Patent Description:
<CIT> relates to a storage-stable injectable preparation comprising a composition comprising aripiprazole as an active ingredient and a dispersion medium.

<NPL>, relates to a two-month dosage regimen for aripiprazole lauroxil, which is an injectable prodrug derivative of aripiprazole.

<NPL> provides a comparison of two different long-acting aripiprazole injectable formulations, based on aripiprazole monohydrate and aripiprazole lauroxil, respectively.

<NPL> concerns the evaluation of a <NUM>-day treatment initiation regimen for aripiprazole lauroxil.

Aripiprazole once monthly is a long acting IM injectable formulation of aripiprazole indicated for maintenance treatment of schizophrenia and bipolar I disorder in adult patients stabilized on oral aripiprazole. In the currently approved label for Ability Maintena(R), a first dose is administered with concomitant oral aripiprazole (<NUM> to <NUM>) for fourteen consecutive days to adult patients stabilized with oral aripiprazole. In patient populations considered to be at potential risk for adherence-related relapse or suboptimal treatment outcomes (e.g., long acting injectable (LAI) patient population), achieving therapeutic plasma concentrations may offer a treatment advantage.

To provide an additional option for this initiation stage, a two-injection start initiation regimen comprising two, separate administrations of aripiprazole once-monthly at separate gluteal and/or deltoid injection sites with a single oral dose of aripiprazole on the first day of treatment is provided based on population pharmacokinetic (popPK) modeling and simulation. For example, the present disclosure is directed to an alternative initiation regimen of two, separate administrations of an aripiprazole intramuscular (IM) depot formulation, such as Ability Maintena(R), together with a shorter oral overlap. Simulations of the alternative initiation regimen of two injections of an aripiprazole intramuscular (IM) depot formulation at separate gluteal and/or deltoid injection sites together with a single oral aripiprazole on the first day of treatment is shown to be sufficient and the alternative initiation regimen may be an additional option for initiation of Ability Maintena(R).

The present invention therefore relates to an aripiprazole intramuscular (IM) depot formulation comprising <NUM> or <NUM> of aripiprazole, for use in a method of dose initiation for an aripiprazole treatment to a patient in need thereof, wherein the patient has schizophrenia or bipolar I disorder, the method comprising:.

In additional aspects, each of the two, separate injections comprises about <NUM> of aripiprazole. Additionally, the methods of the present disclosure further comprise after the first day of treatment, administering a single monthly, maintenance injection of the aripiprazole IM depot formulation. For example, in other aspects, the single monthly, maintenance injection is chosen from about <NUM> and about <NUM> of aripiprazole in the aripiprazole IM depot formulation. In further aspects, when the patient is a CYP2D6 poor metabolizer or is taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors for greater than <NUM> days, the single monthly, maintenance injection is chosen from <NUM> and <NUM> of aripiprazole in the aripiprazole IM depot formulation.

In further aspects, the two, separate injections of the aripiprazole IM depot formulation are administered at separate gluteal injection sites of the patient. Additionally, the two, separate injections of the aripiprazole IM depot formulation are administered at a gluteal injection site and a deltoid injection site of the patient. Further for example, the two, separate injections of the aripiprazole IM depot formulation are administered at separate deltoid injection sites of the patient.

In aspects of the present disclosure, the patient has schizophrenia. In other aspects, the patient has bipolar <NUM> disorder.

In some further aspects, the single dose of oral aripiprazole ranges from about <NUM> to about <NUM> of aripiprazole. For example, the single dose of oral aripiprazole ranges from about <NUM> to about <NUM>. Additionally, for example, the single dose of oral aripiprazole is <NUM>. And, in some further aspects, the single dose of oral aripiprazole is <NUM>.

In some further aspects, when the patient is a CY2D6 poor metabolizer, each of the two, separate injections comprises about <NUM> of aripiprazole and the single dose of oral aripiprazole is about <NUM>.

As used herein, "a" or "an" entity refers to one or more of that entity, e.g., "a compound" refers to one or more compounds or at least one compound unless stated otherwise. As such, the terms "a" (or "an"), "one or more", and "at least one" are used interchangeably herein.

As used herein, the term "about" means approximately, in the region of, roughly, or around. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term "about" is used herein to modify a numerical value above and below the stated value by a variance of <NUM>%.

As used herein, the term "treat," "treating," or "treatment," when used in connection with a disorder or condition, includes any effect, e.g., lessening, reducing, modulating, ameliorating, or eliminating, that results in the improvement of the disorder or condition. Improvements in or lessening the severity of any symptom of the disorder or condition can be readily assessed according to standard methods and techniques known in the art. In some embodiments, the presently disclosed methods or depot formulations can be used to treat schizophrenia and bipolar I disorder, as maintenance monotherapy. In further embodiments, the presently disclosed methods or depot formulations can be used to treat schizophrenia, and acute treatment of manic and mixed episodes associated with Bipolar I disorder.

