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WO2024225441A1 - Initiation de dose pour le traitement de la schizophrénie ou du trouble bipolaire i avec de l'aripiprazole - Google Patents

Initiation de dose pour le traitement de la schizophrénie ou du trouble bipolaire i avec de l'aripiprazole Download PDF

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Publication number
WO2024225441A1
WO2024225441A1 PCT/JP2024/016465 JP2024016465W WO2024225441A1 WO 2024225441 A1 WO2024225441 A1 WO 2024225441A1 JP 2024016465 W JP2024016465 W JP 2024016465W WO 2024225441 A1 WO2024225441 A1 WO 2024225441A1
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aripiprazole
lai
oral
injection
dose
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Matthew HARLIN
Xiaofeng Wang
Yanlin Wang
Arash Raoufinia
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Otsuka Pharmaceutical Co Ltd
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Otsuka Pharmaceutical Co Ltd
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Priority to CN202480025527.1A priority Critical patent/CN120957722A/zh
Priority to AU2024263986A priority patent/AU2024263986A1/en
Publication of WO2024225441A1 publication Critical patent/WO2024225441A1/fr
Priority to IL324134A priority patent/IL324134A/en
Priority to MX2025012679A priority patent/MX2025012679A/es
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Definitions

  • Schizophrenia and bipolar I disorder are complex, chronic mental health disorders, with affected individuals typically experiencing multiple relapses of symptoms that are separated by periods of remission. While daily oral antipsychotic agents have proven effective for many patients achieving and maintaining symptom control, it relies on their consistent and long-term use. Suboptimal adherence to oral medication, however, is common, with data indicating that 30-50% of patients with schizophrenia or BP-I do not take their medication as prescribed.
  • Various strategies for improving adherence to treatment are available, including the use of long-acting injectable (LAI) antipsychotics; LAI formulations offer dosing intervals ranging from 2 weeks to 6 months, reducing the adherence demands on patients, compared with daily dosing. Indeed, data from several real-world studies indicate that LAI formulations of antipsychotics are associated with significant improvements in treatment adherence versus oral antipsychotics in patients with schizophrenia or BP-I.
  • Aripiprazole is an antipsychotic agent that exerts partial agonist activity at dopamine D2 and serotonin 5-HT1A receptors, full agonist activity at dopamine D3 receptors, and antagonist activity at serotonin 5-HT2A receptors.
  • Aripiprazole is available in a once-daily oral formulation and as an extended-release suspension of aripiprazole monohydrate for intramuscular injection, known as aripiprazole, once-monthly (AOM).
  • aripiprazole once-monthly
  • RTU novel ready-to-use
  • the novel formulation contains aripiprazole monohydrate in doses of 960 mg or 720 mg, with the latter dose used in case of any tolerability concerns, in patients who are known cytochrome P450 (CYP) 2D6 poor metabolizers, and in patients who are taking concomitant strong inhibitors of CYP2D6 or CYP3A4.
  • CYP cytochrome P450
  • Aripiprazole 2-month ready-to-use 960 mg was developed to extend the maintenance of therapeutic plasma concentrations of aripiprazole from one month with AOM 400 mg (AOM 400) to two months; this is achieved through several considerations, such as an increase in the administered dose, while maintaining minimum aripiprazole concentrations that are similar to those after multiple doses of AOM and other formulation and administration considerations. Less frequent dosing, among other things, with Ari 2MRTU 960 (i.e., 6 injections per year, versus 12 with AOM) may reduce the medication burden for patients and clinicians and improve adherence to antipsychotic treatment in adult patients with schizophrenia or BP-I.
  • Ari 2MRTU 960 and Ari 2MRTU 720 i.e., Aripiprazole 2-month ready-to-use 720 mg
  • a previously developed and validated population pharmacokinetic (popPK) model for characterizing aripiprazole plasma concentrations following administration of oral aripiprazole, or AOM at the gluteal or deltoid sites was expanded to include the novel RTU LAI formulation of aripiprazole (Ari RTU LAI).
  • the expanded popPK modeling resulted in additional options for dose initiations of aripiprazole treatment of patients.
  • the present disclosure is directed to methods of dose initiation for an aripiprazole treatment to a patient in need thereof by administering two, separate injections of aripiprazole with a first aripiprazole injection of a long acting injectable (LAI) and a second aripiprazole injection of a once-monthly injectable (AOM) with a single dose of oral aripiprazole on a first day of the aripiprazole treatment.
  • LAI long acting injectable
  • AOM once-monthly injectable
  • the present disclosure is directed to methods of dose initiation for an aripiprazole treatment to a patient in need thereof comprising: administering two, separate injections of aripiprazole, wherein a first injection comprises 960 mg or 720 mg of aripiprazole in a long-acting injectable (LAI), and a second injection comprises 400 mg or 300 mg of aripiprazole in a once-monthly (AOM) injectable, to the patient with an injection site chosen from a gluteal site, a deltoid site, and combinations thereof, and a single dose of oral aripiprazole, wherein the step of administering occurs on a first day of the aripiprazole treatment.
  • LAI long-acting injectable
  • AOM once-monthly
  • the present disclosure is directed to methods of treating schizophrenia or bipolar I disorder in a patient in need thereof comprising: administering two, separate injections of aripiprazole, wherein a first injection comprises 960 mg or 720 mg of aripiprazole in a long-acting injectable (LAI), and a second injection comprises 400 mg or 300 mg of aripiprazole in a once-monthly (AOM) injectable, to the patient with an injection site chosen from a gluteal site, a deltoid site, and combinations thereof, and a single dose of oral aripiprazole, wherein the step of administering occurs on a first day of the aripiprazole treatment and wherein the dose of oral aripiprazole ranges from about 10 mg to about 20 mg of aripiprazole; and continuing administering with a maintenance dose of the LAI comprising 960 mg or 720 mg of aripiprazole, wherein the maintenance dose is administered about two months
  • FIG. 1 is a diagram of the base model describing aripiprazole pharmacokinetics following oral, AOM and Ari RTU LAI administration.
  • FIG. 2 is a graph illustrating the simulated pharmacokinetic profile from the final model according to the retained covariates (gender and CYP2D6 status) following six repeated administration of Ari 2MRTU 960 mg of aripiprazole every 8 weeks.
  • FIG. 3A-3D are graphs of the goodness-of-fit plots for the final aripiprazole population pharmacokinetic model.
  • FIG. 4A-4G are graphs of the prediction-corrected visual predictive checks for the final aripiprazole population pharmacokinetic model.
  • FIG. 5A-5F are graphs of the simulated median aripiprazole concentration-time profiles following initiation of Ari 2MRTU 960 mg of aripiprazole across various prior treatment scenarios.
  • FIG. 6 is a graph of the simulated median aripiprazole concentration-time profiles following Ari 2MRTU 960 mg of aripiprazole as scheduled or after a delay of 2, 4, 6, or 8 weeks in patients already stabilized on Ari 2MRTU 960 mg of aripiprazole.
  • FIG. 7 is a graph of simulated median aripiprazole concentration-time profile for Ari 2MRTU 960 on Day 28 following AOM on Day 0 (with overlapping oral aripiprazole 20 mg in patients without prior oral aripiprazole stabilization).
  • FIG. 8A-8D are graphs of simulated median aripiprazole concentration-time profiles following a two-injection start with Ari 2MRTU 960 plus AOM 400 across various prior treatment scenarios.
  • FIG. 9 is a graph of simulated median steady-state aripiprazole concentration-time profile following administration of Ari 2MRTU 720 in CYP2D6 poor metabolizers.
  • FIG. 10 is a graph of simulated median steady-state aripiprazole concentration-time profiles following administration of Ari 2MRTU 720 with strong inhibitors of CYP3A4 or CYP2D6.
