Dose initiation method for aripiprazole treatment

Abstract

The present disclosure provides methods of dose initiation of aripiprazole therapy. In particular, the present disclosure relates to the use of aripiprazole for the preparation of an aripiprazole intramuscular (IM) depot formulation for use in a dose initiation method for aripiprazole treatment of a patient in need thereof wherein the aripiprazole intramuscular (IM) depot formulation comprises 300 mg or 400 mg of aripiprazole, the method comprises: administering to the patient two separate injections of the aripiprazole intramuscular (IM) depot formulation at separate injection sites selected from the group consisting of the gluteus site, the deltoid site, and the gluteus site and the deltoid site, wherein each injection comprises 300 mg or 400 mg of aripiprazole; and administering a single dose of oral aripiprazole, wherein the step of administering two separate injections and oral single dose is performed on the first day of the treatment. The present invention provides the following advantages: (1) the therapeutic aripiprazole plasma concentration is achieved on the first day of treatment; (2) the consistent clinical effect in the whole administration interval is supported; (3) producing aripiprazole plasma concentrations similar to the currently approved (traditional) starting regimen, thus producing similar safety profiles; and (4) providing a new onset selection that eliminates the need for supplementation of 14-day oral tablets, potentially reducing compliance-related treatment insufficiency during the onset phase of treatment.

Description

[0001] This application is a divisional application of international application PCT / JP2021 / 014194, which entered the Chinese national phase on September 29, 2022, with application number 202180025911.8 and invention name “Method for starting dose of aripiprazole treatment”. Technical Field

[0002] This application claims priority to U.S. Provisional Application No. 63 / 003,544, filed on April 1, 2020; the contents of which are incorporated herein by reference in their entirety. Background Art

[0003] Aripiprazole is a partial agonist at dopamine (D2) and serotonin 5-HT1A receptors and an antagonist at serotonin 5-HT2A receptors. It is an atypical antipsychotic that has shown efficacy in clinical trials for the treatment of schizophrenia and bipolar I disorder in adults. AbilifyMaintena (R), an intramuscular (IM) depot formulation of aripiprazole, is an injectable extended-release suspension. It is approved in many countries for the maintenance treatment of schizophrenia in adult patients stabilized on oral aripiprazole. Summary of the invention

[0004] Technical issues

[0005] Monthly Aripiprazole is a long-acting IM injection formulation of aripiprazole that is indicated for the maintenance treatment of schizophrenia and bipolar I disorders in adult patients stabilized on oral aripiprazole. In the currently approved label for AbilifyMaintena(R), the first dose is administered to adult patients stabilized on oral aripiprazole while taking oral aripiprazole (10 mg to 20 mg) for fourteen consecutive days. Achieving therapeutic plasma concentrations may provide a therapeutic advantage in patient populations that are believed to be at potential risk for compliance-related relapse or suboptimal treatment outcomes, such as long-acting injectable (LAI) patient populations.

[0006] Technical Solution

[0007] To provide another option for this initiation phase, a two-injection initiation regimen is provided based on population pharmacokinetic (popPK) modeling and simulations, comprising two separate administrations of monthly aripiprazole at separate gluteal and / or deltoid injection sites along with a single oral dose of aripiprazole on the first day of treatment. For example, the present disclosure relates to an alternative initiation regimen of two separate administrations of an aripiprazole intramuscular (IM) depot formulation, such as Abilify Maintena (R), with a shorter oral overlap. Simulations of an alternative initiation regimen of two injections of an aripiprazole intramuscular (IM) depot formulation at separate gluteal and / or deltoid injection sites along with a single oral dose of aripiprazole on the first day of treatment were shown to be adequate, and the alternative initiation regimen may be used as another option for initiating Abilify Maintena (R) treatment.

[0008] In some aspects, the present disclosure relates to a method for initiating aripiprazole treatment in a patient in need thereof, the method comprising: administering two separate injections of an intramuscular (IM) depot formulation of aripiprazole, wherein each injection comprises about 10 mg to about 500 mg of aripiprazole administered to the patient at separate gluteal and / or deltoid muscle injection sites; and a single dose of oral aripiprazole, wherein the administering step is performed on the first day of treatment.

[0009] In additional aspects, each of the two separate injections comprises about 400 mg of aripiprazole. Additionally, the methods of the present disclosure further comprise administering a single monthly maintenance injection of an aripiprazole IM depot formulation after the first day of treatment. For example, in other aspects, the single monthly maintenance injection is selected from about 300 mg and about 400 mg of aripiprazole in the form of an aripiprazole IM depot formulation. In other aspects, when the patient is a CYP2D6 poor metabolizer or concurrently ingests a CYP3A4 inhibitor or a CYP2D6 inhibitor for more than 14 days, the single monthly maintenance injection is selected from 160 mg and 200 mg of aripiprazole in the form of an aripiprazole IM depot formulation.

[0010] In other aspects, two separate injections of the aripiprazole IM depot formulation are administered to a single gluteal muscle injection site of the patient. Additionally, two separate injections of the aripiprazole IM depot formulation are administered to a single gluteal muscle injection site and a single deltoid muscle injection site of the patient. Additionally, for example, two separate injections of the aripiprazole IM depot formulation are administered to a single deltoid muscle injection site of the patient.

[0011] In aspects of the disclosure, the patient suffers from schizophrenia. In other aspects, the patient suffers from bipolar type 1 disorder.

[0012] In some other aspects, a single dose of oral aripiprazole is in the range of about 2 mg to about 30 mg of aripiprazole. For example, a single dose of oral aripiprazole is in the range of about 10 mg to about 30 mg. Also, for example, a single dose of oral aripiprazole is 20 mg. And in some other aspects, a single dose of oral aripiprazole is 10 mg.

[0013] In some other aspects, when the patient is a CY2D6 poor metabolizer, each of the two separate injections contains about 300 mg of aripiprazole, and the single oral dose of aripiprazole is about 20 mg.

[0014] In some other aspects, the present disclosure relates to an aripiprazole intramuscular (IM) depot formulation comprising about 10 mg to about 500 mg of aripiprazole for administering to a patient in need thereof two separate injections of the aripiprazole intramuscular (IM) depot formulation at an injection site selected from the gluteal muscle site, the deltoid muscle site, and combinations thereof, in combination with a single dose of oral aripiprazole, wherein the administering step is performed on the first day of treatment.

[0015] In some other aspects, the present disclosure relates to aripiprazole or a salt thereof for use in treating schizophrenia or bipolar I disorder, wherein the aripiprazole or a salt thereof is administered to a patient in need thereof by any of the aripiprazole treatment initiation methods disclosed herein. In addition, 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 of the aripiprazole treatment initiation methods disclosed herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] [ Figure 1 ] Figure 1 is a diagram depicting a structural model for the PK of aripiprazole following oral administration and IM injection into the gluteal and deltoid muscles.

[0017] [Figure 2] FIG. 2A to FIG. 2D is a plot of the prediction-corrected visual predictive test of the final combined population pharmacokinetic (popPK) model.