As used herein, a "mammal" refers to domesticated animals (e.g., dogs, cats, and horses) and humans. In some embodiments, the mammal is a human.

Aripiprazole is <NUM>-[<NUM>-[<NUM>-(<NUM>,<NUM>-dichlorophenyl)-<NUM>-piperazinyl]butoxy]-<NUM>,<NUM>-dihydrocarbostyril. The empirical formula is C<NUM>H<NUM>Cl<NUM>N<NUM>O<NUM> and its molecular weight is <NUM>. The chemical structure is:
<CHM>.

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

A pharmaceutical composition comprising aripiprazole is known as an antipsychotic useful for the treatment of schizophrenia and bipolar disorder I.

The aripiprazole traditional dosing regimen includes a recommended starting and maintenance dose of Ability Maintena(R) that is <NUM> or <NUM> monthly (no sooner than <NUM> days after the previous injection). For patients who have never taken aripiprazole, the patient establishes tolerability with oral aripiprazole prior to initiating treatment with Ability Maintena(R). Due to the half-life of oral aripiprazole, it may take up to <NUM> weeks to fully assess tolerability.

After the first Ability Maintena(R) injection, administer oral aripiprazole (<NUM> to <NUM>) for <NUM> consecutive days to achieve therapeutic aripiprazole concentrations during initiation of therapy. For patients already stable on another oral antipsychotic (and known to tolerate aripiprazole), after the first Ability Maintena(R) injection, continue treatment with the antipsychotic for <NUM> consecutive days to maintain therapeutic antipsychotic concentrations during initiation of therapy.

If there are adverse reactions with the <NUM>-mg dosage, one can consider reducing the dosage to <NUM> once monthly.

As such, the currently approved initiation regimen consists of a single IM injection of aripiprazole intramuscular depot formulation together with daily oral tablet administration of aripiprazole (<NUM> to <NUM>) for <NUM> consecutive days.

Reference herein to an aripiprazole intramuscular depot formulation refers to Ability Maintena(R) (aripiprazole), prescribing information for extended-release injectable suspension, for intramuscular use, initial US approval: <NUM>, revised: <NUM>/<NUM>.

The present disclosure is directed to an alternative initiation regimen or dose initiation comprising administering two, separate about <NUM> or <NUM> injections of aripiprazole intramuscular depot formulation (Ability Maintena(R)) at separate gluteal and/or deltoid injection sites together with a single oral aripiprazole dose on the first day of treatment. The single oral dose aripiprazole ranges from about <NUM> to about <NUM>; for example, the single oral dose aripiprazole ranges from about <NUM> to about <NUM>. This alternative initiation regimen provides an option for the first, or initiation, dose of aripiprazole intramuscular depot formulation. Maintenance dosing remains unchanged; for example, maintenance dose follows with single monthly injections thereafter of <NUM> or <NUM> of aripiprazole IM depot formulation. As with the traditional dose initiation regimen, the alternative initiation regimen is applicable to both the deltoid and gluteal administration sites.

The present disclosure utilizes two, separate aripiprazole intramuscular depot formulation injections with a dose of <NUM> or <NUM> of aripiprazole. For example, the methods of the present disclosure administer two, separate <NUM> injections of an aripiprazole intramuscular (IM) depot formulation to the patient at separate gluteal and/or deltoid injection sites with administration occurring on a first day of the treatment. In some embodiments, the two, separate injections of the aripiprazole IM depot formulation are administered at separate gluteal injection sites or at separate deltoid sites of the patient. In a further embodiment, the two, separate injections of the aripiprazole IM depot formulation are administered at a gluteal and a deltoid injection site of the patient. Further, the patient has schizophrenia and for example, the patient has bipolar I disorder.

The rationale for the selection of the alternative initiation regimen dose is based on simulations from a population pharmacokinetic(s) (popPK) model. A range of dose initiation regimens were considered to shorten the length of oral dosing overlap with the first IM depot injection while maintaining median concentrations within the previously defined therapeutic window and similar to those of the currently approved dose initiation regimen (i.e., median, 25th to 75th, and 5th to 95th percentile of concentration). Based on the results of the simulations, the recommended dose for the alternative initiation regimen is <NUM> or <NUM> and in some embodiments, is, e.g., two <NUM> injections of the aripiprazole intramuscular depot formulation at separate gluteal and/or deltoid injection sites together with a single dose of oral aripiprazole on the first day of treatment, for example, the single dose of oral aripiprazole ranges from about <NUM> to <NUM> of aripiprazole and for example, is a single <NUM> dose of oral aripiprazole.