  • FIG. 11 is a graph of simulated median Aripiprazole concentration time profile following administration of Ari 2MRTU 960 (Day 0) with AOM 400 (Day 0) and 20 mg Oral Aripiprazole (Day 0) in all subject (solid line) and in CYP2D6 poor metabolizers (dashed line) or Ari 2MRTU 720 (Day 0) with AOM 300 (Day 0) and 20 mg oral Aripiprazole (Day 0) in CYP2D6 poor metabolizers in subjects already stabilized on 10 mg oral Aripiprazole (dotted line).
  • FIG. 12 is a graph of simulated median Aripiprazole concentration time profile following administration of Ari 2MRTU 960 (Day 0) with AOM 400 (Day 0) and 20 mg oral Aripiprazole (Day 0) in all subject (solid line) and in CYP2D6 poor metabolizers (dashed line) or Ari 2MRTU 720 (Day 0) with AOM 300 (Day 0) and 20 mg oral Aripiprazole (Day 0) in CYP2D6 poor metabolizers in subjects without prior oral Aripiprazole stabilization (dotted line).
  • 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.
  • a compound refers to one or more compounds or at least one compound unless stated otherwise.
  • the terms “a” (or “an”), “one or more”, and “at least one” are used interchangeably 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 5%.
  • 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.
  • a “mammal” refers to domesticated animals (e.g., dogs, cats, and horses) and humans. In some embodiments, the mammal is a human.
  • 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 those 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.
  • the term “aripiprazole” or salt thereof refers to a compound having the structure:
  • the empirical formula is C 23 H 27 Cl 2 N 3 O 2 H 2 O and its molecular weight is 466.40.
  • the present disclosure is directed to methods of dose initiation for an aripiprazole treatment to a patient in need thereof by administering two, separate injections of aripiprazole, wherein a first injection comprises 960 mg or 720 mg of aripiprazole in a long-acting injectable (LAI), and a second injection comprises 400 mg or 300 mg of aripiprazole in a once-monthly (AOM) injectable with a single dose or oral aripiprazole, to the patient with an injection site chosen from a gluteal site, a deltoid site, and combinations thereof, and a single dose of oral aripiprazole, wherein the step of administering occurs on a first day of the aripiprazole treatment.
  • LAI long-acting injectable
  • AOM once-monthly
  • some embodiments of the present disclosure include, but are not limited to:
  • a method of dose initiation for an aripiprazole treatment to a patient in need thereof comprising: administering two, separate injections of aripiprazole, wherein a first injection comprises 960 mg or 720 mg of aripiprazole in a first long-acting injectable (LAI) formulation, and a second injection comprises 400 mg or 300 mg of aripiprazole in a second LAI formulation, to the patient with an injection site chosen from a gluteal site, a deltoid site, and combinations thereof, and a single dose of oral aripiprazole, wherein the step of administering occurs on a first day of the aripiprazole LAI treatment.
  • LAI long-acting injectable
  • the maintenance dose of the first LAI formulation is 720 mg of aripiprazole.
  • the first injection comprises 720 mg of aripiprazole
  • the second injection comprises 400 mg or 300 mg of aripiprazole
  • the single dose of oral aripiprazole comprises about 10 mg or about 20 mg of aripiprazole.
  • the patient is a CYP2D6 poor metabolizer or is taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors for greater than 14 days
  • the first injection comprises 720 mg of aripiprazole
  • the second injection comprises 300 mg of aripiprazole
  • the single dose of oral aripiprazole comprises about 20 mg of aripiprazole.
  • a method of treating schizophrenia or bipolar I disorder in a patient in need thereof comprising: administering two, separate injections of aripiprazole, wherein a first injection comprises 960 mg or 720 mg of aripiprazole in a first long-acting injectable (LAI) formulation, and a second injection comprises 400 mg or 300 mg of aripiprazole in a second LAI formulation, to the patient with an injection site chosen from a gluteal site, a deltoid site, and combinations thereof, and a single dose of oral aripiprazole, wherein the step of administering occurs on a first day of the aripiprazole LAI treatment and wherein the dose of oral aripiprazole ranges from about 10 mg to about 20 mg of aripiprazole; and continuing administering with a maintenance dose of the first LAI formulation comprising 960 mg or 720 mg of aripiprazole, wherein the maintenance dose is administered once in about two months after the first day of
  • a long-acting injectable (LAI) comprising 960 mg or 720 mg of aripiprazole, for use in a method of dose initiation for an aripiprazole treatment to a patient in need thereof, the method comprising: administering two, separate injections of aripiprazole, wherein a first injection comprises 960 mg or 720 mg of aripiprazole in a first long-acting injectable (LAI) formulation, and a second injection comprises 400 mg or 300 mg of aripiprazole in a second LAI formulation, to the patient with an injection site chosen from a gluteal site, a deltoid site, and combinations thereof, and a single dose of oral aripiprazole, wherein the step of administering occurs on a first day of the aripiprazole LAI treatment.
  • LAI long-acting injectable
  • aripiprazole in the manufacture of a medicament for an aripiprazole treatment of schizophrenia or bipolar I disorder, the treatment comprising: administering two, separate injections of aripiprazole, wherein a first injection comprises 960 mg or 720 mg of aripiprazole in a first long-acting injectable (LAI) formulation, and a second injection comprises 400 mg or 300 mg of aripiprazole in a second LAI formulation, to a patient in need thereof with an injection site chosen from a gluteal site, a deltoid site, and combinations thereof, and a single dose of oral aripiprazole, wherein the step of administering occurs on a first day of the aripiprazole LAI treatment.
  • LAI long-acting injectable
  • aripiprazole for treating a patient with schizophrenia or bipolar I disorder, wherein the aripiprazole is for administering two, separate injections of aripiprazole, wherein a first injection comprises 960 mg or 720 mg of aripiprazole in a first long-acting injectable (LAI) formulation, and a second injection comprises 400 mg or 300 mg of aripiprazole in a second LAI formulation, to a patient in need thereof with an injection site chosen from a gluteal site, a deltoid site, and combinations thereof, and a single dose of oral aripiprazole, wherein the step of administering occurs on a first day of the aripiprazole LAI treatment.
  • LAI long-acting injectable
  • LAI long-acting injectable
  • the present disclosure is directed to methods of dose initiation for an aripiprazole treatment to a patient in need thereof by administering two, separate injections of aripiprazole with a first aripiprazole injection of a first long acting injectable (LAI) formulation and a second aripiprazole injection of a second LAI formulation (a once-monthly injectable (AOM)) on a first day of the aripiprazole LAI treatment with a single dose of oral aripiprazole.
  • This dose initiation regimen is also called a "two injection start" in the present disclosure.
  • This dose initiation regimen provides for an Ari RTU LAI PK exposure profile that was comparable to AOM, with a longer dosing interval.
  • Maintenance dosing occurs once in about two months after the first day of the aripiprazole LAI treatment using a maintenance dose of the LAI; for example, maintenance dose follows once in about two months thereafter of 960 mg or 720 mg of aripiprazole first LAI depot formulation.
  • the alternative initiation regimen is applicable to both the deltoid and gluteal administration sites.
  • the present disclosure utilizes two, separate aripiprazole injections with a first injection comprising 960 mg or 720 mg of aripiprazole in a long-acting injectable (LAI) formulation, and a second injection comprising 400 mg or 300 mg of aripiprazole in a second LAI formulation (a once-monthly (AOM) injectable) and a single dose of oral aripiprazole.