[0018] [Figure 3] FIG. 3A to FIG. 3C is a table of simulation purpose and description.

[0019] [Figure 4] FIG. 4A to FIG. 4D Figure 2 is a graph of simulated median (5th-95th percentile) aripiprazole concentration-time profiles following current or alternative starting regimens followed by a 400 mg intramuscular depot dose every 28 days. Shading indicates the 5th to 95th percentiles.

[0020] [Figure 5] Figure 5A and Figure 5Bis a graph of simulated medians, 5th percentiles, 25th to 75th percentiles, and 95th percentiles of the pharmacokinetic profiles following administration of the current or alternate starting regimen to subjects who have been stabilized on 20 mg oral aripiprazole. The shading and dashed lines represent the 5th percentile, 25th to 75th percentiles, and 95th percentiles, respectively.

[0021] [Figure 6] Fig. 6A and Figure 6B Figure 1 is a graph of simulated median aripiprazole concentration time profile box plots and a box plot of Cmax following the Ability Maintena (R) starting regimen for extensive and poor CYP2D6 metabolizers. The box plots show the 5th, 25th, median, 75th, and 95th percentiles of Cmax.

[0022] [Figure 7] Fig. 7A and Figure 7B Figure 2 is a graph of simulated median aripiprazole concentration time profiles and box plots of Cmax following the Ability Maintena(R) starting regimen for extensive and poor metabolizers who have been stabilized on oral aripiprazole. The box plots show the 5th, 25th, median, 75th, and 95th percentiles of Cmax.

[0023] [Figure 8] FIG. 8A to FIG. 8D is a graph of the simulated median pharmacokinetic profiles following initiation and reinitiation with the current or alternate initiation regimen at 5 weeks after the previous intramuscular depot dose.

[0024] [Figure 9] 9A to 9D is a graph of the simulated median pharmacokinetic profiles following initiation and reinitiation with the current or alternate initiation regimen at 6 weeks after the previous intramuscular depot dose.

[0025] [ Fig.10 ] Fig.10 Simulated and measured aripiprazole concentrations following oral and intragluteal depot administration of aripiprazole to support determination of the therapeutic window are described.

[0026] [ Fig.11 ] Fig.11 Figure 2 is a graph of the combined aripiprazole plasma concentration time profiles following administration of a single dose of 780 mg (N=18) or 1200 mg (N=13) of aripiprazole long-acting injection to the gluteal muscle of subjects with schizophrenia and the mean plasma concentrations following administration of a single dose of 400 mg Abilify Maintena (R). The shaded area represents the model-predicted 5th to 95th percentiles of the PK profile following the starting regimen of 20 mg oral + 2×400 mg IM Maintena (R) administered to the gluteal muscle site.

[0027] [ Fig.12 ] Fig.12 Shown are mean (SD) aripiprazole plasma concentration time profiles following administration of a single dose of 780 mg (N=18) or 1200 mg (N=13) aripiprazole 2M ready-to-use depot injection to the gluteal muscle of subjects with schizophrenia.

[0028] [ Fig.13 ] Fig.13 Measured aripiprazole plasma concentrations by week after the first intramuscular depot injection are illustrated. Boxes indicate plasma concentrations exceeding 534 ng / mL during the 2-week 10-20 oral overlap period after the first IM injection. DETAILED DESCRIPTION

[0029] Unless otherwise stated, as used herein, "a" or "an" entity refers to one or more (or one or more) of the entity, for example, "a compound" refers to one or more compounds or at least one compound. Thus, the terms "a" (or "a"), "one or more (or one or more)" and "at least one (or at least one)" are used interchangeably herein.

[0030] As used herein, the term "about" means approximately, roughly, roughly, or roughly. When the term "about" is used in conjunction with a numerical range, it modifies the range to extend the boundaries above and below the numerical values ​​set forth. In general, the term "about" is used herein to modify a numerical value to a deviation of 5% above and below the stated value.

[0031] As used herein, the terms "treat", "treating", and "treatment" when used in conjunction with a condition or disorder include any effect that improves the condition or disorder, such as reducing, decreasing, modulating, ameliorating, or eliminating. The improvement of any symptom of a condition or disorder or the reduction of its severity can be readily assessed according to standard methods and techniques known in the art. In some embodiments, the presently disclosed methods or depot formulations can be used as maintenance monotherapy to treat schizophrenia and bipolar I disorder. In other embodiments, the presently disclosed methods or depot formulations can be used to treat schizophrenia, emergency treatment of manic and mixed events associated with bipolar I disorder, major depressive disorder (MDD), irritability with autism, and Tourette's disorder.

[0032] As used herein, "mammal" refers to domestic animals (eg, dogs, cats, and horses) and humans. In some embodiments, the mammal is a human.

[0033] Implementation method:

[0034] Some embodiments of the present disclosure include but are not limited to:

[0035] 1. A method for initiating aripiprazole treatment in a patient in need thereof, the method comprising:

[0036] The patient is administered two separate injections of an intramuscular (IM) depot formulation of aripiprazole at separate gluteal and / or deltoid muscle injection sites, wherein each injection comprises about 10 mg to about 500 mg of aripiprazole; and a single dose of oral aripiprazole, wherein the administering step is performed on the first day of treatment.

[0037] 2. The method of embodiment 1, wherein the two separate injections each comprise 400 mg aripiprazole.

[0038] 3. The method of embodiment 1 or 2, further comprising administering a single monthly maintenance injection of the aripiprazole IM depot formulation after the first day of the treatment.

[0039] 4. The method of embodiment 3, wherein the single monthly maintenance injection is selected from about 300 mg and about 400 mg of the aripiprazole IM depot formulation.

[0040] 5. The method according to embodiment 3, wherein when the patient is a CYP2D6 poor metabolizer or concomitantly ingests a CYP3A4 inhibitor or a CYP2D6 inhibitor for more than 14 days, the single monthly maintenance injection is selected from 160 mg and 200 mg of the aripiprazole IM depot formulation.

[0041] 6. The method of any one of embodiments 1 to 5, wherein the two separate injections of the aripiprazole IM depot formulation are administered at separate gluteal muscle injection sites of the patient.

[0042] 7. The method of any one of embodiments 1 to 5, wherein the two separate injections of the aripiprazole IM depot formulation are administered to the patient's gluteal and deltoid muscle injection sites.

[0043] 8. The method of any one of embodiments 1 to 5, wherein the two separate injections of the aripiprazole IM depot formulation are administered at separate deltoid muscle injection sites of the patient.

[0044] 9. A method according to any one of embodiments 1 to 8, wherein the patient suffers from schizophrenia.

[0045] 10. The method of any one of embodiments 1 to 8, wherein the patient suffers from bipolar I disorder.

[0046] 11. The method according to any one of embodiments 1 to 10, wherein the single dose of oral aripiprazole is in the range of about 2 mg to about 30 mg of aripiprazole.

[0047] 12. The method of embodiment 11, wherein the single dose of oral aripiprazole is in the range of about 10 mg to about 30 mg.