The objective of the clinical pharmacology studies was to establish a two-injection start regimen for the long-acting injectable aripiprazole once-monthly to obviate the need for <NUM>-day oral aripiprazole supplementation during treatment initial using a PK modeling and simulation approach.

A previously developed popPK model (Food and Drug Administration: Center for Drug Evaluation and Research, Aripiprazole IM Depot Formulation: Clinical Pharmacology and Biopharmaceutics Review (Application No. 202971s000) <NUM>)) which could adequately characterize aripiprazole PK following oral administration and gluteal IM depot injections was expanded to include the deltoid site of injection. The final model was developed using PK data from <NUM> clinical trials following oral administration and IM depot injections (both gluteal and deltoid muscles). A total of <NUM>,<NUM> aripiprazole concentrations (<NUM>% oral, <NUM>% gluteal, <NUM>% deltoid, and <NUM>% triceps or thigh administration) from <NUM> subjects were included in the final analysis dataset. The predictive performance of the final model was assessed by prediction-corrected visual predictive checks (pcVPCs).

The final popPK model was used to simulate and evaluate a range of dose initiation regimens with shorter oral overlap following the first IM depot injection to identify a regimen that: (<NUM>) remains within a previously establish therapeutic window corresponding to the lower bound of the simulated median minimum aripiprazole concentrations at steady state (Cmax,ss) following daily administration of <NUM> oral aripiprazole (<NUM> ng/mL) and the <NUM>th percentile of maximum aripiprazole concentrations at steady state (Cmax,ss) following daily administration of the highest approved oral aripiprazole dose of <NUM> (<NUM> ng/mL); and (<NUM>) results in plasma concentrations similar (i.e., median, <NUM>th to <NUM>th, and <NUM>th to <NUM>th percentile of concentration) to that of the currently approved one-injection start initiation regimen (one <NUM> injection of aripiprazole once-monthly together with <NUM> days of oral aripiprazole [<NUM> to <NUM>]).

A summary of the popPK modeling and simulation to support the alternative initiation regimen is provided, under "popPK Modeling" section header below. Simulations of aripiprazole plasma concentration time profiles following administration of the alternative initiation regimen to subjects without and with prior stabilization on oral aripiprazole (under "Alternative Initiation Regimen Without Prior Oral Aripiprazole Stabilization" and "Alternative Initiation Regimen With Prior Oral Aripiprazole Stabilization" section headers below), to extensive or poor cytochrome P450 2D6 (CYP2D6) metabolizers (under "Subjects who are CYP2D6 Poor Metabolizers" section header below), and in scenarios following missed maintenance doses are also presented in this module (under "Missed Maintenance IM Depot Dose" section header below).

Aripiprazole is a psychotropic drug that is available as an oral (aripiprazole) tablet. In some embodiments, oral tablets of aripiprazole are available in, e.g., <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, and <NUM> strengths. Inactive ingredients in oral tablets, e.g., include cornstarch, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. Colorants can include, e.g., ferric oxide (yellow or red) and FD&C Blue No. <NUM> Aluminum Lake.

Aripiprazole is well absorbed after administration of a tablet, with peak plasma concentrations occurring, e.g., within <NUM> hours to <NUM> hours; the absolute oral bioavailability of the tablet formulation is about <NUM>%. Oral tablets of aripiprazole can be administered with or without food. For example, administration of a <NUM> oral tablet of aripiprazole with a standard high-fat meal did not significantly affect the Cmax or AUC of aripiprazole or its active metabolite, dehydro-aripiprazole, but delayed Tmax by <NUM> hours for aripiprazole and <NUM> hours for dehydro-aripiprazole.

Aripiprazole is metabolized primarily by three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the predominant drug moiety in the systemic circulation. At steady-state, dehydro-aripiprazole, the active metabolite, represents about <NUM>% of aripiprazole AUC in plasma.

Following a single oral dose of [14C]-labeled aripiprazole, approximately <NUM>% and <NUM>% of the administered radioactivity was recovered in the urine and feces, respectively. Less than <NUM>% of unchanged aripiprazole was excreted in the urine and approximately <NUM>% of the oral dose was recovered unchanged in the feces.

The present disclosure utilizes an oral tablet of aripiprazole at a single oral dose chosen from <NUM> to <NUM>, such as single oral doses of <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, and <NUM> of aripiprazole. In some embodiments, the single oral dose ranges from about <NUM> to about <NUM> of aripiprazole, such as about <NUM> of aripiprazole. In some embodiments, the single oral dose is chosen from <NUM> and <NUM> of aripiprazole. In further embodiments, the single oral dose is <NUM> of aripiprazole.

