Aripiprazole dosing strategy

Abstract

To provide an improved method of delivering antipsychotics to improve the patient compliance and maximize the pharmacological profile of an active agent.SOLUTION: The present invention relates to methods of treating schizophrenia using a combination of aripiprazole, aripiprazole lauroxil, and a nanoparticle dispersion of aripiprazole lauroxil.SELECTED DRAWING: None

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims priority based on U.S. Provisional Patent Application No. 62 / 638,587, filed on March 5, 2018. The entire content of this application is incorporated herein by reference.

Background Art

[0002] Schizophrenia is a severe neuropsychiatric disorder that typically onsets in late adolescence or early adulthood. It is characterized by distorted perceptions of reality (hallucinations and delusions), social deficits, disorganized speech and behavior, and mild cognitive impairment. It is a destructive and relatively common disorder that affects approximately 1% of the world's population.

[0003] Patients with schizophrenia require long - term antipsychotic therapy. One limitation of long - acting injectable (LAI) antipsychotic therapy is that some LAI regimens require an oral induction (initiation) regimen that lasts for 2 - 3 weeks to achieve the initial therapeutic concentration. See, for example, Brissos, S. et al. Therapeutic Advances in Psychopharmacology, 2014, 4(5), 198 - 219; Citrome, L. Expert Review of Neurotherapeutics, 2017, 17(10), 1029 - 1043. These oral induction regimens can be difficult for patients who do not want to take pills or for patients who start LAI therapy in the hospital but need to continue the oral induction for some time after discharge.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Patent Document 6

Patent Document 7

Patent Document 8

Patent Document 9

Non-Patent Document

[0005]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Summary of the Invention

Problems to be Solved by the Invention

[0006] Therefore, there is a need for an improved method of delivering antipsychotic drugs that improves patient compliance and maximizes the pharmacological profile of the active agent.

Means for Solving the Problems

[0007] A method of treating schizophrenia in a subject in need thereof, comprising administering to the subject a combination of aripiprazole, a nanoparticle dispersion of aripiprazole lauroxil (AL NCD ) and a long-acting injection (LAI) of aripiprazole lauroxil is provided herein. Conventional administration of the LAI of aripiprazole lauroxil requires a 21-day oral introduction (initiation) of aripiprazole. In contrast, the combination described herein requires only a 1- to 3-day oral aripiprazole introduction period. This minimized introduction period has several advantages, including increased patient compliance.

[0008] Accordingly, in one aspect, a method of treating schizophrenia in a subject in need thereof, comprising a first component comprising about 5 to 50 mg of aripiprazole; a second component comprising about 629 to 695 mg of AL NCD ; and a third component comprising a therapeutically effective amount of aripiprazole lauroxil is provided herein, the method comprising administering the components to the subject in any order.

[0009] In one embodiment, the components of the invention can be administered in any order.

[0010] In one embodiment, all components are pharmaceutical compositions comprising the active ingredients listed above and a pharmaceutically acceptable carrier.

[0011] In one embodiment, AL NCD comprises polysorbate 20, sodium citrate, sodium chloride, an aqueous buffer, and a population of particles of aripiprazole lauroxil. In another embodiment, the population of particles of aripiprazole lauroxil has a volume-based particle size distribution diameter (Dv50) of less than about 1000 nm. In one embodiment, the population of particles of aripiprazole lauroxil has a volume-based particle size distribution diameter (Dv50) between about 175 nm and about 350 nm. In one embodiment, AL NCDhas a ratio of particles to polysorbate 20 of from about 0.1:1 to about 40:1. In one embodiment, AL NCD has a ratio of particles to polysorbate 20 of 17:1. In one embodiment, AL NCD comprises about 26% by mass of aripiprazole lauroxil particles, about 1.53% by mass of polysorbate 20, about 0.76% by mass of sodium citrate, 0.31% by mass of sodium chloride, and an aqueous buffer; the aripiprazole lauroxil particles have a volume-based particle size distribution diameter (Dv50) between about 175 nm and about 350 nm.

[0012] In one embodiment, the first component is administered at a dose of about 30 mg of aripiprazole. In another embodiment, the first component is administered at a dose of about 15 mg of aripiprazole. In yet another embodiment, the second component is administered at a dose of about 675 mg of aripiprazole lauroxil. In another embodiment, the second component is administered at a dose of about 677 mg of aripiprazole lauroxil. In still another embodiment, the third component is administered at a dose of about 300 to 1500 mg of aripiprazole lauroxil. In one embodiment, the third component is administered at a dose of 441, 662, 882 or 1064 mg.

[0013] The components can be administered substantially simultaneously (i.e., generally within a few minutes of each other, or within the time it takes for a person of ordinary skill in the medical or pharmaceutical arts to administer the components). In one embodiment, all of the components of the method are administered substantially simultaneously. In another embodiment, the method includes a regimen in which a first, second, and third component are administered substantially simultaneously and the first component is not readministered within 21 days of the first administration. In yet another embodiment, the method includes a regimen in which a first, second, and third component are administered substantially simultaneously and a second administration of the component is made after 21 days from the first treatment. In still another embodiment, the method includes a regimen in which a first, second, and third component are administered substantially simultaneously and a second treatment including administering only the third component follows. In one embodiment, any or all of the second treatments of the components are made after 21 days from the first treatment. In one embodiment, the first component is administered only once during the treatment period. In one embodiment, the first component is not readministered within 21 days after the first treatment.