[0048] 13. The method of embodiment 11, wherein the single dose of oral aripiprazole is 20 mg.

[0049] 14. The method of embodiment 11, wherein the single dose of oral aripiprazole is 10 mg.

[0050] 15. The method of embodiment 1, wherein when the patient is a CY2D6 poor metabolizer, the two separate injections each contain about 300 mg aripiprazole, and the single dose of oral aripiprazole is about 20 mg.

[0051] The present disclosure relates to an alternative starting regimen of two separate administrations of an aripiprazole intramuscular (IM) depot formulation with a shorter oral overlap. For example, simulations of an alternative starting regimen of two 400 mg injections of an aripiprazole intramuscular (IM) depot formulation (e.g., Abilify Maintena (R)) at separate gluteal and / or deltoid injection sites on the first day of treatment with a single 20 mg dose of oral aripiprazole were shown to be adequate and may be another option for initiating treatment with, for example, Abilify Maintena (R).

[0052] Aripiprazole is 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydroquinolone. The empirical formula is C 23 H 27 Cl2N3O2 and its molecular weight is 448.38. The chemical structure is:

[0053] [Chemicals 1]

[0054] .

[0055] As used herein, reference to aripiprazole is a reference to aripiprazole or a salt thereof, 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 in various anhydrous forms known as anhydrous crystals B, anhydrous crystals C, anhydrous crystals D, anhydrous crystals E, anhydrous crystals F, and anhydrous crystals G. All of these crystalline forms may be used as aripiprazole or a salt thereof in the injectable formulations of the present disclosure, and, for example, aripiprazole is in the form of a monohydrate.

[0056] Pharmaceutical compositions comprising aripiprazole are considered to be antipsychotics useful in the treatment of schizophrenia and bipolar I disorder.

[0057] Traditional dosing regimen of aripiprazole

[0058] The recommended starting and maintenance doses of Abilify Maintena (R) for conventional aripiprazole dosing are 300 mg or 400 mg monthly (no earlier than 26 days after the previous injection). For patients who have never taken aripiprazole, establish tolerance with oral aripiprazole prior to initiating treatment with Abilify Maintena (R). Due to the half-life of oral aripiprazole, full assessment of tolerance may take up to 2 weeks.

[0059] After the first Abilify Maintena(R) injection, administer oral aripiprazole (10 mg to 20 mg) for 14 consecutive days to achieve therapeutic aripiprazole concentrations during initial therapy. For patients who have been stabilized on another oral antipsychotic (and are known to tolerate aripiprazole), continue treatment with the antipsychotic for 14 consecutive days after the first Abilify Maintena(R) injection to maintain therapeutic antipsychotic concentrations during initial therapy.

[0060] If adverse reactions occur at the 400-mg dose, then a dose reduction to 300 mg once monthly may be considered.

[0061] Thus, the currently approved initial regimen consists of a single IM injection of an intramuscular depot formulation of aripiprazole and daily oral tablet administration of aripiprazole (10 to 20 mg) for 14 consecutive days.

[0062] References to aripiprazole intramuscular depot formulations herein refer to Abilify Maintena(R) (aripiprazole), extended-release injectable suspension for intramuscular use, originally approved by the United States in 2002 and revised in June 2020.

[0063] Alternative dosing regimens for aripiprazole

[0064] The present disclosure relates to an alternative initiation regimen or dose initiation comprising two separate injections of about 100 mg to about 500 mg of an intramuscular depot formulation of aripiprazole (Abilify Maintena (R)) administered at separate gluteal and / or deltoid injection sites on the first day of treatment along with a single oral dose of aripiprazole. The single oral dose of aripiprazole is in the range of about 2 mg to about 30 mg; for example, the single oral dose of aripiprazole is in the range of about 10 mg to about 30 mg. This alternative initiation regimen provides an option for the first dose or initiation dose of the intramuscular depot formulation of aripiprazole. Maintenance dosing remains unchanged; for example, the maintenance dose thereafter is given as a single monthly injection of 400 mg or 300 mg of the IM depot formulation of aripiprazole. With respect to the traditional dose initiation regimen, the alternative initiation regimen is applicable to both the deltoid and gluteal administration sites.

[0065] The present disclosure uses two separate aripiprazole intramuscular depot injections at doses ranging from about 100 to about 500 mg of aripiprazole. For example, the methods of the present disclosure administer to a patient two separate 400 mg injections of aripiprazole intramuscular (IM) depot formulation at separate gluteal and / or deltoid muscle injection sites, with administration occurring on the first day of treatment. In some embodiments, two separate injections of aripiprazole IM depot formulation are administered to a patient at separate gluteal muscle injection sites or at separate deltoid muscle sites. In another embodiment, two separate injections of aripiprazole IM depot formulation are administered to a patient at both gluteal and deltoid muscle injection sites. Additionally, the patient suffers from schizophrenia, and for example, the patient suffers from bipolar I disorder.

[0066] The rationale for selecting the alternate starting regimen dose is based on simulations performed by a population pharmacokinetic (popPK) model. A range of dose starting regimens were considered to shorten the length of oral administration overlapping the first IM depot injection while maintaining the median concentration within the previously determined therapeutic window and similar to the median concentration of the currently approved dose starting regimen (i.e., the median, 25th to 75th percentiles, and 5th to 95th percentiles of the concentration). Based on the results of the simulations, the doses suggested for the alternate starting regimens range from about 100 mg to about 500 mg, and in some embodiments, are two 400 mg injections of an intramuscular aripiprazole depot formulation at separate gluteal and / or deltoid injection sites, for example, with a single dose of oral aripiprazole on the first day of treatment, for example, a single dose of oral aripiprazole in the range of about 2 mg to 30 mg of aripiprazole and, for example, a single 20 mg dose of oral aripiprazole.

[0067] Clinical Pharmacology Research

[0068] The goal of the clinical pharmacology study was to use PK modeling and simulation approaches to establish a two-injection starting regimen for once-monthly long-acting injectable aripiprazole that would eliminate the need for a supplemental 14-day course of oral aripiprazole during the initial phase of treatment.

[0069] method

[0070] The popPK model (Food and Drug Administration: Center for Drug Evaluation and Research, Aripiprazole IM Depot Formulation: Clinical Pharmacology and Biopharmaceutics Review (Application No. 202971s000) 2012) previously developed to characterize the PK of aripiprazole after oral administration and gluteal muscle IM depot injection was expanded to include the deltoid muscle injection site. The final model was developed using PK data from 7 clinical trials after oral administration and IM depot injection (gluteal and deltoid muscles). A total of 8,214 aripiprazole concentrations (16% oral, 65% gluteal, 16% deltoid, and 3% triceps or thigh administration) from 817 subjects were included in the final analysis data set. The predictive performance of the final model was evaluated by predictive-corrected visual prediction test (pcVPC).