  • LAI long-acting injectable
  • AOM once-monthly injectable
  • the two, separate LAI and AOM aripiprazole injections are administered at separate gluteal injection sites or at separate deltoid sites of the patient. In a further embodiment, the two, separate LAI and AOM aripiprazole injections are administered at a gluteal and a deltoid injection site of the patient.
  • the present disclosure is further directed to methods of treating schizophrenia or bipolar I disorder in a patient in need thereof comprising: administering two, separate injections of aripiprazole, wherein a first injection comprises 960 mg or 720 mg of aripiprazole in a first long-acting injectable (LAI) formulation, and a second injection comprises 400 mg or 300 mg of aripiprazole in a second LAI formulation (a once-monthly (AOM) injectable), to the patient with an injection site chosen from a gluteal site, a deltoid site, and combinations thereof, and a single dose of oral aripiprazole, wherein the step of administering occurs on a first day of the aripiprazole LAI treatment; and continuing administering with a maintenance dose of the first LAI formulation comprising 960 mg or 720 mg of aripiprazole, wherein the maintenance dose is administered once in about two months after the first day of the aripiprazole treatment.
  • LAI long
  • aripiprazole treatment may exclude administration for establishment of tolerability with oral aripiprazole prior to initiation of LAI treatment with an injection that comprises 960 mg or 720 mg of aripiprazole in a first long-acting injectable (LAI) formulation.
  • LAI long-acting injectable
  • the methods of the present disclosure comprise wherein the two, separate injections of aripiprazole are administered at separate gluteal injection sites of the patient. In some embodiments, the methods of the present invention comprise wherein the two, separate injections of aripiprazole are administered at gluteal and deltoid injection sites of the patient. In some embodiments, the methods of the present disclosure comprise wherein the two, separate injections of aripiprazole are administered at separate deltoid injection sites of the patient.
  • the methods of the present disclosure comprise wherein the patient has schizophrenia or bipolar I disorder. In some embodiments, the methods of the present disclosure comprise wherein the patient has schizophrenia. In some embodiments, the methods of the present disclosure comprise wherein the patient has bipolar I disorder.
  • two separate injections of aripiprazole wherein a first injection comprises 960 mg or 720 mg of aripiprazole in a first long-acting injectable (LAI) formulation, and a second injection comprises 400 mg or 300 mg of aripiprazole in a second LAI formulation (a once-monthly (AOM) injectable) are administered at two different injection sites, along with one 20 mg dose of oral aripiprazole.
  • LAI long-acting injectable
  • the two injection start when initiating with the two injection start, it is preferable to inject into two different sites in two different muscles. It is preferable not to inject both injections concomitantly into the same deltoid or gluteal muscle.
  • LAI long-acting injectable
  • AOM once-monthly
  • oral aripiprazole is not administered from 1 to 13 days after the first day of the aripiprazole LAI treatment.
  • the rationale for the selection of the alternative initiation regimen dose is based on simulations from a population pharmacokinetic(s) (popPK) model.
  • a population pharmacokinetic (popPK) model for characterizing aripiprazole plasma concentrations following administration of oral aripiprazole or aripiprazole once-monthly (AOM) intramuscular injection was expanded to include the RTU LAI formulation of aripiprazole (Ari RTU LAI).
  • AOM population pharmacokinetic
  • Aripiprazole plasma concentration-time profiles were simulated for various Ari RTU LAI initiation and maintenance scenarios in 1,000 virtual patients.
  • the final popPK model which incorporated data for oral aripiprazole, AOM and Ari RTU LAI, was found to be a good fit, with absorption of Ari RTU LAI modeled by a parallel zero-order and lagged first-order process. Simulations across multiple scenarios were performed to inform dosing recommendations, including various treatment initiation regimens for a 2-monthly formulation of Ari RTU LAI in patients with or without prior stabilization on oral aripiprazole, and for patients switching from AOM.
  • LAI First long-acting injectable
  • a first injection comprises 960 mg or 720 mg of aripiprazole in a first long-acting injectable (LAI) formulation.
  • the first injection comprises 960 mg of aripiprazole in the first LAI formulation.
  • the first injection comprises 720 mg of aripiprazole in the first LAI formulation.
  • the methods of the present disclosure comprise administering a maintenance dose of the first LAI formulation.
  • the maintenance dose of the first LAI formulation comprises 960 mg or 720 mg of aripiprazole.
  • the maintenance dose comprises 960 mg of aripiprazole in the first LAI formulation.
  • the maintenance dose comprises 720 mg of aripiprazole in the first LAI formulation.
  • the first LAI formulation comprises a composition comprising aripiprazole, a specific suspending agent (suspending agent (A)), and a dispersion medium.
  • the injectable preparation of the present disclosure comprises at least water as a dispersion medium.
  • Water, or an aqueous solvent comprising water and an organic solvent can be used as a dispersion medium comprising at least water.
  • the dispersion medium is water, and further for example, sterile water for injection.
  • the specific suspending agent (suspending agent A) contained in the first LAI formulation comprises at least one suspending agent chosen from (i) and (ii): (i) polyvinylpyrrolidone, and (ii) polyethylene glycol and carboxymethyl cellulose or a salt thereof.
  • the first LAI formulation comprises aripiprazole or a salt thereof, water, and at least one suspending agent chosen from groups (i) and (ii): (i) polyvinylpyrrolidone, and (ii) polyethylene glycol and carboxymethylcellulose or a salt thereof, wherein aripiprazole or a salt thereof has a mean primary particle diameter ranging from about 0.5 ⁇ m to about 30 ⁇ m and the concentration of aripiprazole or a salt thereof ranges from about 200 mg/mL to about 600 mg/mL.
  • RTU two months ready to use
  • LAI long acting injectable
  • the injectable preparation of the LAI preparation is, for example, Abilify Asimtufii (R), Abilify Maintena (R) 720 mg prolonged-release suspension for injection in pre-filled syringe or Abilify Maintena (R) 960 mg prolonged-release suspension for injection in pre-filled syringe.
  • the injectable preparation of the present disclosure comprises aripiprazole or a salt thereof (which hereafter may be referred to as “the aripiprazole injectable preparation of the present disclosure”)
  • the concentration of aripiprazole or a salt thereof ranges from about 200 mg/mL to about 600 mg/mL.
  • the first LAI formulation of aripiprazole become a gel upon standing, which precipitation and caking of the particles of aripiprazole can be inhibited, thereby providing excellent storage stability.
  • the injectable preparation even in the form of a gel, can easily gain fluidity when subjected to a mild impact, the preparation can be easily injected at the time of use (at the time of injection).
  • the gelled injectable preparation gains fluidity (forms a sol state) by simply pressing the plunger of a syringe and ejecting the preparation through a syringe needle, the preparation can be smoothly ejected through the needle as is. Therefore, the preparation can have a thixotropic property, and be well dispersed intramuscularly or subcutaneously with relatively less local disturbance and pain at the time of injection.
  • the first LAI formulation of the present disclosure comprises aripiprazole or a salt thereof, a combination of the use of a specific suspending agent (suspending agent A) and a specific concentration of aripiprazole or a salt thereof (from about 200 mg/mL to about 600 mg/mL, such as from about 250 mg/mL to about 450 mg/mL, and from about 300 mg/mL to about 400 mg/mL) is used.
  • a specific suspending agent sustained release of a specific concentration of aripiprazole or a salt thereof
  • concentration described above is calculated as aripiprazole.
  • the first LAI formulation comprises aripiprazole in a concentration of about 200 mg/mL to about 600 mg/mL, such as about 200 mg/mL to about 500 mg/mL, for example, about 250 mg/mL to about 450 mg/mL, further for example, about 300 mg/mL to about 400 mg/mL, and further for example, about 300 mg/mL.