[0014] In one embodiment, the method includes a regimen in which the first component is administered only on the first and / or second day of treatment, the second component is administered only on the first day of treatment, and the third component is administered only once within the first 10 days of treatment. In another embodiment, the regimen further includes a second administration of only the third component. In yet another embodiment, the third component is administered on the first day of treatment. In still another embodiment, the third component is administered on the second day of treatment. In one embodiment, the third component is administered 7 to 10 days after the start of the treatment regimen. In another embodiment, the third component is administered 3 to 6 days after the start of the treatment regimen. In yet another embodiment, the first component is administered only on the first and second days of treatment. In still another embodiment, the first component is administered only on the first day of treatment.

[0015] In one embodiment, the first component is administered orally. In one embodiment, the second component is administered intramuscularly. In one embodiment, the second component is administered intramuscularly to the deltoid or gluteal muscle. In one embodiment, the second component is administered intramuscularly to the deltoid muscle. In one embodiment, the third component is administered intramuscularly. In one embodiment, the third component is administered intramuscularly to the deltoid or gluteal muscle.

[0016] In another aspect, a method of treating schizophrenia in a subject in need thereof, a first component comprising aripiprazole; AL NCD a second component comprising; a third component comprising aripiprazole lauroxil administering to the subject, the combined dosage of the first, second and third components is sufficient to maintain a therapeutically effective average plasma level of aripiprazole in the subject, A method is provided herein. Figure 8 shows the average plasma levels obtained using this method.

[0017] In one embodiment, the therapeutically effective average plasma level of aripiprazole is about 102 - 435 ng / mL at steady state plasma level. In one embodiment, the therapeutically effective average plasma level of aripiprazole is greater than about 102 ng / mL at steady state plasma level. In one embodiment, the therapeutically effective average plasma level of aripiprazole is less than about 435 ng / mL at steady state plasma level. In one embodiment, the therapeutically effective average plasma level of aripiprazole is between about 102 ng / mL and about 435 ng / mL at steady state plasma level. In one embodiment, the therapeutically effective average plasma level of aripiprazole is reached within 24 hours of the first treatment. In one embodiment, the therapeutically effective average plasma level of aripiprazole is maintained for 21 days or more.

[0018] In another aspect, a kit for treating schizophrenia, comprising a therapeutically effective amount of a first component comprising aripiprazole; AL NCD a second component comprising; a third component comprising aripiprazole lauroxil and comprising, further comprising instructions for administration, the instructions specifying oral administration of the first component, intramuscular administration of the second component, and intramuscular administration of the third component, a kit is provided herein.

Brief Description of the Drawings

[0019]

Figure 1

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Figure 8

DETAILED DESCRIPTION OF THE INVENTION

[0020] Aripiprazole lauroxil (AL), a prodrug of the atypical antipsychotic aripiprazole, is available as a long-acting intramuscular (IM) injection indicated for the treatment of schizophrenia. See, for example, Meltzer, H.Y. et al., J. Clin. Psychiatry, 2015, 76(8), 1085-1090. Treatment with AL can be initiated in patients at any of four available doses: 441 mg, 662 mg, 882 mg, or 1064 mg. The dissolution characteristics of AL allow for long dosing intervals. For example, there is a 1064 mg AL dose specifically indicated as a 2-month dosing interval option. The slow dissolution of AL results in an initial delay between the first AL injection and the attainment of effective concentrations of aripiprazole. Currently, a 21-day oral aripiprazole supplementation is required with the first AL administration to provide a sufficient antipsychotic effective range during treatment initiation.

[0021] The oral requirements on day 21 pose the issue of being able to be prematurely discontinued as oral medication. In the context of starting AL, too early discontinuation of oral aripiprazole supplementation at the start may lead to a decrease in aripiprazole levels below the therapeutic plasma concentration. Therefore, it is necessary to provide an alternative starting regimen for AL that does not require continued oral supplementation.

[0022] The combinations and dosing strategies described herein address this need. A Phase 1 pharmacokinetic (PK) study showed that AL NCD on day 1 (1-day starting regimen) and a single 30 mg oral aripiprazole tablet resulted in aripiprazole plasma concentrations similar to the 21-day starting regimen when starting with AL441 or 882 mg. Thus, a method of treating schizophrenia in a subject in need thereof, comprising administering to the subject a first component comprising aripiprazole; AL NCD a second component comprising; and a third component comprising a therapeutically effective amount of aripiprazole lauroxil is provided herein. In one embodiment, the first component is administered at a dose of about 30 mg, the second component is administered at a dose of about 675 mg, and the third component is administered at a dose of 441, 662, 882 or 1064 mg. In yet another embodiment, the first component is administered at a dose of about 30 mg, the second component is administered at a dose of about 677 mg, and the third component is administered at a dose of 441, 662, 882 or 1064 mg. In another embodiment, the combined dose of the first, second and third components is sufficient to maintain a therapeutically effective average plasma level of aripiprazole in the subject. The threshold for the therapeutically effective average plasma level of aripiprazole is about 102 ng / mL. Figure 8 shows that the 662 and 882 mg doses of AL NCD in combination with aripiprazole and aripiprazole lauroxil result in average plasma levels above the threshold.

[0023] The FDA has also established a maximum threshold for the acceptable average plasma level of 435 ng / mL. Figures 7A, 7B, and 7C show scatter plots of the average plasma levels of aripiprazole after injection of only AL NCD at doses of 441 mg (Figure 7A), 662 mg (Figure 7B), and 882 mg (Figure 7C). As demonstrated by these figures, the 882 mg dose of AL NCD results in average plasma levels above the maximum level recommended by the FDA.

[0024] Definitions The definitions of the various terms used herein are listed below. These definitions apply to the terms used throughout this specification and the claims, individually or as part of a larger group, unless limited to specific examples.

[0025] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In general, the nomenclature used herein, as well as the experimental procedures of cell culture, molecular genetics, organic chemistry, and peptide chemistry, are well known and commonly used in the art.