[0071] The final popPK model was used to simulate and evaluate a range of dose initiation schedules with a short oral overlap after the first IM depot injection to identify a schedule that: (1) remained within the previously established therapeutic window corresponding to the lower bound of the simulated median minimum aripiprazole concentration (Cmax,ss) at steady state following administration of 10 mg oral aripiprazole daily (94.0 ng / mL) and the 95th percentile of the maximum aripiprazole concentration (Cmax,ss) at steady state following administration of the highest approved oral aripiprazole dose of 30 mg daily (741 ng / mL); and (2) resulted in plasma concentrations (i.e., median, 25th to 75th percentiles, and 5th to 95th percentiles of concentrations) similar to the currently approved initiation schedule that begins with a single injection (one 400 mg injection of monthly aripiprazole plus 14 days of oral aripiprazole [10 to 20 mg]).

[0072] An overview of popPK modeling and simulations used to support alternative starting regimens is provided below under the subsection heading "popPK Modeling". Also presented in this section are simulations of aripiprazole plasma concentration time profiles following administration of alternative starting regimens for subjects without prior stabilization with oral aripiprazole and with prior stabilization with oral aripiprazole (under the subsection headings "Alternative Starting Regimens Without Prior Oral Aripiprazole Stabilization" and "Alternative Starting Regimens With Prior Oral Aripiprazole Stabilization" below), for extensive or poor cytochrome P450 2D6 (CYP2D6) metabolizers (under the subsection heading "Subjects Who Are CYP2D6 Poor Metabolizers" below), and in a regimen that follows a missed maintenance dose (under the subsection heading "Missed Maintenance IM Depot Dose" below).

[0073] Aripiprazole oral preparation

[0074] Aripiprazole is a psychotropic drug that can be used as an oral (Aripiprazole) tablet. In some embodiments, oral tablets of Aripiprazole are available in strengths such as 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. Colorants may include, for example, ferric oxide (yellow or red) and FD&C blue No. 2 aluminum lake.

[0075] Aripiprazole is completely absorbed after tablet administration, e.g., peak plasma concentrations occur within 3 to 5 hours; the absolute oral bioavailability of the tablet formulation is about 87%. Oral tablets of aripiprazole can be administered with or without food. For example, administration of a 15 mg oral aripiprazole tablet with a standard high-fat meal does not significantly affect the Cmax or AUC of aripiprazole or its active metabolite, dehydroaripiprazole, but delays the Tmax of aripiprazole by 3 hours and by 12 hours for dehydroaripiprazole.

[0076] Aripiprazole is metabolized primarily through three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for the dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the major drug fraction in systemic circulation. At steady state, the active metabolite, dehydroaripiprazole, contributes approximately 40% of the aripiprazole AUC in plasma.

[0077] Following 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 unchanged aripiprazole was excreted in the urine and approximately 18% of the unchanged oral dose was recovered in the feces.

[0078] The present disclosure uses aripiprazole oral tablets having a single oral dose selected from 2 mg to 30 mg, such as a single oral dose of 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg of aripiprazole. In some embodiments, the single oral dose is in the range of about 10 mg to about 30 mg of aripiprazole, such as about 20 mg of aripiprazole. In some embodiments, the single oral dose is selected from 10 mg and 20 mg of aripiprazole. In other embodiments, the single oral dose is 20 mg of aripiprazole.

[0079] Aripiprazole intramuscular depot

[0080] In some embodiments, the intramuscular aripiprazole depot formulation comprises aripiprazole monohydrate; the aripiprazole monohydrate is 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydroquinolone monohydrate. The empirical formula is C 23 H 27 Cl2N3O2•H2O and its molecular weight is 466.40. The chemical structure is:

[0081] [Chemicals 2]

[0082] .

[0083] For example, in some embodiments, the aripiprazole intramuscular (IM) depot formulation is an extended release injectable suspension contained in a prefilled dual chamber syringe and a 400-mg or 300-mg strength vial in a 400-mg or 300-mg strength. The labeled strength is calculated based on the anhydrous form (aripiprazole). In some embodiments, the inactive ingredients (per unit dose administered) of the 400-mg and 300-mg strength products include sodium carboxymethylcellulose (16.64 mg and 12.48 mg, respectively), mannitol (83.2 mg and 62.4 mg, respectively), sodium phosphate monobasic monohydrate (1.48 mg and 1.11 mg, respectively), and sodium hydroxide (pH adjuster). In other embodiments, dose adjustment can be made using the extended release injectable suspension in a 400-mg or 300-mg strength in a prefilled dual chamber syringe and a 400-mg or 300-mg strength vial; in other words, in patients who are poor metabolizers of CYP2D6 and in patients who are also taking a CYP3A4 inhibitor or a CYP2D6 inhibitor. Dose adjustment for 200 mg and 160 mg can be obtained by intramuscular deltoid or gluteal injection using a 300-mg or 400-mg strength vial for patients who have taken a CYP2D6 inhibitor, a CYP3A4 inhibitor, or a CYP3A4 for more than 14 days. The presently disclosed aripiprazole IM depot formulation Ability Maintena(R) for use in suspension in extended release form is described in U.S. Pat. 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 herein by reference in their entirety.

[0084] In some embodiments, the activity of the aripiprazole intramuscular depot formulation is presumably due primarily to the parent drug, aripiprazole, and to a lesser extent to its major metabolite, dehydroaripiprazole, which has been shown to have an affinity for the D2 receptor similar to that of the parent drug and represents approximately 29% of the parent drug exposure in plasma.

[0085] Due to the low solubility of aripiprazole particles, aripiprazole is absorbed slowly and for a long time into the systemic circulation after intramuscular injection. After a single dose of aripiprazole intramuscular depot formulation in the deltoid and gluteal muscles, the extent of aripiprazole absorption (AUCt, AUC∞) was similar at both injection sites, but the absorption rate (Cmax) was 31% higher after administration to the deltoid muscle than to the gluteal muscle site. However, at steady state, the AUC and Cmax of the two injection sites were similar. After multiple intramuscular doses, the plasma concentration of aripiprazole gradually increased to a maximum plasma concentration at a median Tmax of about 5-7 days for the gluteal muscle and about 4 days for the deltoid muscle. After administration to the gluteal muscle, the average apparent aripiprazole terminal elimination half-life after multiple injections was about 29.9 days and about 46.5 days for injections of 300 mg and 400 mg of aripiprazole intramuscular depot formulations every 4 weeks, respectively. For both administration sites, steady-state concentrations were achieved in typical subjects by the fourth dose.Approximately dose-proportional increases in aripiprazole and dehydroaripiprazole exposure were observed following four-week injections of 300 mg and 400 mg aripiprazole intramuscular depot formulations.

[0086] Elimination of aripiprazole is 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.