In some embodiments, aripiprazole intramuscular depot formulation comprises aripiprazole monohydrate; aripiprazole monohydrate is <NUM>-[<NUM>-[<NUM>-(<NUM>,<NUM>-dichlorophenyl)-<NUM>-piperazinyl] butoxy]-<NUM>,<NUM> dihydrocarbostyril monohydrate. The empirical formula is C<NUM>H<NUM>Cl<NUM>N<NUM>O<NUM>·H<NUM>O and its molecular weight is <NUM>. The chemical structure is:
<CHM>.

For example, in some embodiments, aripiprazole intramuscular (IM) depot formulation is an extended-release injectable suspension in <NUM>-mg or <NUM>-mg strength in pre-filled dual chamber syringes and <NUM>-mg or <NUM>-mg strength vials. The labeled strengths are calculated based on the anhydrous form (aripiprazole). In some embodiments, inactive ingredients (per administered dose) for <NUM>-mg and <NUM>-mg strength products, respectively, include carboxymethyl cellulose sodium (<NUM> and <NUM>), mannitol (<NUM> and <NUM>), sodium phosphate monobasic monohydrate (<NUM> and <NUM>) and sodium hydroxide (pH adjuster). In further embodiments, the extended-release injectable suspension in <NUM>-mg or <NUM>-mg strength in pre-filled dual chamber syringes and <NUM>-mg or <NUM>-mg strength vials can be used to make dosage adjustments; that is, in patents who are CYP2D6 poor metabolizers and in patents taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors. Dosage adjustments for <NUM> and <NUM> can be obtained by using the <NUM>-mg or <NUM>-mg strength vials for intramuscular deltoid or gluteal injection for patients taking CYP2D6 inhibitors, CYP3A4 inhibitors, or CYP3A4 for greater than <NUM> days. The presently disclosed aripiprazole IM depot formulation, Ability Maintena(R), for suspension in an extended-release form is described in <CIT>,<CIT>,<CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, and <CIT>.

In some embodiments, the activity of the aripiprazole intramuscular depot formulation is presumably primarily due to the parent drug, aripiprazole, and to a lesser extent, to its major metabolite, dehydro-aripiprazole, which has been shown to have affinities for D2 receptors similar to the parent drug and represents about <NUM>% of the parent drug exposure in plasma.

Aripiprazole absorption into the systemic circulation is slow and prolonged following intramuscular injection due to low solubility of aripiprazole particles. Following a single-dose administration of the aripiprazole intramuscular depot formulation in the deltoid and gluteal muscle, the extent of absorption (AUCt, AUC∞) of aripiprazole was similar for both injection sites, but the rate of absorption (Cmax) was <NUM>% higher following administration to the deltoid compared to the gluteal site. However, at steady state, AUC and Cmax were similar for both sites of injection. Following multiple intramuscular doses, the plasma concentrations of aripiprazole gradually rise to maximum plasma concentrations at a median Tmax of about <NUM> - <NUM> days for the gluteal muscle and about <NUM> days for the deltoid muscle. After gluteal administration, the mean apparent aripiprazole terminal elimination half-life was about <NUM> days and about <NUM> days after multiple injections for every <NUM>-week injection of the aripiprazole intramuscular depot formulation <NUM> and <NUM>, respectively. Steady state concentrations for the typical subject were attained by the fourth dose for both sites of administration. Approximate dose-proportional increases in aripiprazole and dehydro-aripiprazole exposure were observed after every four-week of the aripiprazole intramuscular depot formulation injections of <NUM> and <NUM>.

Elimination of aripiprazole is mainly through hepatic metabolism involving two P450 isozymes, CYP2D6 and CYP3A4. Aripiprazole is not a substrate of CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2E1 enzymes. Aripiprazole also does not undergo direct glucuronidation.

The present disclosure utilizes two, separate aripiprazole intramuscular depot formulation injections, wherein each of the two-aripiprazole intramuscular depot formulation injections comprise a dose of <NUM> or <NUM> of aripiprazole. For example, the methods of the present disclosure administer two, separate <NUM> or <NUM> injections of an aripiprazole intramuscular (IM) depot formulation to the patient at separate gluteal and/or deltoid injection sites with administration occurring on a first day of the treatment. In some embodiments, the two, separate injections of the aripiprazole IM depot formulation are administered at separate gluteal injection sites or at separate deltoid sites of the patient. In a further embodiment, the two, separate injections of the aripiprazole IM depot formulation are administered at a gluteal and deltoid injection site of the patient. Further, the patient has schizophrenia and for example, the patient has bipolar I disorder.