[0026] As used herein, the articles "a" and "an" refer to one or more (i.e., at least one) of the grammatical objects of the article. By way of example, "an element" means one element or more than one element. Further, the use of the term "including" and other forms such as "include", "includes", and "included" is not limiting.

[0027] As used herein, the term "about" is understood by those of ordinary skill in the art and varies somewhat depending on the context in which it is used. As used herein, when referring to measurable values such as amounts, durations of time, etc., the term "about" is intended to encompass variations of ±20% or ±10%, including ±5%, ±1%, and ±0.1% from the specified value, when such variations are appropriate for carrying out the disclosed method.

[0028] As used in this specification and the claims, the term "comprising" may include embodiments of "consisting of" and "consisting essentially of". The terms "comprise(s)", "include(s)", "having", "has", "may", "contain(s)" and variations thereof are intended, as used herein, to be open-ended transitional phrases, terms or words that require the presence of the indicated component / step and permit the presence of other components / steps. However, such descriptions should also be construed as describing a composition or method as "consisting of" and "consisting essentially of" the recited compounds, which permits only the presence of the indicated compounds and any pharmaceutically acceptable carriers and excludes other compounds.

[0029] As used herein, the terms "treat", "treated", "treating" or "treatment" include the alleviation or reduction of at least one symptom associated with or caused by the condition, disorder or disease being treated. For example, treatment can be the alleviation of one or several symptoms of a disorder.

[0030] As used herein, the terms "prevent" or "prevention" mean, when nothing has occurred, the absence of the onset of a disorder or disease, or when a disorder or disease has already occurred, the absence of the onset of further disorders or diseases. Also considered is the ability to prevent some or all of the symptoms associated with a disorder or disease.

[0031] As used herein, the term "use" includes any one or more of the following embodiments of the present invention: Unless otherwise specified, as appropriate and when convenient, use in the treatment of schizophrenia, for example, use in the manufacture of pharmaceutical compositions for use in the treatment of these diseases, such as use in the manufacture of pharmaceuticals; methods of using the compounds of the present invention in the treatment of these diseases; pharmaceutical preparations having the compounds of the present invention for treating these diseases; and compounds of the present invention for use in the treatment of these diseases.

[0032] As used herein, the terms "patient", "individual" or "subject" are intended to include organisms that may suffer from or be afflicted with a disease, disorder or condition associated with the activity of a protein kinase, such as prokaryotes and eukaryotes. Examples of subjects include mammals such as humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats and transgenic non-human animals. In certain embodiments, the subject is a human, such as a human suffering from, at risk of suffering from or potentially suffering from schizophrenia. In another embodiment, the subject is a cell.

[0033] As used in connection with the methods of treatment / prevention and the use of the compounds and pharmaceutical compositions thereof described herein, an "individual in need thereof" can be an individual diagnosed with or previously treated for the condition to be treated. For prevention, an individual in need thereof can also be an individual at risk for the condition (e.g., family history of the condition, lifestyle factors indicating risk for the condition, etc.). Typically, when the step of administering a compound of the invention is disclosed herein, the invention further contemplates the step of identifying an individual or subject in need of or being treated for a particular treatment or having a particular condition to be treated.

[0034] In some embodiments, the individual is a mammal including, but not limited to, cows, horses, cats, rabbits, dogs, rodents or primates. In some embodiments, the mammal is a primate. In some embodiments, the primate is a human. In some embodiments, the individual is a human including adults, children and premature infants. In some embodiments, the individual is a non-mammal. In some variations, the primate is a non-human primate such as chimpanzees and other apes and monkey species. The term "individual" does not imply a particular age or gender.

[0035] As used herein, the terms "effective amount", "pharmaceutically effective amount" and "therapeutically effective amount" refer to an amount of a drug that is non-toxic but sufficient to produce the desired biological result. This result can be a decrease or alleviation of the signs, symptoms or causes of a disease, or any other desired change in a biological system. The appropriate therapeutic amount in an individual case can be determined by one of ordinary skill in the art using routine experimentation.

[0036] As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound effective in the present invention and a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates the administration of the compound to a patient or subject. There are a plurality of techniques for administering the compound in the art, including, but not limited to, intravenous administration, oral administration, aerosol administration, parenteral administration, ocular administration, pulmonary administration and topical administration.

[0037] As used herein, the terms "combination", "therapeutic combination" or "pharmaceutical combination" refer to a fixed combination in a single dosage form, or an unfixed combination, or two or more therapeutic agents administered simultaneously or separately and independently within a time interval, particularly where these time intervals allow for combination administration in which the combination partners exhibit synergy, e.g., a synergistic effect, and include kits of parts for such combination administration.

[0038] As used herein, the term "weight percent" is intended to refer to the amount by mass of a constituent of a composition as a percentage of the total mass of the composition, the amount by mass of a compound and / or component in the composition. Weight % can also be calculated by multiplying the mass fraction by 100. "Mass fraction" is the ratio of the mass m1 of a substance to the total mass m T of the composition, such that the weight percent = (m1 / m T ) * × 100.

[0039] "Aqueous buffer" refers to an aqueous solution that resists changes in hydronium and hydroxide ion concentrations (and thus the resulting pH) upon addition of small amounts of acid or base or upon dilution. Buffer solutions consist of a weak acid and its conjugate base (more common), or a weak base and its conjugate acid (less common). Buffers can be prepared by methods well known in the art using appropriate buffering agents that provide the desired pH value. Examples of suitable buffering agents include hydrochloric acid, lactic acid, acetic acid, citric acid, malic acid, maleic acid, pyruvic acid, succinic acid, tris-hydroxymethylaminomethane, sodium hydroxide, sodium bicarbonate, phosphoric acid, sodium phosphate, and other biologically acceptable buffering agents. Aqueous buffers are readily commercially available and can be used in the preparation of the compositions of the invention without further treatment.

