any other claim that depends from the same base claim. Where elements are presented as a list, e.g., in Markush group format, each subgroup of elements is also disclosed, and any element(s) can be removed from the group. In general, when the present disclosure, or aspects of the present disclosure, are referred to as including certain elements and / or features, it should be understood that an embodiment of the present disclosure or aspects of the present disclosure consists of or consists essentially of such elements and / or features. For simplicity, embodiments are not specifically described herein. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise apparent from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges can assume any specific value or sub-range within the ranges set forth in different embodiments of this disclosure, down to one-tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0142] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the disclosure described herein which equivalents are intended to be encompassed by the claims.

Claims

1. 1. A method of initiating aripiprazole therapy in a patient in need thereof, comprising:

1. A method comprising administering two separate injections of an aripiprazole intramuscular (IM) depot formulation, each injection comprising about 10 mg to about 500 mg of aripiprazole to a patient at separate injection sites selected from a gluteal muscle site, a deltoid muscle site, and a combination thereof, and a single dose of oral aripiprazole, wherein the administering step occurs on day 1 of treatment.

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

3. 3. The method of claim 1 or 2, further comprising administering a single monthly maintenance injection of an IM depot formulation of aripiprazole after the first day of treatment.

4. 4. The method of claim 3, wherein the single monthly maintenance injection is selected from about 300 mg and about 400 mg aripiprazole IM depot formulations.

5. 4. The method of claim 3, wherein the single monthly maintenance injection is selected from aripiprazole 160 mg and 200 mg aripiprazole IM depot formulations if the patient is a CYP2D6 poor metabolizer or if the patient is taking a concomitant CYP3A4 inhibitor or CYP2D6 inhibitor for more than 14 days.

6. 6. The method of any one of claims 1 to 5, wherein two separate injections of the aripiprazole IM depot formulation are administered at separate injection sites in the patient's gluteal muscles.

7. 6. The method of any one of claims 1 to 5, wherein two separate injections of the aripiprazole IM depot formulation are administered to the patient at injection sites in the gluteal and deltoid muscles.

8. 6. The method of any one of claims 1 to 5, wherein two separate injections of the aripiprazole IM depot formulation are administered at separate injection sites in the patient's deltoid muscle.

9. The method of any one of claims 1 to 8, wherein the patient has schizophrenia.

10. The method of any one of claims 1 to 8, wherein the patient has bipolar I disorder.

11. 11. The method of any one of claims 1 to 10, wherein the single dose of oral aripiprazole ranges from about 2 mg to about 30 mg of aripiprazole.

12. 12. The method of claim 11, wherein a single dose of oral aripiprazole ranges from about 10 mg to about 30 mg.

13. 12. The method of claim 11, wherein the single dose of oral aripiprazole is 20 mg.

14. 12. The method of claim 11, wherein the single dose of oral aripiprazole is 10 mg.

15. 10. The method of claim 1, wherein if the patient is a CY2D6 poor metabolizer, each of the two separate injections comprises about 300 mg of aripiprazole, and the single dose of oral aripiprazole is about 20 mg.

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