The previously proposed therapeutic window corresponding to the lower bound of the simulated median minimum aripiprazole concentrations at steady state (Cmin,ss) following daily administration of <NUM> oral aripiprazole (<NUM> ng/mL) and a conservative upper bound of the simulated 75th percentile of maximum aripiprazole concentrations at steady state (Cmax,ss) following daily administration of the highest approved oral aripiprazole dose of <NUM> (<NUM> ng/mL) is provided in <FIG>. The statistics related to the simulations in this disclosure are presented with median, 25th to 75th and 5th to 95th percentile of concentration. Thus, for head to head comparison of these simulations with the previously proposed therapeutic window (<FIG>), a horizontal reference line denoting the 95th percentile of the previously simulated Cmax,ss concentrations following daily administration of <NUM> oral aripiprazole (<NUM> ng/mL) is added to simulations provided in this disclosure.

Based on simulations provided under the "Simulation Results" header found below, aripiprazole concentrations during dose initiation could reach the 95th percentile of the previously simulated Cmax,ss concentrations following daily administration of <NUM> oral aripiprazole (<NUM> ng/mL), thus the following supportive information in lieu of clinical data is provided:.

A population PK analysis was conducted to expand the previously submitted popPK model to incorporate the deltoid site of injection and perform simulations to examine predicted plasma concentrations following administration of the alternative initiation regimen at both deltoid and gluteal sites. A summary of the final combined popPK model is provided under the "popPK" heading below. A summary of the results of a single ascending dose phase <NUM> trial to determine the PK, safety and tolerability following gluteal administration of a single high dose formulation of aripiprazole LAI that is provided under the "popPK" heading below.

A total of <NUM> aripiprazole concentrations (<NUM>% oral, <NUM>% gluteal, <NUM>% deltoid, and <NUM>% triceps or thigh administration) from <NUM> subjects were included in a final combined analysis dataset. Pharmacokinetic data included in this analysis consisted of data included from a previous popPK report as well as aripiprazole concentrations following deltoid or gluteal injections from <NUM> additional trials conducted to support addition of the deltoid muscle as a site of administration.

The model was a <NUM>-compartment model with sigmoid absorption for oral administration (Ka), and 1st order absorption for IM (mainly gluteal) administration (IMKa).

The final combined model included the deltoid injection site into the previously developed model by adding a deltoid depot compartment with a separate absorption rate constant (DKa) to the original model. No further structural change or covariate analysis was conducted. A diagram of the structure of the final combined model is presented in <FIG>, with updates to the original model to incorporate the deltoid site of injection shown in broken lines. In <FIG>, the following abbreviations are used: CMT = compartment; DKa = deltoid IM 1st order absorption rate constant; Frelative = relative bioavailability; IMKa = gluteal IM 1st order absorption rate constant; Ka = oral 1st order absorption rate constant; R1 = rate of dose into oral absorption compartment; Vc = apparent central volume of distribution; Vp1 = volume of distribution in Peripheral compartment <NUM>; Vp2 = volume of distribution in Peripheral compartment <NUM>; Q1 = inter-compartmental clearance <NUM>; Q2 = inter-compartmental clearance <NUM>. The final popPK model was a linear <NUM>-compartment PK model, which utilizes sigmoid absorption for oral administration and separate 1st order absorption for the gluteal and deltoid IM injections of aripiprazole once-monthly.

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 following deltoid administration. The inter-individual variability (IIV) for the oral absorption rate constant (Ka) was fixed to the value estimated in the original model, while IIV for clearance (CL), central volume of distribution (Vc), and the first order absorption rate constants following IM injections (IMKa and DKa) were estimated or re-estimated using the final combined analysis dataset.

It was assumed that the covariate effect remained the same as the original model, and that the gender and body mass index (BMI) effect on IMKa, estimated from data following IM injection in gluteus maximus mainly, is also present for the deltoid injection. No additional covariate analysis was performed. Parameter definition and values of the final combined model are presented in Table <NUM> below:.

From Table <NUM>, it is noted that %CV is the percent coefficient of variation and RSE is standard error relative to the mean.

The predictive performance of the final combined model was assessed by prediction-corrected visual predictive checks (pcVPCs). The pcVPCs of the final combined population PK model for deltoid and gluteal sites of administration following the first and the fifth monthly administrations are presented in <FIG>. In <FIG>, the following abbreviations are used: CI = confidence interval; and the visual predictive check following the 1st gluteal injection includes PK data from subjects co-administered with oral aripiprazole. Overall, the pcVPCs showed good predictive performance of the final combined model for the deltoid and gluteal sites of administration as the distributions of the observed data are comparable with the 5th to 95th percentile of concentrations of the model-based simulation. Overall, pcVPCs confirmed the variability seen in the observed PK data could be adequately described by the final popPK model, as the distributions of the observed data are comparable with the <NUM>% prediction intervals of the model-based simulation following single and multiple administrations in the deltoid and gluteal sites.