[0040] As used herein, the "average plasma level" of a substance refers to the average level of the substance found in a plurality of plasma samples. The average plasma level is obtained by summing the concentrations of the substance found in the plasma samples and then dividing the sum by the number of plasma samples.

[0041] As used herein, "steady-state plasma level" is intended to indicate the total exposure over one dosing interval (at steady state) divided by the time of the dosing interval. Thus, the average concentration does not change even if the concentration rises and falls during the dosing interval at steady state. Once at steady state, all doses give the same maximum serum concentration (Cmax), minimum serum concentration (Cmin), area under the curve (AUC), and steady-state concentration (Css), resulting in Css = AUC / dosing interval.

[0042] Pharmaceutical composition Disclosed herein are methods and dosing regimens for treating schizophrenia in a subject in need thereof, the method comprising administering to the subject a first component comprising aripiprazole. U.S. Patent Nos. 4,734,416 and 5,006,528 disclose aripiprazole, 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydro-2(1H)-quinolinone or 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydrocarbostyryl as atypical antipsychotics useful for the treatment of schizophrenia, bipolar disorder, depression, and other CNS disorders. These documents are hereby incorporated by reference in their entirety. Aripiprazole has the following chemical structure:

[0043]

Chemical formula

[0044] Aripiprazole is sold under the trade name ABILIFY®. It also acts as a dopamine D2 partial agonist, a serotonin 5-HT1A receptor agonist, and an antagonist of the serotonin 5-HT2A receptor. ABILIFY® is currently orally administered once daily as ABILIFY® (aripiprazole) tablets, ABILIFY DISCMELT® (aripiprazole) orally disintegrating tablets, and ABILIFY® (aripiprazole) oral solution. In one embodiment, the aripiprazole component is a pharmaceutical composition comprising aripiprazole and a pharmaceutically acceptable carrier.

[0045] The methods and dosing regimens also include the component aripiprazole lauroxil. U.S. Pat. Nos. 8,431,576, 8,796,276, 9,034,867, 9,193,685, 9,452,131, and 9,526,726 disclose aripiprazole lauroxil, (7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methyl dodecanoate, as an extended-release prodrug of aripiprazole useful for the treatment of schizophrenia, bipolar disorder, depression, and other CNS disorders. These documents are hereby incorporated by reference in their entirety. Aripiprazole lauroxil has the following chemical structure:

[0046]

Chemical formula

[0047] Aripiprazole lauroxil is sold under the trade name ARISTADA® and is currently administered intramuscularly.

[0048] In one embodiment, the aripiprazole lauroxil component is a pharmaceutical composition comprising an aripiprazole lauroxil component and a pharmaceutically acceptable carrier. In one embodiment, the aripiprazole lauroxil component is a pharmaceutical composition comprising aripiprazole lauroxil, sorbitan laurate, polysorbate 20 and an aqueous vehicle.

[0049] The methods and dosing regimens also include a component that is a nanoparticle dispersion of aripiprazole lauroxil (AL NCD ). U.S. Patent No. 10,016,415 discloses AL NCD . AL NCD is a pharmaceutical composition comprising a population of particles of polysorbate 20, sodium citrate, sodium chloride, an aqueous buffer and aripiprazole lauroxil, which is useful for the treatment of schizophrenia, bipolar disorder, depression and other CNS disorders.

[0050] The particle size of the nanoparticle dispersion can be measured using techniques such as light scattering, using water or a dilute surface stabilizer solution as a diluent. The measured values can be verified using microscopy. The particle size distribution can be determined using a Horiba 950 particle size analyzer as a wet suspension. The volume-based particle size (Dv50) is represented herein by the average volume diameter of the particles. Particle size measurements can also be performed using PCS (dynamic light scattering measurement).

[0051] In one embodiment, the population of particles of aripiprazole lauroxil in AL NCD has a volume-based particle distribution diameter (Dv50) of less than about 1000 nm. In one embodiment, the population of particles of aripiprazole lauroxil in AL NCD has a volume-based particle distribution diameter (Dv50) between about 175 nm and about 350 nm.

[0052] In one embodiment, AL NCD has a ratio of particles to polysorbate 20 between about 0.1:1 and about 40:1. In one embodiment, AL NCD has a ratio of particles to polysorbate 20 of 17:1.

[0053] In one embodiment, AL NCD comprises about 20-30% by mass of aripiprazole lauroxil, about 1-2% by mass of polysorbate 20, about 0.5-1% by mass of sodium citrate, 0.1-0.5% by mass of sodium chloride and an aqueous buffer. In one embodiment, AL NCD comprises about 26% by mass of aripiprazole lauroxil, about 1.53% by mass of polysorbate 20, about 0.76% by mass of sodium citrate, 0.31% by mass of sodium chloride and an aqueous buffer.

[0054] In one embodiment, AL NCD comprises about 26% by mass of aripiprazole lauroxil particles, about 1.53% by mass of polysorbate 20, about 0.76% by mass of sodium citrate, 0.31% by mass of sodium citrate and an aqueous buffer; the particles of aripiprazole lauroxil have a volume-based particle size distribution diameter (Dv50) between about 175 nm and about 350 nm.

[0055] Treatment methods The methods and dosing regimens provided herein can be used to treat various disorders in a subject in need thereof. For example, the pharmaceutical compositions described herein can be used to treat subjects having depression, schizophrenia and bipolar disorder.