[0087] The present disclosure uses two separate aripiprazole intramuscular depot injections at doses ranging from about 100 mg to about 500 mg of aripiprazole, and further, by way of example, each of the two aripiprazole intramuscular depot injections contains a dose of 300 mg or 400 mg of aripiprazole. For example, the methods of the present disclosure administer to a patient two separate 300 mg or 400 mg injections of aripiprazole intramuscular (IM) depot at separate gluteal and / or deltoid muscle injection sites, the administration being performed on the first day of treatment. In some embodiments, two separate injections of aripiprazole IM depot are administered to a patient at separate gluteal muscle injection sites or at separate deltoid muscle sites. In another embodiment, two separate injections of aripiprazole IM depot are administered to a patient at both gluteal and deltoid muscle injection sites. Additionally, the patient suffers from schizophrenia, and by way of example, the patient suffers from bipolar I disorder.

[0088] Example

[0089] Aripiprazole plasma concentrations during the therapeutic window and dose initiation with alternative initiation regimens

[0090] Fig.10The previously proposed therapeutic window is provided in the present disclosure, which corresponds to a lower bound (94.0 ng / mL) of the simulated median minimum aripiprazole concentration (Cmin,ss) at steady state following administration of 10 mg oral aripiprazole per day and a conservative upper bound (534 ng / mL) of the simulated 75th percentile of the maximum aripiprazole concentration (Cmax,ss) at steady state following administration of 30 mg oral aripiprazole per day. Statistics related to the simulations in the present disclosure are presented using the median, 25th to 75th percentiles, and 5th to 95th percentiles of the concentrations. Therefore, head-to-head comparisons of these simulations with the previously proposed therapeutic window ( Fig.10 ), a horizontal reference line was added to the simulations provided by the present disclosure, which represented the 95th percentile of the previously simulated Cmax,ss concentration (741 ng / mL) after daily administration of 30 mg oral aripiprazole.

[0091] Based on the simulations provided under the heading “Simulation Results” found below, aripiprazole concentrations during dose initiation may reach the 95th percentile of previously simulated Cmax,ss concentrations following daily administration of 30 mg oral aripiprazole (741 ng / mL), and therefore the following supportive information is provided in lieu of clinical data:

[0092] - The observed PK and safety data for a subset of subjects in this trial whose aripiprazole plasma concentrations were within the 5th to 95th percentile of simulated concentrations following administration of the proposed alternative starting regimen were evaluated and are presented below under the heading "Comparison of Results and Analysis Between Trials". Overall, the safety profile for these subjects was consistent with the known safety profile of Abilify Maintena(R).

[0093] - Measured aripiprazole concentrations exceeded the 75th and 95th percentiles of the simulated 30 mg oral Cmax,ss and were well tolerated in a previously submitted Phase 3 safety and efficacy trial (clinicaltrials.gov identifier: NCT00705783, entitled “Aripiprazole Intramuscular Depot as Maintenance Treatment in Patients with Schizophrenia (ASPIRE)”). Fig.13 Plasma concentrations exceeding these levels during dose initiation are highlighted. Fig.13 , SD equals standard deviation.

[0094] Summary of individual study results

[0095] A population PK analysis was performed to expand the previously submitted popPK model to incorporate the deltoid injection site, and simulations were performed to examine the predicted plasma concentrations following administration of alternative starting regimens at the deltoid and gluteal sites. An overview of the final combined popPK model is provided below under the heading "popPK". An overview of the results of a single ascending dose Phase 1 trial to determine the PK, safety, and tolerability of aripiprazole LAI formulation following single high-dose administration to the gluteal muscle is provided below under the heading "popPK".

[0096] PopPK Modeling: Population Pharmacokinetic Analysis of Aripiprazole Following Oral Administration and Intramuscular Injection in the Gluteal or Deltoid Muscles in Adult Subjects

[0097] A total of 8214 aripiprazole concentrations from 817 subjects were included in the final combined analysis data set (16% oral, 65% gluteal, 16% deltoid, and 3% triceps or thigh administration). The pharmacokinetic data included in this analysis consisted of data included in the previous popPK report as well as aripiprazole concentrations following deltoid or gluteal injections from 2 additional trials conducted to support the addition of the deltoid as an administration site.

[0098] The model was a 3-compartment model with sigmoidal absorption (Ka) for oral administration and first order absorption (IMKa) for IM (primarily gluteal) administration.

[0099] The final combined model incorporated the deltoid injection site into the previously developed model by adding the deltoid reservoir compartment with a separate absorption rate constant (DKa) to the original model. No other structural changes or covariate analyses were performed. A diagram of the structure of the final combined model is presented in Figure 1 In , an update to the original model to incorporate the deltoid injection site is shown in dashed lines. Figure 1 In the present study, the following abbreviations were used: CMT = compartment; DKa = deltoid IM 1st order absorption rate constant; Frel = relative bioavailability; IMKa = gluteal IM 1st order absorption rate constant; Ka = oral 1st order absorption rate constant; R1 = rate of entry of dose into oral absorption compartment; Vc = apparent central volume of distribution; Vp1 = volume of distribution 1 in peripheral compartment; Vp2 = volume of distribution 2 in peripheral compartment; Q1 = intercompartmental clearance 1; Q2 = intercompartmental clearance 2. The final popPK model was a linear 3-compartmental PK model utilizing sigmoidal absorption from oral administration and separate 1st order absorption from monthly gluteal and deltoid IM injections of aripiprazole.

[0100] All population PK parameters were fixed to the values ​​estimated in the original model for oral and gluteal administration, except for DKa, which was estimated using data after deltoid administration. The inter-individual variability (IIV) of the oral absorption rate constant (Ka) was fixed to the value estimated in the original model, while the IIV of clearance (CL), central volume of distribution (Vc), and first-order absorption rate constants after IM injection (IMKa and DKa) were estimated or re-estimated using the final combined analysis data set.

[0101] It was assumed that the covariate effects remained the same as in the original model, and the effects of sex and body mass index (BMI) on IMKa were also presented for deltoid injections, estimated from data after IM injections performed primarily in the gluteus maximus. No other covariate analyses were performed. The parameter definitions and values ​​of the final combined model are presented in Table 1 below:

[0102] [Table 1]

[0103]

[0104]

[0105] From Table 1, it should be noted that CV% is the percent coefficient of variation and RSE is the standard error about the mean.

[0106] The predictive performance of the final combined model was evaluated by prediction-corrected visual predictive testing (pcVPC). The pcVPC of the final combined population PK model for the deltoid and gluteal muscle administration sites after the first and fifth monthly administrations is presented in FIG. 2A to FIG. 2D In. FIG. 2A to FIG. 2D In the pcVPC, the following abbreviations are used: CI = confidence interval; and the visual predictive test after the first gluteal injection includes PK data from subjects co-administered with oral aripiprazole. Overall, pcVPC shows good predictive performance of the final combined model for the deltoid and gluteal administration sites, as the distribution of the observed data is similar to the 5th to 95th percentiles of the model-based simulated concentrations. Overall, pcVPC confirms that the variability seen in the observed PK data can be adequately described by the final popPK model, as the distribution of the observed data is similar to the 90% prediction intervals of the model-based simulations after single and multiple administrations at the deltoid and gluteal sites.