The final combined model was utilized to simulate aripiprazole plasma concentration-time profiles following oral, gluteal, and/or deltoid administration of aripiprazole. To compare simulated PK profiles, a virtual population consisting of <NUM> subjects with similar demographic characteristics to the subjects enrolled in the clinical trials in the final analysis dataset (provided under "popPK Model") was used to ensure only the dosing regimen changed across simulations. Individual PK parameters for subjects in the final analysis dataset (all assigned as CYP2D6 extensive metabolizers (EM) except for simulation 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 <NUM>-hour sampling interval for <NUM> hours post the preceding oral dose and every <NUM>-hour sampling post the preceding IM Depot dose. A full listing of all simulations performed is provided in <FIG>.

Several scenarios for dose initiation were simulated to assess the time to achieve concentrations within the therapeutic window as provided above under the heading entitled "Therapeutic Window and Aripiprazole Plasma Concentrations During Dose Initiation with Alternative Initiation Regimen. " The median and 5th to 95th percentile of concentration of simulated aripiprazole plasma PK profiles for the currently approved initiation regimen (<NUM> with <NUM> days of <NUM> to <NUM> oral dosing) and the alternative initiation regimen (<NUM> x <NUM> with <NUM> day of <NUM> oral dosing) administered as two separate injections in the gluteal and/or deltoid sites are shown in <FIG>. In <FIG>, approved initiation regimen was <NUM> to <NUM> oral (<NUM> days) and <NUM> IM depot (day <NUM>).

Based on the simulations, in <FIG>, the median and 5th to 95th percentile of concentration of the aripiprazole PK profile following administration of the proposed alternative initiation regimen is comparable to the approved initiation regimen of <NUM> aripiprazole IM on Day <NUM> + <NUM> to <NUM> oral aripiprazole for <NUM> days, for example:.

In the approved label for Ability Maintena(R), the first dose is administered with concomitant oral aripiprazole (<NUM> to <NUM>) for <NUM> consecutive days to adult patients stabilized with oral aripiprazole. Thus, simulations were performed to predict and compare plasma concentrations during the <NUM> days following administration of the currently approved and the alternative initiation regimen to patients stabilized with <NUM> aripiprazole, which is the highest typical oral dose a patient would be receiving prior to initiating treatment with IM depot of aripirazole. The median, 5th, 25th to 75th, and 95th percentile of simulated aripiprazole plasma PK profiles for the currently approved and the alternative initiation regimen administered as two separate injections in the gluteal or deltoid sites of subjects with prior stabilization on an oral aripiprazole dose of <NUM> are presented in <FIG> and <FIG>. In <FIG> and <FIG>, the approved initiation regimen was <NUM> to <NUM> oral (<NUM> days) and <NUM> IM depot (Day <NUM>). The starting concentration at time zero is the average concentration at steady state for subjects stabilized on <NUM> oral aripiprazole.

Based on the simulations, the median and 5th to 95th percentile of concentration of the aripiprazole PK profile following administration of the alternative initiation regimen is comparable to the approved initiation regimen when administered to subjects already stabilized on <NUM> oral aripiprazole:.

In subjects who are known to be cytochrome P450 2D6 poor metabolizers (CYP2D6 PM), the currently approved IM depot initiation dose should be reduced from <NUM> to <NUM> due to an approximately <NUM>% lower apparent clearance of aripiprazole. Simulations were thus performed to predict aripiprazole concentrations following administration of the alternative initiation regimen to CYP2D6 extensive metabolizers (EM) and PM subjects. A comparison of the simulated median concentration time profiles and boxplots of maximum aripiprazole plasma concentrations (Cmax) following a single dose of <NUM> oral aripiprazole along with two administrations of either <NUM> (CYP2D6 EM and PM subjects) or <NUM> (only CYP2D6 PM subjects) Ability Maintena(R) in the gluteal or deltoid sites is presented in <FIG> and <FIG>. In <FIG> and <FIG>, the approved initiation regimen was <NUM> to <NUM> oral (<NUM> days) and <NUM> IM depot (Day <NUM>).