[0056] In one aspect, a method of treating these disorders, such as schizophrenia, in a subject in need thereof, a first component comprising aripiprazole; AL NCD a second component comprising; a third component comprising a therapeutically effective amount of aripiprazole lauroxil and administering to the subject are provided herein.

[0057] In one aspect, a method of treating schizophrenia in a subject in need thereof, a first component comprising about 5-50 mg of aripiprazole; About 629 to 695 mg of AL NCD and a second component comprising; a third component comprising a therapeutically effective amount of aripiprazole lauroxil A method is provided herein that includes the step of administering to a subject.

[0058] In another aspect, a method of treating schizophrenia in a subject in need thereof, comprising a first component comprising aripiprazole; and AL NCD a second component comprising; a third component comprising aripiprazole lauroxil and the step of administering to a subject, wherein the combined dosage of the first, second, and third components is sufficient to maintain a therapeutically effective mean plasma level of aripiprazole in the subject. A method is provided herein.

[0059] In one embodiment, the therapeutically effective mean plasma level of aripiprazole is about 102 to 435 ng / mL at steady state plasma level. In another embodiment, the therapeutically effective mean plasma level of aripiprazole is greater than about 102 ng / mL at steady state plasma level. In another embodiment, the therapeutically effective mean plasma level of aripiprazole is less than about 435 ng / mL at steady state plasma level. In another embodiment, the therapeutically effective mean plasma level of aripiprazole is reached within 24 hours of initial treatment. In another embodiment, the therapeutically effective mean plasma level of aripiprazole is maintained for 21 days or more.

[0060] In one aspect, a kit for treating schizophrenia, comprising a therapeutically effective amount of a first component comprising aripiprazole; and AL NCD a second component comprising; a third component comprising aripiprazole lauroxil and comprising A kit is provided herein that further includes instructions for administration, the instructions specifying oral administration of a first component, intramuscular administration of a second component, and intramuscular administration of a third component.

[0061] In one embodiment, a therapeutically effective amount of a drug is administered to a subject using the pharmaceutical compositions provided herein. The term "therapeutically effective amount" is further intended to define an amount that results in an improvement in any parameter or clinical symptom. The actual dosage varies in each patient and does not necessarily indicate complete elimination of all disease symptoms. In the case of antipsychotics, management of exacerbation of psychiatric symptoms and maintenance of remission are the main goals of therapy, and the selection of the appropriate drug and dosage in a particular disease involves a comparative consideration of these goals with minimization of adverse events caused by the drug.

[0062] A therapeutically effective amount of the compounds used in the treatments described herein can be readily determined by a attending diagnostician as one of ordinary skill in the art by use of the prior art and by observing the results obtained under similar circumstances. In determining the therapeutically effective dosage, several factors are considered by the attending diagnostician, including but not limited to mammalian species; its size, age and general health; the specific disease involved; the degree or incidence or severity of the disease; the response of the individual patient; the specific compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dosing regimen selected; the use of concomitant medications; and other relevant circumstances.

[0063] Administration / Dosage The actual dosage levels of the components of the methods and dosing regimens provided herein can be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient without being toxic to the patient.

[0064] In particular, the selected dosage level depends on various factors including the activity of the particular compound used, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or substances used in combination with the compound, the age, sex, weight, condition, general health and previous medical history of the patient being treated, and similar factors well known in the medical arts.

[0065] A medical doctor, such as a physician or veterinarian, having the skills possessed by those skilled in the art can readily determine and prescribe an effective amount of the pharmaceutical composition required. For example, a physician or veterinarian can initiate administration of the pharmaceutical composition by administering a compound disclosed at a level lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0066] The compounds of the methods and dosing regimens provided herein can be administered orally in a single or multiple doses in an amount of about 10 mg to about 2000 mg (including, for example, about 10 mg to about 500 mg) / day. Thus, in one embodiment of the treatment method provided herein, the first component (aripiprazole) is administered at a dosage of about 5 to 50 mg / day. In a further embodiment, the first component (aripiprazole) is administered at a dosage of about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg or 100 mg / day. In a further embodiment, the first component (aripiprazole) is administered at a dosage of about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg or 30 mg / day. In a further embodiment, the first component (aripiprazole) is administered at a dosage of about 30 mg / day. In yet another embodiment, the first component (aripiprazole) is administered at a dosage of about 15 mg / day over a period of 2 days. In yet another embodiment, the first component (aripiprazole) is administered at a dosage of about 10 mg / day over a period of 3 days.

[0067] The compounds of the methods and dosing regimens provided herein can be administered intramuscularly in a single or multiple doses in an amount of about 10 mg to about 2000 mg (including, for example, about 10 mg to about 500 mg) / day. Thus, in one embodiment of the treatment method provided herein, the second component (AL NCD ) is administered at a dosage of about 629 to 695 mg / day. In a further embodiment, the second component (AL NCD) is administered at a dosage of about 630 mg, 640 mg, 650 mg, 660 mg, 662 mg, 670 mg, 675 mg, 677 mg, 680 mg, 690 mg or 700 mg / day. In a further embodiment, the second component (AL NCD ) is administered at a dosage of about 675 mg / day. In another embodiment, the second component (AL NCD ) is administered at a dosage of about 677 mg / day.

[0068] The compounds of the methods and dosing regimens provided herein can be administered intramuscularly in a single or multiple dose in an amount of about 10 mg to about 2000 mg per day (including, for example, about 300 mg to about 1500 mg or about 629 to about 695 mg). Thus, in one embodiment of the methods of treatment provided herein, the third component (aripiprazole lauroxil) is administered at a dosage of about 300 - 1500 mg / day. In further embodiments, the third component (aripiprazole lauroxil) is administered at a dosage of about 441 mg, 662 mg, 882 mg or 1064 mg / day.