[0107] Simulation Results

[0108] The final combined model was used to simulate aripiprazole plasma concentration-time profiles following oral, gluteal, and / or deltoid administration of aripiprazole. To compare the simulated PK profiles, a virtual population of 817 subjects (provided under "popPK model") consisting of demographic characteristics similar to those recruited in the clinical trial was used in the final analysis data set to ensure that only the dosing regimen was changed between simulations. Individual PK parameters for subjects in the final analysis data set (all assigned as CYP2D6 extensive metabolizers (EM) except for simulations of CYP2D6 poor metabolizers [PM] subjects) were generated from the final combined PK model and its final parameter estimates. Individual PK profiles following oral, gluteal, and deltoid administration of aripiprazole were simulated using a 2-hour sampling interval 24 hours after the previous oral dose and sampling every 24 hours after the previous IM depot dose. FIG. 3A to FIG. 3C A complete list of all simulations performed is provided in .

[0109] Alternative starting regimens without prior oral aripiprazole stabilization

[0110] Several schedules of dose initiation were simulated to assess the time to achieve concentrations within the therapeutic window as provided above under the heading "Therapeutic Window and Aripiprazole Plasma Concentrations During Dose Initiation with Alternative Initiation Schedules." FIG. 4A to FIG. 4D The median and 5th to 95th percentile concentrations of simulated aripiprazole plasma PK profiles for the currently approved starting regimen (400 mg plus 14 days of 10 to 20 mg oral dosing) and an alternative starting regimen (2 x 400 mg plus 1 day of 20 mg oral dosing) administered as two separate injections in the gluteal and / or deltoid muscle sites are shown in FIG. FIG. 4A to FIG. 4D The approved starting regimen is 10 to 20 mg orally (14 days) and 400 mg IM depot (day 1).

[0111] According to the simulation, FIG. 4A to FIG. 4D The median and 5th to 95th percentile concentrations of the aripiprazole PK profile following administration of the proposed alternative starting regimens were similar to the approved starting regimen of 400 mg aripiprazole IM on day 1 plus 10 mg to 20 mg oral aripiprazole for 14 days, for example:

[0112] - The median aripiprazole PK profile following the alternative starting regimen reached therapeutic levels on the first day (94.0 ng / mL for 10 mg daily aripiprazole Cmin,ss) and remained above the lower threshold of the therapeutic window thereafter.

[0113] - The 95th percentile of simulated concentrations following the proposed alternative starting regimen is similar to or lower than the 95th percentile of the currently approved regimen and is within the upper limit of the therapeutic window, as discussed above.

[0114] - Plasma concentrations for all regimens exceeded the previously used conservative upper limit of the 75th percentile of simulated Cmax,ss following daily administration of 541 ng / mL but were still below the 95th percentile of simulated 30 mg oral Cmax,ss (741 ng / mL).

[0115] - Alternative starting regimens do not affect steady-state maintenance concentrations.

[0116] Alternative starting regimens in the setting of prior oral aripiprazole stabilization

[0117] In the approved labeling for Abilify Maintena(R), the first dose is administered to adult patients stabilized on oral aripiprazole concurrently with oral aripiprazole (10 to 20 mg) for 14 consecutive days. Therefore, simulations were performed to predict and compare plasma concentrations over 28 days following administration of the currently approved starting regimen and the alternative starting regimen to patients stabilized on 20 mg aripiprazole, the highest typical oral dose that patients would receive prior to initiating IM depot treatment with aripiprazole. The median, 5th percentile, 25th to 75th percentiles, and 95th percentiles of the simulated aripiprazole plasma PK profiles for the currently approved starting regimen and the alternative starting regimen administered as two separate injections in the gluteal or deltoid muscle sites of subjects previously stabilized on a 20 mg oral aripiprazole dose are presented in Figure 5A and Figure 5B In. Figure 5A and 5B In the FDA-approved initial regimen, 10 to 20 mg oral aripiprazole (14 days) and 400 mg IM depot (day 1) were used. The initial concentration at time zero was the mean concentration at steady state in subjects stabilized on 20 mg oral aripiprazole.

[0118] Based on simulations, the median and 5th to 95th percentile concentrations of the aripiprazole PK profile following administration of the alternate starting regimen were similar to the approved starting regimen when administered to subjects who had been stabilized on 20 mg oral aripiprazole:

[0119] - The 95th percentile of simulated concentrations following the alternative starting regimen is similar to or lower than the 95th percentile of the approved regimen.

[0120] - Alternative starting regimens do not affect steady-state maintenance concentrations.

[0121] Subjects who are CYP2D6 poor metabolizers

[0122] 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 because the apparent clearance of aripiprazole is approximately 50% lower. Therefore, simulations were performed to predict aripiprazole concentrations following administration of an alternative starting regimen to CYP2D6 extensive metabolizers (EM) and PM subjects. Comparison of simulated median concentration-time profiles and boxplots of maximum aripiprazole plasma concentrations (Cmax) following a single 20 mg oral dose of aripiprazole and two administrations of 400 mg (CYP2D6 EM and PM subjects) or 300 mg (CYP2D6 PM subjects only) of Abilify Maintena (R) in the gluteal or deltoid muscle sites is presented in Fig. 6A and 6B In. Fig. 6A and Figure 6B The approved starting regimen is 10 to 20 mg orally (14 days) and 400 mg IM depot (day 1).

[0123] Simulations of plasma concentrations were performed to allow comparison of simulated median concentration-time profiles and boxplots of aripiprazole Cmax following a single dose of 20 mg oral aripiprazole and two administrations of 400 mg (CYP2D6 EM and PM subjects) or 300 mg (CYP2D6 PM subjects only) IM depot aripiprazole formulations into the gluteal or deltoid sites in subjects or patients pre-stabilized with 20 mg (EM) or 10 mg (PM) oral aripiprazole. These simulations are presented in Fig. 7A and Figure 7B In. Fig. 7A and Figure 7B In the 2019 Phase 2 trial, the approved starting regimen was 10 to 20 mg oral (14 days) + 400 mg IM depot (day 1). The starting concentration at time zero was the mean concentration 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 prior oral dose was reduced by half (10 mg instead of 20 mg).

[0124] As expected, simulations produced the following results: When both CYP2D6 PM subjects and CYP2D6 EM subjects received two 400 mg IM depot aripiprazole administrations, CYP2D6 PM subjects exhibited higher aripiprazole Cmax and exposure than CYP2D6 EM subjects. Therefore, it is recommended that known CYP2D6 PM subjects or patients reduce the dose from two 400 mg IM depot aripiprazole administrations to two 300 mg IM depot aripiprazole administrations while taking a single 20 mg oral aripiprazole dose when using the proposed regimen to ensure that concentrations following the alternative starting regimen are similar to the currently approved regimen and remain within or slightly above the therapeutic window.

[0125] Missing maintenance IM depot dose

[0126] Simulations were performed to evaluate aripiprazole concentrations following omission of the second, third, fourth, or steady-state dose of an IM depot aripiprazole formulation to determine whether an alternative initiation regimen could be applied when the currently approved initiation regimen requires 2 weeks of oral aripiprazole administration concurrently with a single IM depot aripiprazole injection.