  • the concentration of polyvinylpyrrolidone ranges from about 0.1 mg/mL to about 100 mg/mL, such as about 1 mg/mL to about 50 mg/mL, and further for example about 2 mg/mL to about 20 mg/mL.
  • the first LAI formulation of the present disclosure comprises (i) polyvinylpyrrolidone as suspending agent A, and further comprises one or more other suspending agents
  • at least one member is chosen from polyethylene glycol and carboxymethylcellulose or a salt thereof be contained as the one or more other suspending agents.
  • these injectable preparations of the present disclosure comprise (i) polyvinylpyrrolidone as suspending agent A, and when they further comprise one or more other suspending agents, they comprise suspending agents of any combination of (i-1) to (i-3) shown below.
  • the concentration of polyvinylpyrrolidone is, as described above, about 0.1 mg/mL to about 100 mg/mL, such as about 1 mg/mL to about 50 mg/mL, and further for example, about 2 mg/mL to about 20 mg/mL.
  • the concentration of polyethylene glycol is about 0.05 mg/mL to about 100 mg/mL and for example, about 0.1 mg/mL to about 50 mg/mL.
  • the concentration of carboxymethylcellulose or a salt thereof is about 0.5 mg/mL to about 50 mg/mL, such as about 1 mg/mL to about 30 mg/mL, and further for example, about 2 mg/mL to about 20 mg/mL.
  • the molecular weight of carboxymethylcellulose or a salt thereof ranges from 49,000 to 300,000. Furthermore, by containing polyethylene glycol, syneresis can be prevented even when the resulting injectable preparation is stored for a long period of time. In some embodiments, the molecular weight of polyethylene glycol ranges from 400 to 4,000. In some embodiments, (i-3) is present in the injectable preparation.
  • the average molecular weight of carboxymethylcellulose or a salt thereof is, for example, 5,000 or more, preferably 10,000 or more, more preferably 20,000 or more, more preferably 30,000 or more, more preferably 40,000 or more, more preferably 50,000 or more.
  • the average molecular weight of carboxymethylcellulose or a salt thereof is, for example, 300,000 or less, preferably 250,000 or less, more preferably 200,000 or less, more preferably 150,000 or less.
  • the average molecular weight of carboxymethylcellulose or a salt thereof is, for example, between 5,000 and 300,000, preferably between 10,000 and 250,000, preferably between 20,000 and 200,000, preferably 50,000 and 150,000.
  • the viscosity of a 2% (weight/volume) aqueous solution of carboxymethylcellulose or a salt thereof is, for example, 1,000 mPa ⁇ s or less, preferably 800 mPa ⁇ s or less. In other embodiments, the viscosity is, for example, 10 mPa ⁇ s or more, preferably 50 mPa ⁇ s or more. In still other embodiments, the viscosity is, for example, between 10 and 1,000 mPa ⁇ s, preferably between 50 and 800 mPa ⁇ s. The viscosity can be measured according to the method described in the USP-NF (for example, the 2019 edition USP42-NF37).
  • the concentration of polyethylene glycol is about 0.05 mg/mL to about 2 mg/mL and further for example, about 0.1 mg/mL to about 1 mg/mL.
  • the concentration of carboxymethylcellulose or a salt thereof is about 0.5 mg/mL to about 50 mg/mL, such as about 1 mg/mL to about 30 mg/mL, and such as about 2 mg/mL to about 20 mg/mL.
  • the injectable preparation of the present disclosure comprises, as suspending agent A, (ii) polyethylene glycol and carboxymethylcellulose or a salt thereof, and when it further comprises one or more other suspending agents, the suspending agents of (i-3) are contained.
  • the concentrations of polyethylene glycol, carboxymethylcellulose or a salt thereof, and polyvinylpyrrolidone are the same as described in (i-3) above.
  • the composition comprises about 0.5 mg/mL to about 20 mg/mL of polyvinylpyrrolidone, about 0.1 mg/mL to about 100 mg/mL of polyethylene glycol, about 0.5 mg/mL to about 50 mg/mL of carboxymethylcellulose or a salt thereof, and about 250 mg/mL to about 450 mg/mL (such as about 300 mg/mL to about 400 mg/mL) of aripiprazole or a salt thereof.
  • the polyethylene glycol may be polyethylene glycol 400 or polyethylene glycol 4000.
  • the polyvinylpyrrolidone has a K value of about 12 to about 20.
  • the aripiprazole or a salt thereof has a mean primary particle diameter of about 1 ⁇ m to 10 ⁇ m.
  • the mean primary particle diameter ranges from about 0.5 ⁇ m to about 30 ⁇ m and for example, about 1 ⁇ m to about 20 ⁇ m.
  • the aripiprazole or a salt thereof has a mean primary particle diameter of about 1 ⁇ m to about 50 ⁇ m, such as about 1 ⁇ m to about 10 ⁇ m, and further for example, about 2 ⁇ m to about 5 ⁇ m.
  • the mean secondary particle diameter is up to but not exceeding three times and further for example, up to but not exceeding twice the mean primary particle diameter.
  • the first LAI formulation of the present disclosure is suitably formulated into a dosage form that can be administered once every two months.
  • concentration of aripiprazole or a salt thereof in the first LAI formulation of the present disclosure that is administered once every two months is, calculated as aripiprazole, about 200 mg/mL to about 600 mg/mL, such as about 250 mg/mL to about 500 mg/mL, further for example, about 300 mg/mL to 400 mg/mL, and further for example, about 300 mg/mL.
  • the dosage volume is about 2 mL to about 4 mL, such as about 2.2 mL to about 3.5 mL, further for example, about 2.3 mL to about 3.4 mL, and further for example, about 3.2 mL.
  • the first LAI formulation of the present disclosure achieves the effects ( ⁇ ) and ( ⁇ ) described above. They may be in the form of a gel or they may have fluidity (i.e., they may be in the form of a sol). As described above, the achievement of the effects of the effects ( ⁇ ) and ( ⁇ ) can objectively confirmed by the use of a rotary rheometer.
  • the first LAI formulation may be formulated into a dosage form of a prefilled sol-gel formed injection (also herein referred to as a “prefilled sol-gel formed injectable preparation”). This injectable formulation exhibits a thixotropic property. And the formulation may be in the form of a gel when allowed to stand, and may change to a sol when subjected to an impact.
  • a method for producing the first LAI formulation comprises preparing a liquid mixture of the starting materials and pulverizing aripiprazole or a salt thereof, contained in the liquid mixture to a desired mean primary particle diameter, optionally followed by aging.
  • a method for producing the gel first LAI formulation according to the present invention comprises allowing a liquid mixture to stand at 5 to 70°C for 5 minutes or more, the liquid mixture comprising aripiprazole or a salt thereof with a mean primary particle diameter of about 0.5 ⁇ m to about 30 ⁇ m in a concentration of about 200 mg/mL to about 600 mg/mL, water, and at least one suspending agent chosen from (i) and (ii): (i) polyvinylpyrrolidone and (ii) polyethylene glycol and carboxymethyl cellulose or a salt thereof.
  • a production method comprising the following steps can be used: pulverizing aripiprazole or a salt thereof to a mean primary particle diameter of about 0.5 ⁇ m to about 30 ⁇ m in a liquid mixture comprising the aripiprazole or a salt thereof in a concentration of about 200 mg/mL to about 600 mg/mL, water, and at least one suspending agent selected from the group consisting of (i) and (ii): (i) polyvinylpyrrolidone and (ii) polyethylene glycol and carboxymethyl cellulose or a salt thereof; and allowing the pulverized liquid mixture to stand at 5°C to 70°C for 5 minutes or more.