[0069] In certain embodiments, it is particularly advantageous to formulate the compounds into dosage unit forms for ease of administration and uniformity of dosage. As used herein, a dosage unit form refers to physically discrete units suitable as unit dosages for the patients to be treated; each unit containing a predetermined quantity of the disclosed compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle. The dosage unit forms of the present invention are determined by and directly depend on (a) the particular properties of the disclosed compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding / formulating such disclosed compounds for the treatment of the patient's restlessness, depression, bipolar disorder, autism-related irritability and psychotic conditions (including acute mania, schizophrenia and schizophrenia-like disorders).

[0070] In one embodiment, the components of the methods and dosing regimens provided herein are formulated using one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the pharmaceutical composition of the invention comprises a therapeutically effective amount of the disclosed compound and a pharmaceutically acceptable carrier.

[0071] As used herein, references to "dose" or "dosage" relate to the dose of the active agent. For example, " NCD a second component comprising NCD " refers to the amount of AL comprising 629 - 695 mg of aripiprazole lauroxil. As discussed above, the aripiprazole and / or aripiprazole lauroxil component may be a pharmaceutical composition comprising an active agent and a pharmaceutically acceptable carrier. Any reference to "dose" or "dosage" of these components refers to the dose or dosage of the active agent (aripiprazole and / or aripiprazole lauroxil, regardless of the pharmaceutically acceptable carrier).

[0072] In one embodiment, the active agent in the first component is aripiprazole. In another embodiment, the active agent in the second component is aripiprazole lauroxil. In yet another embodiment, the active agent in the third component is aripiprazole.

[0073] Schizophrenia can be treated using various dosing regimens. In some embodiments, the daily dose, such as any of the exemplary doses described above, is administered once, twice, three times, or four times a day for 3, 4, 5, 6, 7, 8, 9, or 10 days. In one embodiment, the method comprises a regimen in which the first, second, and third components are administered substantially simultaneously.

[0074] In one embodiment, the dosage of the first component is administered over the first three days of treatment. In one embodiment, the first component is administered over the first two days of treatment. In one embodiment, the first component is administered only on the first day of treatment. In one embodiment, the first component is administered only once during the treatment period. In one embodiment, the first component is not readministered within 21 days after the first treatment.

[0075] In one embodiment, the first, second, and third components are administered substantially simultaneously, and the first component is not readministered within 21 days of the first administration.

[0076] In one embodiment, the first, second, and third components are administered substantially simultaneously, followed by a second treatment that includes administering only the third component.

[0077] In one embodiment, the second treatment is performed 21 days or more after the first treatment.

[0078] In one embodiment, the method includes a regimen in which the first component is administered only on the first and / or second day of treatment, the second component is administered only on the first day of treatment, and the third component is administered once within the first 10 days of treatment. In another embodiment, the regimen further includes a second administration of only the third component. In yet another embodiment, the third component is administered on the first day of treatment. In still another embodiment, the third component is administered on the second day of treatment. In one embodiment, the third component is administered 7 to 10 days after the start of the treatment regimen. In one embodiment, the third component is administered 3 to 6 days after the start of the treatment regimen. In another embodiment, the first component is administered only on the first and second days of treatment. In yet another embodiment, the first component is administered only on the first day of treatment.

[0079] In one embodiment, the method includes a regimen in which the first component is administered at a dosage of 15 mg / day only on the first and second days of treatment, the second component is administered only on the first day of treatment, and the third component is administered on the second day of treatment.

[0080] In one embodiment, the method includes a regimen in which a first component is administered only on the first day of treatment, a second component is administered only on the first day of treatment, and a third component is administered 7 to 10 days after the start of the treatment regimen. In yet another embodiment, the third component is administered 7, 8, 9, or 10 days after the start of the treatment regimen. In yet another embodiment, the third component is administered 7 days after the start of the treatment regimen. In yet another embodiment, the third component is administered 8 days after the start of the treatment regimen. In one embodiment, the third component is administered 9 days after the start of the treatment regimen. In another embodiment, the third component is administered 10 days after the start of the treatment regimen.

[0081] In one embodiment, the method includes a regimen in which a first component is administered only on the first day of treatment, a second component is administered only on the first day of treatment, and a third component is administered 3 to 6 days after the start of the treatment regimen. In yet another embodiment, the third component is administered 3, 4, 5, or 6 days after the start of the treatment regimen. In yet another embodiment, the third component is administered 3 days after the start of the treatment regimen. In yet another embodiment, the third component is administered 4 days after the start of the treatment regimen. In one embodiment, the third component is administered 5 days after the start of the treatment regimen. In another embodiment, the third component is administered 6 days after the start of the treatment regimen.

[0082] Any route of administration of the compositions of the present invention includes oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual, or topical. The compounds for use in the methods and dosing regimens provided herein can be formulated for administration by any suitable route, such as oral or parenteral, for example transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., transvaginal and perivaginal), intranasal, and (trans)rectal), intravesical, intralung, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intratracheal, inhalation, and topical administration.

[0083] In one embodiment, the preferred route of administration for the first component (aripiprazole) is oral.

[0084] In one embodiment, the second component (ALNCD ) The preferred route of administration for is intramuscular. In a further embodiment, the second component (AL NCD ) The preferred route of administration for is intramuscular into the deltoid or gluteal muscle. In a further embodiment, the second component (AL NCD ) The preferred route of administration for is intramuscular into the deltoid muscle.

[0085] In one embodiment, the preferred route of administration for the third component (aripiprazole lauroxil) is intramuscular. In a further embodiment, the preferred route of administration for the third component (aripiprazole lauroxil) is intramuscular into the deltoid or gluteal muscle.