[0127] Comparison of simulated median aripiprazole plasma concentrations following administration of an alternative starting regimen or the currently approved starting regimen in the gluteal or deltoid muscle sites when a second or third IM depot aripiprazole formulation dose is administered 5 weeks after the previous injection is provided in FIG. 8A to FIG. 8D In. FIG. 8A to FIG. 8D The approved starting regimen is 10 to 20 mg orally (14 days) and 400 mg IM depot (day 1).

[0128] 9A to 9D A comparison of simulated median aripiprazole plasma concentrations following administration of an alternative starting regimen or the currently approved starting regimen in the gluteal or deltoid muscle sites when the 4th or 5th (steady-state) dose is administered 6 weeks after the previous injection is provided in. 9A to 9D The approved starting regimen is 10 to 20 mg orally (14 days) and 400 mg IM depot (day 1).

[0129] In all simulations, administration of the alternative initiation regimen after omission of the maintenance IM depot resulted in median aripiprazole concentrations above the lower threshold of the therapeutic window and similar to median aripiprazole concentrations following the approved initiation regimen.

[0130] Based on the results of the simulation, when a maintenance IM depot dose is missed, an alternative initiation regimen may be administered to replace 14 days of oral aripiprazole concurrently with a single IM depot formulation of aripiprazole injected on Day 1. Such a treatment strategy after a missed dose is consistent with the strategy in the Abilify Maintena(R) labeling.

[0131] Comparison and analysis of results between trials

[0132] An analysis was performed to evaluate safety results observed from a subset of 17 subjects from the Phase I clinical trial described below, where plasma concentration-time profiles were within the 5th to 95th percentiles of simulated concentrations following administration of the alternative starting regimen and were consistently higher than the mean PK profile following a single gluteal administration of 400 mg Abilify Maintena (R). A graphical comparison of all aripiprazole concentration-time profiles (from previous clinical trials) following a single dose of 780 mg (N = 18) or 1200 mg (N = 13) aripiprazole LAI administered to the gluteal muscle is presented in Fig.11 In Figure 1, the aripiprazole concentration-time profiles from a subset of 17 subjects are highlighted in red. Fig.11 in which N equals the number of subjects; the subset of 17 subjects was from trials in which the plasma concentration-time profiles were within the 5th to 95th percentiles of simulated concentrations following administration of the alternative starting regimen and were consistently above the mean PK profile following a single gluteal administration of 400 mg Abilify Maintena (R); and the lower limit of quantitation for aripiprazole was 0.500 ng / mL.

[0133] For reference, also presented are the mean (i.e., lower black horizontal line) aripiprazole plasma concentration-time profiles following administration of a single 400 mg dose of Abilify Maintena(R) to the gluteal muscle and the 5th to 95th percentiles (shaded area) of simulated concentrations following administration of an alternative starting regimen (20 mg oral [Day 1] + 2 x 400 mg aripiprazole IM depot [Day 1]) to the gluteal muscle site (Final Combination Model).

[0134] Of the 17 subjects identified, 7 subjects were treated with 1200 mg aripiprazole LAI and 10 subjects were treated with 780 mg aripiprazole LAI. Review of the safety data from these subjects did not identify any unexpected AEs and concluded that their safety profile was consistent with the known safety profile of Abilify Maintena(R).

[0135] in conclusion

[0136] Simulations suggest that a two-injection initiation regimen of monthly aripiprazole administered twice at separate gluteal and / or deltoid injection sites on the first day of the treatment regimen along with a single 20 mg dose of oral aripiprazole will: (1) achieve therapeutic aripiprazole plasma concentrations on the first day of treatment; (2) support a consistent clinical effect throughout the dosing interval; (3) produce similar aripiprazole plasma concentrations, and therefore a similar safety profile, as the currently approved (traditional) initiation regimen; and (4) provide a new initiation option that eliminates the need for a supplemental 14-day oral tablet, potentially reducing adherence-related undertreatment during the treatment initiation phase.

[0137] A phase 1, open-label, single ascending-dose, parallel-group trial to determine the pharmacokinetics, safety, and tolerability of intramuscular aripiprazole administered to the gluteal muscle for 2 months in adult subjects with schizophrenia.

[0138] This trial was an open-label, single ascending dose, parallel-group, multicenter trial to determine the PK, safety, and tolerability of a high-dose aripiprazole LAI formulation of 780 mg (Cohort 1) and 1200 mg (Cohort 2) administered as a single dose in the gluteal muscle of adult subjects with schizophrenia. The data from this trial are supportive information because it evaluates examples in which aripiprazole plasma concentrations increase at similar rates and reach levels predicted in simulations of alternative starting regimens. Overall, aripiprazole LAI was well tolerated when administered IM to adult subjects with schizophrenia at 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 faster absorption rates, such that aripiprazole plasma concentration-time profiles were within the 5th to 95th percentiles of simulated concentrations following administration of the recommended alternative starting regimen and were consistently higher than the mean PK profile following a single gluteal administration of 400 mg Abilify Maintena (R) ( Figure 1 ). Safety data from this subset of subjects were evaluated and compared with the known safety profile of Abilify Maintena (R). Additional details of this analysis are provided under the section entitled "Comparison of results between trials and analysis".

[0139] Aripiprazole LAI is an extended release presentation for administration every 2 months at the dose levels evaluated. The dosing interval of aripiprazole LAI is extended primarily by increasing the dose while maintaining a minimum aripiprazole concentration similar to Abilify Maintena (R) after multiple doses. Aripiprazole LAI is engineered to have a higher aripiprazole concentration in the drug product (300 mg / mL compared to 200 mg / mL) and with a minor vehicle change compared to the currently sold / approved Abilify Maintena (R). The average aripiprazole particle size distribution and dissolution profile of the aripiprazole LAI formulation are similar to the Abilify Maintena (R) formulation, and the formulation is expected to have a similar extended release profile compared to the approved Abilify Maintena (R) formulation. The mean (standard deviation [SD]) aripiprazole plasma concentration time profiles after a single dose of 780 mg or 1200 mg aripiprazole administered to the gluteal muscle of subjects with schizophrenia are presented in Fig.12 middle.

[0140] A summary of aripiprazole PK parameters following single-dose administration of a single dose of 780 mg or 1200 mg aripiprazole to the gluteal muscle in subjects with schizophrenia is presented in Table 2 below.

[0141] [Table 2]

[0142]

[0143] From Table 2, it should be noted that 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 to the last measurable concentration at time t; CL / F is the apparent clearance rate of the drug from plasma after extravascular administration; RTU is ready-to-use; Tmax is the time to maximum (peak) plasma concentration; t1 / 2 is the elimination half-life. In addition, a Median (minimum - maximum); b n = 14; and c n = 11.

[0144] Conclusions from this data include, for example:

[0145] - Aripiprazole LAI was well tolerated when administered IM at single doses of 780 and 1200 mg to adult subjects with schizophrenia.