  • the present disclosure comprises the administration of the first LAI formulation resulting in a total amount of aripiprazole of 960 mg or 720 mg, for example 960 mg, further for example from 720 mg, administered to the patient, wherein the injectable preparation may be optionally administered in one or more divided injections.
  • the administration of the first LAI formulation results in a total amount of aripiprazole of about 960 mg to the patient, wherein one or more injectable formulations are administered.
  • one (1) injection of the first LAI formulation comprising 960 mg/mL of aripiprazole is administered.
  • the 960 mg dosage may be optionally administered in separate injections at short intervals.
  • the first injection comprises 960 mg of aripiprazole.
  • the administration of the first LAI formulation results in a total amount of aripiprazole of about 720 mg to the patient, wherein one or more injectable formulations are administered.
  • one (1) injection of the first LAI formulation comprising 720 mg/mL of aripiprazole is administered.
  • the first injection comprises 720 mg of aripiprazole.
  • the 720 mg dosage may be optionally administered in separate injections at short intervals. The number of injections and the concentration of the aripiprazole varies in view of the total amount of aripiprazole to be administered and the concentration of aripiprazole contained in each of the injectable preparations, as described above.
  • the administration of the first LAI formulation to the subject is injected intramuscularly.
  • administering intramuscularly is at a site chosen from a deltoid, a gluteal muscle, and combinations thereof.
  • the site is the gluteal muscle.
  • the injection site may encompass various locations of the deltoid and/or gluteal muscles.
  • maintenance dosing occurs once in about two months after the first day of the aripiprazole LAI treatment using a maintenance dose of the first LAI formulation; for example, maintenance dose follows once in about two months thereafter of 960 mg or 720 mg of first LAI formulation.
  • the alternative initiation regimen is applicable to both the deltoid and gluteal administration sites.
  • the methods of administering the first LAI formulation of aripiprazole disclosed herein occur at a frequency of about once every two months.
  • the first LAI formulation is administered about once every 42 to 70 days or at any integer in between and including the end points, e.g., every 49 to 63 days, e.g., every 50 to 60 days, i.e., 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 or 62 days.
  • the first LAI formulation is administered about once every 56 days, e.g., once every 54 days to 58 days.
  • the first LAI formulation is administered about once every 8 weeks, e.g., once every 6 weeks to 10 weeks.
  • the maintenance dose is 960 mg of the first LAI formulation. In some embodiments, the maintenance dose is 720 mg of the first LAI formulation.
  • the present disclosure is further directed when the patient is a CYP2D6 poor metabolizer or is taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors for greater than 14 days, the maintenance dose of the first LAI formulation is 720 mg of aripiprazole.
  • the first LAI formulation of the present disclosure can be filled as is into a syringe for use as a prefilled syringe. This simplifies the structure of the syringe and reduces size and weight.
  • the first LAI formulation comprises 960 mg of aripiprazole in a prefilled syringe. In some embodiments, the first LAI formulation comprises 720 mg of aripiprazole in a prefilled syringe.
  • a sol suspension can be administered by simply pressing the plunger rod of the syringe and ejecting the first LAI formulation of the present disclosure through a syringe needle.
  • This provides a prefilled syringe that offers clinical convenience and operability, thus is highly useful medically and industrially.
  • An example of producing such a prefilled syringe is such that the first LAI formulation is produced in the manner as described above, the formulation is prefilled into a syringe, and then left to stand in the manner as described above to cause the first LAI formulation to gel.
  • the first LAI formulation comprises 720 mg or 960 mg dose strength in pre-filled syringes and the strengths are calculated based on the anhydrous form (aripiprazole).
  • concentration of aripiprazole is 200 mg/mL to 600 mg/mL.
  • inactive ingredients are carboxymethylcellulose sodium (0.5 mg/mL to 50 mg/mL), polyethylene glycol 400 (0.05 mg/mL to 2 mg/mL), povidone (0.1 mg/mL to 100 mg/mL), sodium chloride (0.1 mg/mL to 50 mg/mL), sodium phosphate monobasic monohydrate (0.1 mg/mL to 10 mg/mL), sodium hydroxide (to adjust pH) and water for injection (q.s.).
  • the first LAI formulation comprises 720 mg or 960 mg dose strength in pre-filled syringes and the strengths are calculated based on the anhydrous form (aripiprazole).
  • Inactive ingredients are carboxymethylcellulose sodium (5 mg/mL), polyethylene glycol 400 (1 mg/mL), povidone (4 mg/mL), sodium chloride (6.1 mg/mL), sodium phosphate monobasic monohydrate (0.74 mg/mL), sodium hydroxide (to adjust pH) and water for injection (q.s.).
  • the first LAI formulation comprises 960 mg dose strength of aripiprazole in a pre-filled syringe with a volume of about 3.2 mL.
  • the first LAI formulation comprises 720 mg dose strength of aripiprazole in a pre-filled syringe with a volume of about 2.4 mL.
  • the present disclosure also includes a kit equipped with the above-described prefilled syringe.
  • a second injection comprises 400 mg or 300 mg of aripiprazole in a second LAI formulation (a once-monthly (AOM) injectable). In some embodiments, the second injection comprises 400 mg of aripiprazole in the second LAI formulation (AOM injectable). In some embodiments, the second injection comprises 300 mg of aripiprazole in the second LAI formulation (AOM injectable).
  • aripiprazole intramuscular depot formulation comprises aripiprazole monohydrate; aripiprazole monohydrate is 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydrocarbostyril monohydrate.
  • the second injection is aripiprazole intramuscular (IM) depot formulation which is an extended-release injectable suspension in 400-mg or 300-mg strength in pre-filled dual chamber syringes and 400-mg or 300-mg strength vials.
  • the second injection comprising 400 mg or 300 mg of aripiprazole in a second LAI formulation includes lyophilized powder or lyophilized cake for injectable suspension.
  • the labeled strengths are calculated based on the anhydrous form (aripiprazole).
  • inactive ingredients (per administered dose) for 400-mg and 300-mg strength products include carboxymethyl cellulose sodium (16.64 mg and 12.48 mg), mannitol (83.2 mg and 62.4 mg), sodium phosphate monobasic monohydrate (1.48 mg and 1.11 mg) and sodium hydroxide (pH adjuster).
  • the extended-release injectable suspension in 400-mg or 300-mg strength in pre-filled dual chamber syringes and 400-mg or 300-mg strength vials can be used to make dosage adjustments; that is, in patients who are CYP2D6 poor metabolizers and in patients taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors.
  • Dosage adjustments for 200 mg and 160 mg can be obtained by using the 300-mg or 400-mg strength vials for intramuscular deltoid or gluteal injection for patients taking CYP2D6 inhibitors, CYP3A4 inhibitors, or CYP3A4 for greater than 14 days.
  • the presently disclosed second LAI formulation (aripiprazole IM depot formulation), Abilify Maintena(R), for suspension in an extended-release form is described in U.S. Pat. Nos.
  • 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 29% 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.
  • the extent of absorption (AUCt, AUC ⁇ ) of aripiprazole was similar for both injection sites, but the rate of absorption (Cmax) was 31% higher following administration to the deltoid compared to the gluteal site.
  • AUC and Cmax were similar for both sites of injection.
  • the plasma concentrations of aripiprazole gradually rise to maximum plasma concentrations at a median Tmax of about 5-7 days for the gluteal muscle and about 4 days for the deltoid muscle.
  • the mean apparent aripiprazole terminal elimination half-life was about 29.9 days and about 46.5 days after multiple injections for every 4-week injection of the aripiprazole intramuscular depot formulation 300 mg and 400 mg, 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 300 mg and 400 mg.
  • 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 methods of the present disclosure comprise administering a single dose of oral aripiprazole.
  • the dose of oral aripiprazole ranges from about 10 mg to about 20 mg of aripiprazole.