[0086] In one embodiment, the route of administration for the first component (aripiprazole) is oral, the route of administration for the second component (AL NCD ) is intramuscular, and the route of administration for the third component (aripiprazole lauroxil) is intramuscular.

[0087] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magma, lozenges, creams, pastes, plasters, lotions, disks, suppositories, liquid sprays for nasal or oral administration, dry powders or aerosolized formulations for inhalation, compositions and formulations for intravesical administration, and the like. It should be understood that the formulations and compositions that will be useful in the present invention are not limited to the specific formulations and compositions described herein.

[0088] For oral administration, tablets, dragees, solutions, drops, suppositories or capsules, caplets and gelcaps are particularly suitable. Compositions intended for oral use can be prepared according to any method known in the art, and such compositions can contain one or more agents selected from the group consisting of inert and non-toxic pharmaceutical excipients suitable for the manufacture of tablets. Such excipients include, for example, inert diluents such as lactose; granulating agents and disintegrants such as corn starch; binders such as starch; and lubricants such as magnesium stearate. Tablets may not be coated, or may be coated by known techniques for elegance or to delay the release of the active ingredient. Formulations for oral use can also be provided as hard gelatin capsules in which the active ingredient is mixed with an inert diluent.

[0089] For parenteral administration, the disclosed compounds can be formulated for administration by injection or infusion, such as intravenous, intramuscular or subcutaneous injection or infusion, or bolus administration or continuous infusion. Suspensions, solutions or emulsions in oily or aqueous vehicles, optionally containing other formulating agents such as suspending, stabilizing or dispersing agents, can be used.

[0090] One of ordinary skill in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims and examples described herein. Such equivalents are considered to be within the scope of the present invention and are covered by the appended claims. For example, modifications of reaction conditions, including but not limited to reaction times, reaction sizes / volumes, and experimental reagents such as solvents, catalysts, pressures, atmospheric conditions such as nitrogen atmosphere, and reducing / oxidizing agents, which are recognized in the art as alternatives and which require no more than routine experimentation, are understood to be within the scope of this application.

[0091] Whenever values and ranges are provided herein, it should be understood that all values and ranges subsumed within these values and ranges are intended to be encompassed within the scope of the present invention. Further, all values falling within these ranges, as well as the upper or lower limits of value ranges, are also contemplated by this application. The following examples further illustrate aspects of the present invention. However, these are in no way limitations of the teachings or disclosures of the present invention shown.

Example

[0092] (Example 1) Test Design and Treatment Regimen The tests were conducted in accordance with the Helsinki Declaration and good clinical practice guidelines agreed upon by the International Conference on Harmonization of Pharmaceutical Regulations in 1997. The test protocol, amendments, and informed consent forms were approved by the independent ethics committees / institutional review boards at each site. All patients provided written informed consent prior to entering the study.

[0093] As used herein, AL NCD refers to a pharmaceutical composition comprising about 26% by mass of aripiprazole lauroxil particles, about 1.53% by mass of polysorbate 20, about 0.76% by mass of sodium citrate, 0.31% by mass of sodium chloride, and an aqueous buffer, wherein the particles of aripiprazole lauroxil have a volume-based particle size distribution diameter (Dv50) between about 175 nm and about 350 nm.

[0094] This was a phase 1 double-blind placebo-controlled trial to evaluate the PK, safety, and tolerability of two starting regimens for initiating treatment with AL in patients with schizophrenia. The first regimen was a single 662 mg AL combined with a single oral dose of 30 mg of aripiprazole NCDIt was a once-daily start regimen that included administration. The second regimen was a 21-day oral start regimen based on the regimen used in the important 12-week Phase 3 trial of AL. In this Phase 1 trial, the once-daily start regimen was compared with the 21-day start regimen (starting with AL 441 or 882 mg in combination with oral aripiprazole for 21 days).

[0095] The study period was approximately 6 months and consisted of a screening, inpatient administration, outpatient, and follow-up period (Figure 1). Patients in the prospective study were evaluated during a 30-day screening period before dosing. During this period, patients who had not received aripiprazole were given a 5 mg test dose 30 and 29 days before entering the study. A total of 160 patients were planned to be enrolled and randomized 1:1:1:1 into one of four treatment groups as follows: once-daily start regimen group (30 mg oral aripiprazole + AL NCD , + AL 441 or 882 mg [day 1], then 20 days of oral placebo), or 21-day start regimen group (15 mg oral aripiprazole + placebo IM, + AL 441 or 882 mg [day 1], followed by 20 days of oral aripiprazole 15 mg / day). In all study groups, the order of administration on day 1 was as follows: first, oral aripiprazole; second, AL NCD or placebo IM injection (administered within 15 minutes of oral aripiprazole); third, AL IM injection (administered within 30 minutes of the AL NCD or placebo IM injection). AL NCD or placebo was administered as an IM injection into the gluteus maximus muscle. For AL administration, a single 441 mg dose was given into the deltoid muscle, or a single 882 mg dose was given into the gluteus maximus muscle on the opposite side of the AL NCD (or placebo) injection.

[0096] The patient was admitted as an inpatient one day before the originally scheduled administration and maintained as an inpatient for the first 15 days. After discharge, the patient returned for 17 outpatient follow-up evaluations, with the last evaluation conducted on day 141. PK samples were collected daily on days 1 to 15, every other day on days 17 to 25, on days 28 and 31, once a week on days 35 to 85, and on days 113 and 114. On days 1 and 21, samples were collected at multiple time points (detailed in Example 3).