[0146] - Administration of a single dose of 780 or 1200 mg aripiprazole LAI to the gluteal muscle increased aripiprazole Cmax and exposure (area under the concentration-time curve [AUC] calculated from time zero to infinity [AUC∞] and AUC calculated to the last measurable concentration at time t [AUCt]) by 100% and 200%, respectively, compared to that measured following a previous single dose of 400 mg Abilify Maintena (R) to the gluteal muscle.

[0147] - Single dose administration of 780 or 1200 mg aripiprazole LAI to the gluteal muscle produced slightly less than proportional increases in aripiprazole Cmax and slightly more than dose-proportional increases in exposure (AUCt and AUC∞), based on mean values ​​corrected for dose.

[0148] - Administration of 780 mg aripiprazole LAI to the gluteal muscle produced shorter median values ​​for time to maximum (peak) plasma concentration (Tmax) of aripiprazole when compared to the 1200 mg dose (25.1 days vs. 41.0 days).

[0149] - The mean terminal elimination half-life (t1 / 2) values ​​of aripiprazole following administration of 780 or 1200 mg aripiprazole LAI to the gluteal muscle were similar (22.1 days and 20.0 days, respectively) and were similar to the median t1 / 2 following single-dose administration of 400 mg Abilify Maintena (R) to the gluteal muscle (24.0 days).

[0150] - Based on examination of mean, median, and individual concentration-time curves, a steady increase in aripiprazole concentrations was observed following administration of 780 or 1200 mg aripiprazole LAI to the gluteal muscle, followed by a decline and the appearance of a second peak in concentrations.

[0151] - In addition, this Phase I trial supports the use of the dose-initiation method disclosed herein for aripiprazole treatment of patients in need thereof, the method comprising administering to the patient two separate injections of an intramuscular (IM) depot formulation of aripiprazole in the range of about 10 mg to about 500 mg of aripiprazole at separate gluteal and / or deltoid injection sites, and a single dose of oral aripiprazole, wherein administration is performed on the first day of treatment. In other words, the use of two injections in the range of about 10 mg to about 500 mg of aripiprazole did not produce any unexpected AEs, and the safety profile was consistent with the known safety profile of Ability Maintena(R).

[0152] All publications and patents mentioned herein are 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.

[0153] Claims or descriptions that include "or" or "and / or" between at least one member are considered satisfied when one, more than one, or all of the group members are present in, used in, or otherwise related to a given product or method, unless indicated to the contrary or otherwise obvious from the context. The present disclosure includes embodiments in which exactly one group member is present in, used in, or otherwise related to a given product or method. The present disclosure includes embodiments in which more than one or all of the group members are present in, used in, or otherwise related to a given product or method.

[0154] In addition, the present disclosure encompasses all changes, combinations and arrangements in which at least one limitation, element, item and description item from at least one of the listed claims are introduced into another claim. For example, any claim subordinate to another claim may be modified to include at least one limitation present in any other claim subordinate to the same basic claim. In the case of presenting a plurality of elements in a list form (e.g., in the form of Markush groups), each subgroup of the element is also disclosed, and any one or more elements may be removed from the group. It should be understood that, in general, in the case of the present disclosure or aspects of the present disclosure including or referred to as including specific elements and / or features, the embodiments of the present disclosure or aspects of the present disclosure are composed of such elements and / or features or are substantially composed of such elements and / or features. For the purpose of simplicity, those embodiments that have not yet been specifically described are also within the scope described herein. In the case of giving a range, the endpoint is included. In addition, unless otherwise noted or otherwise apparent from the context and the understanding of those skilled in the art, the value represented by the range in the different embodiments of the present disclosure may be assumed to be any specific value or subrange within the stated range, to the tenth of the lower unit of the range, unless the context clearly indicates otherwise.

[0155] 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. Such equivalents are intended to be encompassed by the claims.

Claims

1. Use of aripiprazole for preparing an intramuscular (IM) depot formulation of aripiprazole for use in a dose initiation method for aripiprazole treatment of a patient in need thereof, wherein the intramuscular (IM) depot formulation of aripiprazole comprises 300 mg or 400 mg of aripiprazole, the method comprising: administering to said patient two separate injections of said aripiprazole intramuscular (IM) depot formulation at separate injection sites selected from the group consisting of the gluteal site, the deltoid site, and the gluteal site and deltoid site, wherein each injection contains 300 mg or 400 mg of aripiprazole; and administering a single dose of oral aripiprazole, The step wherein two separate injections and a single oral dose are administered is performed on the first day of said treatment.

2. The use according to claim 1, wherein the patient in need of aripiprazole treatment is a patient who has been previously stabilized with oral aripiprazole or a patient who has not been previously stabilized with oral aripiprazole.

3. The use according to claim 1, wherein the patient in need of aripiprazole treatment is a patient previously stabilized with oral aripiprazole.

4. The use according to any one of claims 1 to 3, wherein two separate injections each contain 400 mg of aripiprazole.

5. The use according to any one of claims 1 to 3, wherein two separate injections each contain 300 mg of aripiprazole.

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

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

8. The use according to any one of claims 1 to 3, wherein when the patient is a CYP2D6 poor metabolizer or is concomitantly taking a CYP3A4 inhibitor or a CYP2D6 inhibitor for more than 14 days, the aripiprazole treatment comprises a single monthly administration of a maintenance injection of aripiprazole in the form of an aripiprazole IM depot formulation selected from 160 mg and 200 mg.

9. The use according to claim 6, wherein the maintenance injection is administered no earlier than 26 days after the previous injection.

10. The use according to any one of claims 1 to 3, wherein two separate injections of the aripiprazole IM depot formulation are administered to separate gluteal and / or deltoid muscle injection sites of the patient.

11. The use according to any one of claims 1 to 3, wherein two separate injections of the aripiprazole IM depot formulation are administered to the patient at separate gluteal muscle injection sites.

12. The use according to any one of claims 1 to 3, wherein two separate injections of the aripiprazole IM depot formulation are administered to the patient at the gluteal and deltoid injection sites.

13. The use according to any one of claims 1 to 3, wherein two separate injections of the aripiprazole IM depot formulation are administered to the patient at separate deltoid muscle injection sites.

14. The use according to any one of claims 1 to 3, wherein the patient suffers from schizophrenia.

15. The use according to any one of claims 1 to 3, wherein the patient suffers from bipolar I disorder.

16. The use according to any one of claims 1 to 3, wherein the single dose of oral aripiprazole is in the range of 2 mg to 30 mg aripiprazole.

17. The use according to claim 16, wherein the single dose of oral aripiprazole is in the range of 10 mg to 30 mg.

18. The use according to claim 16, wherein the single dose of oral aripiprazole is 20 mg.

19. The use according to claim 16, wherein the single dose of oral aripiprazole is 10 mg.

20. The use of claim 1, wherein when the patient is a CYP2D6 poor metabolizer, the two separate injections each contain 300 mg aripiprazole and the single dose of oral aripiprazole is 20 mg.

21. The use according to any one of claims 1 to 3, wherein the aripiprazole is in the form of a salt.

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