  • the dose of oral aripiprazole is 20 mg.
  • the dose of oral aripiprazole is 10 mg.
  • the methods are administered when the patient has or has not been previously stabilized on oral aripiprazole before the treatment. In some embodiments, the methods are administered when the patient has been previously stabilized on oral aripiprazole before the treatment. In some embodiments, the methods are administered when the patient has not been previously stabilized on oral aripiprazole before the treatment.
  • oral tablets of aripiprazole are available in, e.g., 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg 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. 2 Aluminum Lake.
  • Aripiprazole is well absorbed after administration of a tablet, with peak plasma concentrations occurring, e.g., within 3 hours 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.
  • administration of a 15 mg oral tablet of aripiprazole with a standard high-fat meal did not significantly affect the Cmax or AUC of aripiprazole or its active metabolite, dehydro-aripiprazole, but delayed Tmax by 3 hours for aripiprazole and 12 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 40% of aripiprazole AUC in plasma.
  • the present disclosure utilizes an oral tablet of aripiprazole at a single oral dose chosen from about 10 mg to about 20 mg, such as single oral doses of 10 mg, 15 mg, and 20 mg of aripiprazole.
  • the single oral dose ranges from about 10 mg to about 20 mg of aripiprazole, such as about 20 mg of aripiprazole.
  • the single oral dose is chosen from 10 mg and 20 mg of aripiprazole.
  • the single oral dose is 20 mg of aripiprazole.
  • the single oral dose is 10 mg of aripiprazole.
  • the present disclosure is directed to methods comprising wherein the patient is a CYP2D6 poor metabolizer or is taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors for greater than 14 days, the first injection comprises 720 mg of aripiprazole, the second injection comprises 300 mg of aripiprazole, and the single dose of oral aripiprazole comprises about 20 mg of aripiprazole.
  • the present disclosure is directed to methods comprising wherein the first injection comprises 960 mg of aripiprazole, the second injection comprises 400 mg of aripiprazole, and the single dose of oral aripiprazole comprises about 20 mg of aripiprazole.
  • PK data from ten clinical trials were used for the development of the popPK model.
  • Data for oral aripiprazole and AOM injected at the gluteal or deltoid site were from a previously developed and validated popPK model, as described by Wang and colleagues.[Wang et al. 2021]
  • the previous model was expanded to include data for the RTU LAI formulation of aripiprazole, which were derived from three clinical trials undertaken in 374 patients with schizophrenia or BP-I. Across the three trials, 240 patients received at least one dose of Ari RTU LAI. In all, the final combined analysis dataset comprised 1,191 individuals with 8,899 aripiprazole concentration samples.
  • the starting point for the popPK model development was the prior popPK model for oral aripiprazole and AOM, as described above. In brief, this was a 3 compartment model with linear elimination, sigmoid absorption (zero order followed by first order) for oral administration, and first-order absorption for the AOM formulation. Covariate effects included: CYP2D6 metabolizer status on apparent clearance (CL/F); co administration of strong inhibitors of CYP2D6 or CYP3A4 on clearance; and the effect of gender and body mass index (BMI) on the first-order absorption rate constant (Ka) for the AOM formulation.
  • CL/F apparent clearance
  • BMI body mass index
  • PK data for the Ari RTU LAI formulation were added to the analysis data, and an absorption compartment specific to the Ari RTU LAI formulation was added to the model. Covariate effects from the prior model for oral aripiprazole and AOM were retained, while additional covariates related to the absorption and relative bioavailability of the Ari RTU LAI formulation were explored (i.e., injection site and volume). Age, gender, and BMI were also evaluated as standard demographic variables. As a first step, potential relationships were investigated graphically by plotting individual random effects versus covariates (scatter plots for continuous covariates, side-by-side box plots for categorical covariates).
  • the goodness of fit of the final model was assessed by standard diagnostic plots (e.g., observed concentration versus population predictions [PRED], observed concentration versus individual predictions, conditional weighted residuals [CWRES] versus PRED and time after first dose).
  • the predictive performance of the final model was evaluated using visual predictive checks (VPCs) by simulating 500 replicates of the combined dataset. If significant categorical covariate effects were identified in the final model, simulations were performed to visualize these effects on the concentration-time profile following repeated administration of Ari 2MRTU 960.
  • aripiprazole plasma concentrations were assayed using validated high-performance liquid chromatography with tandem mass spectrophotometry.
  • a linear calibration curve was used, with the calibration range varying across the different trials, as follows: 1-250 ng/mL in Studies 31-98-206, 31-98-207, and CN138020; 0.5-250 ng/mL in Studies 31-05-244 and 31-07-246; and 0.5-500 ng/mL in Studies 31-11-290, 31-12-298, 031-201-00104, 031-201-00181, and 031-201-00279.
  • missed/delayed doses to evaluate the impact of a lack of adherence, as defined by different scenarios, with Ari 2MRTU 960 doses delayed by 2, 4, 6, and 8 weeks
  • CYP2D6 metabolizer status to evaluate lower dosing in CYP2D6 poor metabolizers
  • drug-drug interactions to evaluate lower dosing with concomitant use of strong inhibitors of CYP2D6 or CYP3A4.
  • PK parameters for the virtual patients were derived from patient covariates and random effects according to the popPK model and were used to simulate individual PK profiles according to each dosing scenario.
  • Model covariates i.e., gender, BMI, and CYP2D6 metabolizer status, as included in the popPK model
  • random effects and covariates were resampled from individuals with the most relevant and robust information for each parameter of interest.
  • the virtual patient population remained constant, comprising a mixture of normal and poor metabolizers of CYP2D6 as obtained by the resampling procedure with poor metabolizers making up approximately 5% of the population.
  • the only exception to this was for scenarios that required all patients to be normal or poor CYP2D6 metabolizers; in this situation, the status was changed accordingly for the whole virtual patient population.
  • the site of administration was the gluteal muscle to allow easier comparison to Ari RTU LAI, which is gluteal only.
  • Rich PK profiles were simulated by sampling concentrations every 2 hours post-dose for 24 hours following oral dosing and every 24 hours post-dose following AOM or Ari RTU LAI dosing.
  • the popPK model was developed using non-linear mixed effects modeling software (NONMEM v7.4.2; Icon Development Solutions, Ellicott City, MD, USA). Estimation was performed by first-order conditional estimation with interaction; if satisfactory convergence could not be achieved, estimation was performed by stochastic approximation expectation-maximization followed by importance sampling for evaluating the MVOF. Data preparation, graphical analysis, model diagnostics, and statistical summaries were performed using R (v4.0.5 and above; R Foundation for Statistical Computing, Vienna, Austria) and RStudio (v1.2.5042 and above; RStudio, Inc.). All simulations were performed using Pumas (v2.0; Pumas-AI, Inc., Centreville, VA, USA).
  • the model that best fit the data was a 3-compartment model with linear elimination and different absorption models for the oral, AOM, and Ari RTU LAI formulations (FIG. 1).
  • FIG. 1 *Vc/F has a different numerical value for the Ari RTU LAI formulation.
  • AOM 400 is aripiprazole once-monthly 400 mg; Ari is aripiprazole; CL/F is apparent clearance; F rel,AOM is relative bioavailability of the AOM formulation; F rel,LAI is relative bioavailability of the Ari RTU LAI formulation; K a,deltoid is absorption rate constant for the AOM formulation at the deltoid site; K a,gluteal is absorption rate constant for the AOM formulation at the gluteal site; K a,LAI is absorption rate constant for the Ari RTU LAI formulation; K a,oral is absorption rate constant for the oral formulation; LAI is long acting injectable; Q 1 /F is apparent inter-compartmental clearance 1; Q 2 /F is apparent inter-compartmental clearance 2; RTU is ready-to-use; Vc/F is apparent central volume; Vp 1 /
  • Absorption of the Ari RTU LAI formulation was modeled by a parallel zero-order and lagged first-order process that accounted for the complex absorption process inherent to LAIs.