Simulations of plasma concentrations were performed to also allow comparison of the simulated median concentration time profiles and boxplots of aripiprazole Cmax following a single dose of <NUM> oral aripiprazole along with two administrations of either <NUM> (CYP2D6 EM and PM subjects) or <NUM> (CYP2D6 PM subjects only) IM depot aripiprazole formulation in the gluteal or deltoid sites of subjects or patients with prior stabilization on <NUM> (EM) or <NUM> (PM) oral aripiprazole. These simulations are presented in <FIG> and <FIG>. In <FIG> and <FIG>, the approved initiation regimen is <NUM> to <NUM> oral (<NUM> days) + <NUM> IM depot (Day <NUM>). The starting concentration at time zero is the average concentration at steady state for CYP2D6 EM stabilized on <NUM> oral aripiprazole and PM subjects stabilized on <NUM> oral aripiprazole. For PMs, prior oral dose was reduced by half (<NUM> instead of <NUM>).

As expected, simulations resulted in CYP2D6 PM subjects exhibiting higher aripiprazole Cmax and exposure compared to CYP2D6 EM subjects when both receive two administrations of <NUM> IM depot aripiprazole formulation. Thus, a dose reduction of the proposed regimen from two <NUM> IM depot aripiprazole formulation administrations to two <NUM> IM depot aripiprazole formulation administrations along with a single dose of <NUM> oral aripiprazole is recommended for known CYP2D6 PM subjects or patients to ensure concentrations following the alternative initiation regimen are comparable to the currently approved regimen and remain within or slightly above the therapeutic window.

Simulations were performed to assess aripiprazole concentrations following a missed second, third, fourth, or steady-state dose of IM depot aripiprazole formulation to determine whether the alternative initiation regimen could be applicable to situations when the currently approved initiation regimen requires concurrent oral administration of aripiprazole for <NUM> weeks with a single IM depot aripiprazole formulation injection.

A comparison of the simulated median aripiprazole plasma concentrations following administration of the alternative initiation regimen or the currently approved initiation regimen in the gluteal or deltoid site when the second or third IM depot aripiprazole formulation dose is administered <NUM> weeks after the previous injection are provided in <FIG>. In <FIG>, the approved initiation regimen was <NUM> to <NUM> oral (<NUM> days) and <NUM> IM depot (Day <NUM>).

A comparison of the simulated median aripiprazole plasma concentrations following administration of the alternative initiation regimen or the currently approved initiation regimen in the gluteal or deltoid site when the 4th or 5th (steady-state) dose is administered <NUM> weeks after the previous injection are provided in <FIG>. In <FIG>, the approved initiation regimen was <NUM> to <NUM> oral (<NUM> days) and <NUM> IM depot (Day <NUM>).

In all simulations, administration of the alternative initiation regimen following a missed maintenance IM depot resulted in median aripiprazole concentrations above the lower threshold of the therapeutic window and similar to those following the approved initiation regimen.

Based on the results of the simulations, the alternative initiation regimen may be administered in place of concomitant oral aripiprazole for <NUM> days together with a single IM depot formulation of aripiprazole injection on Day <NUM> when a maintenance IM depot dose is missed. Such a treatment strategy following a missed dose is consistent with that in the Ability Maintena(R) label.

An analysis was performed to evaluate observed safety outcomes from a subset of <NUM> subjects from the phase I clinical trial describe below with plasma concentration time profiles that fall within the 5th to 95th percentile of simulated concentrations following administration of the alternative initiation regimen and are consistently above the mean PK profile following a single gluteal administration of <NUM> Ability Maintena(R). A graphical comparison of all aripiprazole concentration time profiles following a single dose of <NUM> (N = <NUM>) or <NUM> (N = <NUM>) aripiprazole LAI to the gluteal muscle (from a previous clinical trial), with aripiprazole concentration time profiles from the subset of <NUM> subjects highlighted in red, is presented in <FIG>. In <FIG>, the N equals the number of subjects; the subset of <NUM> subjects from a trial with plasma concentration time profiles that fall within the 5th to 95th percentile of simulated concentration following administration of the alternative initiation regimen and are consistently above the mean PK profile following a single gluteal administration of <NUM> Ability Maintena(R); and lower limit of quantitation of aripiprazole was <NUM> ng/mL.

For reference, the mean (i.e., the lower dark horizontal line) aripiprazole plasma concentration time profile following administration of a single dose of <NUM> Ability Maintena(R) to the gluteal muscle and the 5th to 95th percentile of simulated concentrations (final combined model) following administration of the alternative initiation regimen (<NUM> oral [Day <NUM>] + <NUM> x <NUM> aripiprazole IM depot formulation [Day <NUM>]) to the gluteal site (shaded area) are also presented.

Of the <NUM> subjects identified, <NUM> subjects were treated with <NUM> aripiprazole LAI and <NUM> subjects were treated with <NUM> aripiprazole LAI. A review of the safety data from these subjects did not identify any unexpected AEs and it was concluded that their safety profile was in accordance with the known safety profile of Ability Maintena(R).