  • Absorption of the Ari RTU LAI formulation was parameterized by the fraction of total dose absorbed by the first-order process rather than the zero-order process (FRAC1), the duration of zero-order absorption (DUR0), the time lag for the start of the first-order process (LAG1), the absorption rate constant for the first-order process (K a RTU), and bioavailability of the Ari RTU LAI formulation relative to the oral formulation (F relative RTU).
  • Table 1 Pharmacokinetic parameters for the final aripiprazole population pharmacokinetic model.
  • AOM aripiprazole once-monthly
  • Ari aripiprazole
  • BMI body mass index
  • CV coefficient of variation
  • CYP cytochrome P450
  • K a first-order absorption rate constant
  • LAI long-acting injectable
  • NA not applicable
  • RSE relative standard error
  • RTU ready-to-use
  • SD standard deviation.
  • the first peak in concentration occurred at 6.75 days (162.1 hours) post-dose for the Ari RTU LAI formulation.
  • the fractions absorbed by the first-order and zero-order processes were 79.3% and 20.7%, respectively, in females and 62.7% and 37.3%, respectively, in males.
  • First-order absorption started after a lag of 17.5 days (419 hours).
  • the K a was 0.00127 per hour, corresponding to an absorption half-life of 22.7 days.
  • males the K a was 0.00242 per hour, corresponding to an absorption half-life of 11.9 days.
  • the second peak occurred at 41 days post-dose in a typical female and at 32 days post-dose in a typical male.
  • the second peak occurred at 33 days post-dose in a typical female and at 28 days post-dose in a typical male.
  • F relative of the Ari RTU LAI formulation was 1.58 versus the oral formulation and 1.06 versus the AOM formulation.
  • K a RTU i.e., the absorption rate constant
  • FRAC1 i.e., the fraction of first-order absorption
  • Typical PK profiles were simulated for covariate combinations of interest, with all other covariates fixed to their reference values and all random effects fixed to zero. These were plotted on the same graph for visual comparison over 48 weeks (i.e., 6 consecutive administrations of Ari 2MRTU 960 dosed 8 weeks apart), with average concentration at steady state (C avg,ss ), C max,ss , and C min,ss compared across covariate categories. Since CYP2D6 metabolizer status was identified as a covariate on the CL/F of aripiprazole in the prior model, and was retained in the current analysis, simulations were performed separately for poor and normal metabolizers of CYP2D6.
  • Ari 2MRTU 960 aripiprazole 2-month ready-to-use 960 mg; C avg,ss , average concentration at steady state; C max,ss , maximum concentration at steady state; C min,ss , minimum concentration at steady state; CYP, cytochrome P450.
  • FIG. 3 circles represent observed data.
  • Solid black lines in the figures in the upper panel represent a line of unity.
  • Solid black lines in the figures in the lower panel indicate the zero intercept.
  • Black dashed lines with conditional weighted residuals equal to ⁇ 4 are provided as reference lines to check for potential outliers.
  • Grey dashed lines represent a locally estimated scatterplot smoother.
  • the abbreviation AOM is aripiprazole once-monthly; and Ari RTU LAI is aripiprazole ready-to-use long-acting injectable.
  • the predictive performance of the model was considered adequate based on prediction-corrected VPC (pcVPC) and non-parametric VPC. Overall, the pcVPC showed good predictive performance of the final model (FIG. 4), as evidenced by distributions of the observed data that were comparable with the 90% prediction intervals for the individual predictions.
  • dashed lines represent observed data (median; 5 th and 95 th percentile, black).
  • Solid lines represent simulated data (median; 5 th and 95 th percentile, black). Shaded regions represent the 95% confidence interval of the simulated median and the 5 th and 95 th percentile.
  • AOM is aripiprazole once-monthly
  • Ari RTU LAI is aripiprazole ready-to-use long-acting injectable.
  • the final popPK model was used to simulate aripiprazole plasma concentration-time profiles as a means of exploring aspects of Ari 2MRTU dosing, reflecting various scenarios that might arise in clinical practice.
  • Ari 2MRTU 960 resulted in plasma concentrations of aripiprazole that were comparable to AOM 400. This was the case for: initiation of Ari 2MRTU 960 following a switch from AOM 400 (FIG. 5A); initiation of Ari 2MRTU 960 plus 14 days of overlapping oral aripiprazole in patients previously stabilized on oral aripiprazole 10 or 20 mg/day (FIGs. 5B and 5C); initiation of Ari 2MRTU 960 plus 14 days of overlapping oral aripiprazole in patients not previously stabilized on oral aripiprazole (FIGs.
  • FIG. 5D and 5E initiation of Ari 2MRTU 960 on Day 28 following administration of AOM 400 on Day 0 plus 14 days of overlapping oral aripiprazole in patients previously stabilized on oral aripiprazole 20 mg/day
  • FIG. 5F initiation of Ari 2MRTU 960 on Day 28 following administration of AOM 400 on Day 0 plus 14 days of overlapping oral aripiprazole 20 mg/day in patients not previously stabilized on oral aripiprazole
  • FIG. 7 is a graph of simulated median aripiprazole concentration-time profile for Ari 2MRTU 960 on Day 28 following AOM on Day 0 (with overlapping oral aripiprazole 20 mg in patients without prior oral aripiprazole stabilization).
  • FIG. 7 includes a solid black line, representing simulation results for the same patients treated with AOM 400 on Days 28 and 56.
  • Reference lines represent the plasma concentration identified as the lower efficacy threshold for the prevention of impending relapse (95 ng/mL), and 75th percentile of simulated C max,ss following a daily dose of oral aripiprazole 30 mg (534 ng/mL).
  • each figure includes a solid black line, representing simulation results for the same patients treated with AOM 400 (with the same oral overlap, where relevant).
  • Reference lines represent the plasma concentration identified as the lower efficacy threshold for the prevention of impending relapse (95 ng/mL), and 75th percentile of simulated C max,ss following a daily dose of oral aripiprazole 30 mg (534 ng/mL).
  • the abbreviation for AOM 400 is aripiprazole once-monthly 400 mg; Ari 2MRTU 960 is aripiprazole 2-month ready-to-use 960 mg; and C max,ss is maximum concentration at steady state.
  • a red line representing simulation results for the same patients treated with Ari 2MRTU 960 on Day 0 with overlapping oral aripiprazole 10 mg or 20 mg on Day 0-13.
  • Figure 8D includes solid red and dotted green lines, representing simulation results for the same patients treated with Ari 2MRTU 960 on Day 0 with overlapping oral aripiprazole 10 mg or 20 mg, respectively, on Day 0-13.
  • Reference lines represent the plasma concentration identified as the lower efficacy threshold for the prevention of impending relapse (95 ng/mL), and the 75 th percentile of simulated C max,ss following a daily dose of oral aripiprazole 30 mg (534 ng/mL).
  • AOM 400 is aripiprazole once-monthly 400 mg
  • Ari 2MRTU 960 is aripiprazole 2-month ready-to-use 960 mg
  • C max,ss is maximum concentration at steady state.
  • Simulated median Aripiprazole concentration with a two-injection start in CYP2D6 poor metabolizers i.e., Ari 2MRTU 720 plus AOM 300 at separate injection sites plus a single dose of oral aripiprazole 20 mg, all on the first day of treatment
  • Reference lines represent median C min,ss following a daily dose of 10 mg oral aripiprazole (94.0 ng/mL), 75 th percentile of C max,ss following a daily dose of 30 mg oral aripiprazole (534 ng/mL), and 95 th percentile of C max,ss following a daily dose of 30 mg oral aripiprazole (741 ng/mL).