Simulations indicated that the two-injection start regimen of two administrations of aripiprazole once-monthly at separate gluteal and/or deltoid injection sites with a single <NUM> dose of oral aripiprazole on the first day of treatment regimen would: (<NUM>) achieve therapeutic aripiprazole plasma concentrations on the first day of treatment; (<NUM>) support consistent clinical effectiveness over the entire dosing interval; (<NUM>) result in comparable aripiprazole plasma concentrations thus, safety profile, to the currently approved (traditional) initiation regimen; and (<NUM>) provide a new initiation option which obviates the need for the <NUM>-day oral tablet supplementation, potentially reducing compliance related undertreatment during the initiation phase of treatment.

A Phase <NUM>, Open Label, Single Ascending Dose, Parallel Arm Trial to Determine the Pharmacokinetics, Safety, and Tolerability of Aripiprazole <NUM> Month Intramuscular Depot Administered Gluteally in Adult Subjects with Schizophrenia.

This trial was an open-label, single ascending dose, parallel-arm, multiple-center trial to determine the PK, safety, and tolerability of single-dose administration of <NUM> (Cohort <NUM>) and <NUM> (Cohort <NUM>) of a high dose formulation of aripiprazole LAI that is in the gluteal muscle of adult subjects with schizophrenia. Data from this trial is supportive information, as it was evaluated for instances in which aripiprazole plasma concentrations increased at a similar rate and reached levels predicted in simulations for the alternative initiation regimen. Overall, aripiprazole LAI was well tolerated when administered IM as a single dose of <NUM> and <NUM> to adult subjects with schizophrenia. In a subset of <NUM> subjects, the administration of aripiprazole LAI resulted in higher aripiprazole plasma concentrations as well as faster absorption rates, resulting in aripiprazole plasma concentration time profiles that fell within the 5th to 95th percentile of simulated concentrations following administration of the proposed alternative initiation regimen and were consistently above the mean PK profile following a single gluteal administration of <NUM> Ability Maintena(R) (<FIG>). Safety data from this subset of subjects was evaluated and compared to the known safety profile of Ability Maintena(R). Further details of this analysis are provided under the section entitled "Comparison and Analyses of Results Across Trials.

The aripiprazole LAI was an extended release presentation for dosing every <NUM> months at the dose levels evaluated. The extension of the dosing interval for the aripiprazole LAI was primarily through an increase in the dose while maintaining minimum aripiprazole concentrations that are comparable to Ability Maintena(R) after multiple doses. The aripiprazole LAI was engineered with higher aripiprazole concentrations in the drug product (<NUM>/mL vs <NUM>/mL) and minor changes to the vehicle compared to currently marketed/approved Ability Maintena(R). The mean aripiprazole particle size distribution and the dissolution profile for the aripiprazole LAI formulation were comparable with the Ability Maintena(R) formulation and the formulation was expected to have a similar extended release profile compared with the approved Ability Maintena(R) formulation. Mean (standard deviation [SD]) aripiprazole plasma concentration time profiles following administration of a single dose of <NUM> or <NUM> aripiprazole to the gluteal muscle in subjects with schizophrenia are presented in <FIG>.

A summary of the aripiprazole PK parameters following single-dose administration of a single dose of <NUM> or <NUM> aripiprazole to the gluteal muscle in subjects with schizophrenia is presented in Table <NUM> below.

From Table <NUM>, it is noted that AUC∞ is area under the concentration-time curve calculated from time zero to infinity; AUCt is area under the concentration-time curve calculated to the last observable concentration at time t; CL/F is apparent clearance of drug from plasma after extravascular administration; RTU is ready to use; tmax is time to maximum (peak) plasma concentration; t1/<NUM> is elimination half-life. Additionally, aMedian (minimum-maximum); bn = <NUM>; and cn = <NUM>.

Conclusions from this data include, for example:.

Claims or descriptions that include "or" or "and/or" between at least one members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The disclosure includes embodiments in which more than one, or all the group members are present in, employed in, or otherwise relevant to a given product or process.

Claim 1:
An aripiprazole intramuscular (IM) depot formulation comprising <NUM> or <NUM> of aripiprazole, for use in a method of dose initiation for an aripiprazole treatment to a patient in need thereof, wherein the patient has schizophrenia or bipolar I disorder, the method comprising:
administering two, separate injections of the aripiprazole intramuscular (IM) depot formulation, wherein each injection comprises <NUM> or <NUM> of aripiprazole, to the patient at separate injection sites chosen from gluteal injection sites, deltoid injection sites, and a gluteal injection site and a deltoid injection site, and a single dose of oral aripiprazole,
wherein the step of administering the two separate injections and the single oral dose occurs on a first day of the treatment.