  • Missed/delayed doses were simulated to explore the impact of imperfect adherence with Ari 2MRTU 960 (FIG. 6).
  • trough median plasma concentrations at the time of dosing were 191 ng/mL, 144 ng/mL, 110 ng/mL, and 80.1 ng/mL respectively.
  • trough median plasma concentrations had increased to 231 ng/mL, 217 ng/mL, 205 ng/mL, and 196 ng/mL, respectively (in the last case, the dose was given with 14 days of overlapping oral aripiprazole 10 mg/day).
  • reference lines represent the plasma concentration identified as the lower efficacy threshold for the prevention of impending relapse (95 ng/mL),[Wang et al., 2022] and 75th percentile of simulated C max,ss following a daily dose of oral aripiprazole 30 mg (534 ng/mL).
  • the abbreviation Ari 2MRTU 960 is aripiprazole 2-month ready-to-use 960 mg and C max,ss is maximum concentration at steady state.
  • Ari 2MRTU 720 was simulated in CYP2D6 poor metabolizers, with results demonstrating non-inferior steady-state concentrations of aripiprazole versus AOM 300 (FIG. 9).
  • FIG. 9 for comparative purposes, the figure includes a solid black line, representing simulation results for the same patients treated with AOM 300.
  • Reference lines represent the plasma concentration identified as the lower efficacy threshold for the prevention of impending relapse (95 ng/mL), and the 75 th percentile of simulated C max,ss following a daily dose of oral aripiprazole 30 mg (534 ng/mL).
  • AOM 300 is aripiprazole once-monthly 300 mg
  • Ari 2MRTU 720 is aripiprazole 2-month ready-to-use 720 mg
  • C max,ss is maximum concentration at steady state
  • CYP is cytochrome P450.
  • Ari 2MRTU 720 plus a concomitant CYP3A4 strong inhibitor resulted in median steady-state plasma concentrations that were comparable to Ari 2MRTU 960 without a concomitant CYP3A4 or CYP2D6 strong inhibitor.
  • administration of Ari 2MRTU 720 with a concomitant CYP2D6 strong inhibitor resulted in higher median steady-state plasma concentrations versus Ari 2MRTU 960 without a concomitant CYP3A4 or CYP2D6 strong inhibitor (FIG. 10).
  • FIG. 10 for comparative purposes, the figure includes a solid black line, representing simulation results for the same patients treated with Ari 2MRTU 960.
  • Reference lines represent the plasma concentration identified as the lower efficacy threshold for the prevention of impending relapse (95 ng/mL),[Wang et al 2022] and the 75 th percentile of simulated C max,ss following a daily dose of oral aripiprazole 30 mg (534 ng/mL).
  • the abbreviations are Ari 2MRTU 720 is aripiprazole 2-month ready-to-use 720 mg; Ari 2MRTU 960 is aripiprazole 2-month ready-to-use 960 mg; Cmax,ss is maximum concentration at steady state; and CYP is cytochrome P450.
  • PopPK analyses are a well-established quantitative means of explaining variability in drug concentrations among individuals, including as a result of intrinsic factors, extrinsic factors, differences in dosing, and routes of administration. Such analyses are frequently undertaken as part of the drug development process to inform dosing regimens to be tested in future clinical trials. PopPK models can also be used to simulate PK profiles for scenarios that are beyond those that have been clinically studied.
  • aripiprazole PK following administration of Ari RTU LAI was best characterized by a linear 3-compartment model with parallel zero- and lagged first-order absorption.
  • gender was identified as a statistically significant covariate; specifically, gender was found to affect the fraction of first-order absorption and the first-order K a , with faster absorption observed in males versus females.
  • the final popPK model was used to conduct simulations to evaluate dosing of Ari 2MRTU 960 and Ari 2MRTU 720 across multiple realistic clinical situations.
  • Various treatment initiation scenarios were simulated, which accounted for different prior treatments (i.e., whether or not patients were stabilized on oral aripiprazole or AOM 400).
  • the use of overlapping oral aripiprazole for 14 days, or a two-injection start with Ari 2MRTU 960 plus AOM and a single dose of oral aripiprazole, were also simulated as a means of more rapidly reaching exposures in the therapeutic range, given the very slow absorption of Ari 2MRTU 960.
  • the data presented here provide clinicians with useful information regarding a variety of dosing scenarios for a two-monthly RTU LAI formulation of aripiprazole. It is impractical/infeasible to include all potential dosing scenarios in efficacy and safety trials, but popPK modelling and simulation addresses this, by generating PK profiles for scenarios beyond those specifically studied as part of the clinical trial program. In this manner, modelling and simulations act as ‘virtual’ clinical trials, allowing more scenarios to be investigated than could be conducted in real-life clinical trials. Nonetheless, any simulations presented here must be viewed in context with the approved use of Ari 2MRTU 960 and Ari 2MRTU 720, according to patient type, prior treatment, and/or country/region.
  • the popPK model was developed to characterize the PK of Ari 2MRTU 960, which was then used to perform model-based simulations exploring various aspects of dosing of this novel formulation.
  • the final model was considered fit for purpose, adequately describing the PK of plasma aripiprazole concentrations following administration of Ari 2MRTU 960; the model also established estimates for key popPK parameters and identified sources of variability in drug exposure. Simulations across a variety of dosing regimens that could reasonably be encountered in clinical practice demonstrated a PK exposure profile that was comparable to AOM, with a longer dosing interval.
  • 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.
  • the disclosure encompasses all variations, combinations, and permutations in which at least one limitation, element, clause, and descriptive term from at least one of the listed claims is introduced into another claim.
  • any claim that is dependent on another claim can be modified to include at least one limitation found in any other claim that is dependent on the same base claim.
  • elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should be understood that, in general, where the disclosure, or aspects of the disclosure, is/are referred to as comprising particular elements and/or features, embodiments of the disclosure or aspects of the disclosure consist, or consist essentially of, such elements and/or features.

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Abstract

La présente invention concerne des procédés d'initiation de dose pour un traitement par aripiprazole à un patient en ayant besoin par l'administration de deux injections séparées d'aripiprazole avec une première injection d'aripiprazole d'un injectable à action prolongée (LAI) et une seconde injection d'aripiprazole d'un injectable une fois par mois (AOM) le premier jour du traitement par aripiprazole, et d'une dose unique d'aripiprazole par voie orale. Le dosage d'entretien se produit environ deux mois après le premier jour du traitement par aripiprazole à l'aide d'une dose d'entretien de la LAI. Les présents procédés sont applicables à la fois aux sites d'administration deltoïde et fessier.
PCT/JP2024/016465 2023-04-26 2024-04-26 Initiation de dose pour le traitement de la schizophrénie ou du trouble bipolaire i avec de l'aripiprazole Pending WO2024225441A1 (fr)

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CN202480025527.1A CN120957722A (zh) 2023-04-26 2024-04-26 用阿立哌唑治疗精神分裂症或i型双相障碍的剂量启动
AU2024263986A AU2024263986A1 (en) 2023-04-26 2024-04-26 Dose initiation for schizophrenia or bipolar i disorder treatment with aripiprazole
IL324134A IL324134A (en) 2023-04-26 2025-10-22 Starting dose for the treatment of schizophrenia or bipolar I disorder with aripiprazole
MX2025012679A MX2025012679A (es) 2023-04-26 2025-10-23 Inicio de dosis para el tratamiento de la esquizofrenia o el trastorno bipolar i con aripiprazol

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