[0097] (Example 2) Study population Eligible patients were adults aged 18 to 65 years who had received a diagnosis of chronic schizophrenia or schizoaffective disorder based on the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) and had a documented history of tolerance to aripiprazole or demonstrated tolerance to the test dose during screening. In this study, patients were required to be clinically stable as defined by having no hospitalization for acute psychiatric aversion within 3 months prior to screening and having a Clinical Global Impression-Severity (CGI-S) score of 3 or less at screening and at the start of the study. Patients had no dosing changes between screening and randomization and had been on a stable oral antipsychotic dosing regimen (excluding aripiprazole and clozapine) for more than 2 months prior to screening.

[0098] Important exclusion criteria included patients who had received oral aripiprazole within 28 days prior to randomization or other LAI antipsychotics within 3 months prior to hospitalization, and patients who were currently participating in a clinical trial with an investigational medicinal product or had participated in one within 3 months prior to hospitalization. Patients who had received AL or IM depot aripiprazole within 6 months prior to hospitalization were also excluded. A history of major psychopathology other than schizophrenia or schizoaffective disorder at screening or hospitalization, CYP2D6 poor metabolizer status, or a positive test for illicit drug use was not tolerated.

[0099] (Example 3) Study evaluations Blood samples for liquid chromatography-tandem mass spectrometry were collected to analyze the plasma concentration of aripiprazole. Samples were collected on Day 1, 1 hour before dosing and at 1, 2, 3, 4, 5, 6, and 8 hours (±15 minutes) after dosing. From Day 2 to Day 20 after the start, a single sample was collected before oral aripiprazole (or oral placebo) administration. As on Day 1, after collection of the pre-dose sample on Day 21, additional samples were collected at 1, 2, 3, 4, 5, 6, and 8 hours (±15 minutes) after dosing. From Day 23 to Day 85, a single sample was collected within ±2 hours of the oral dosing time on Day 1, or as close as possible to that time frame. On Day 113 and Day 141, single PK samples were collected.

[0100] All safety analyses were performed using observational data from the safety population, and the measurements included adverse events (AEs), vital sign measurements, body weight, laboratory test results, ECG findings, Columbia Suicide Severity Rating Scale (C-SSRS) responses, movement disorder measurements, CGI-S responses, and injection site evaluations.

[0101] AEs were evaluated daily from Day 1 to Day 15, every other day from Day 17 to Day 25, on Day 28 and Day 31, once a week from Day 35 to Day 85, and on Day 113 and Day 114. Injection site evaluations were performed daily from Day 1 to Day 15, every other day from Day 17 to Day 25, and on Day 28. The injection site and the surrounding area were evaluated separately for each injection (AL NCD or placebo injection and the AL site). Observed injection site reactions were followed until they resolved.

[0102] (Example 4) Statistical Analysis The test population consisted of the safety population (all patients who received the test drug) and the PK population (all patients who received the test drug and had one or more measurable concentrations of aripiprazole).

[0103] The AUC calculated from Day 0 to Day 28 (AUC 0~28) was calculated using the linear trapezoidal method and included only the pre - oral - administration concentrations collected on day 1 and day 21. The actual elapsed time since dosing was used to estimate individual parameters. Additionally, the percentage of patients who reached the known therapeutic concentration of aripiprazole within 4 days after the start of AL was calculated. The 1 - day start regimen was designed to match the oral start regimen indicated in the AL prescribing information and achieve therapeutic concentration within 4 days. The aripiprazole concentration and AUC 0~28 were descriptively summarized.

[0104] A post - hoc evaluation was conducted to compare the results of aripiprazole concentrations from this trial with the concentrations observed from a 12 - week phase 3 efficacy trial (using a 21 - day oral regimen).

[0105] Safety and tolerability parameters were estimated in the safety population. Descriptive statistics were used to summarize newly occurring or worsening AEs at the administration of the first dose of the investigational drug (AL NCD and single - dose 30 mg oral aripiprazole administration or placebo injection and 21 - day oral aripiprazole 15 mg, + AL441 or 882 mg).

[0106] (Example 5) Patient characteristics and baseline characteristics In total, 161 patients were enrolled, received one of the start regimens, and were included in the PK and safety populations (Table 1). Patients were randomized to receive a 1 - day start regimen (n = 80) or a 21 - day start regimen (n = 81) along with a starting dose of AL of 441 or 882 mg. In total, 39 patients were enrolled in the AL441 mg / 1 - day start group and 41 patients were enrolled in the AL881 mg / 1 - day start group. Among the patients enrolled in the 21 - day start regimen group, 40 patients were assigned to the AL441 mg / 21 - day start group and 41 patients were assigned to the Al882 mg / 21 - day start group.

[0107] A total of 133 patients (82.6%) completed the trial. Among the 28 patients (17.4%) who did not complete the trial, the reasons for trial discontinuation were failure to follow up and discontinuation by the patient (n = 10 each, 6.2%), AE (n = 5, 3.1%), protocol deviation (n = 2, 1.2%), and non-compliance with dosing (n = 1, 0.6%).

[0108] The patient demographics are summarized in Table 1. The mean age and BMI of the patients were 44 years and 29.5 kg / m 2 respectively. Overall, the treatment groups were well balanced with respect to demographics and baseline characteristics.

[0109]

Table 1

[0110] (Example 6) Pharmacokinetic Results Results from the once-daily start regimen showed mean plasma aripiprazole concentrations and exposures within the first month comparable to those of the 21-day start regimen (Figure 2). In the first 24 hours after start, higher aripiprazole concentrations were observed in the once-daily start regimen compared to the 21-day start regimen due to the higher dose of aripiprazole administered on day 1 in the once-daily start regimen (30 mg vs. 15 mg). Since the once-daily start regimen was designed to reproduce the 21-day start regimen in achieving therapeutic aripiprazole concentrations within 4 days of the first AL administration, particular interest was placed on the plasma concentration on day 4 after start. As shown in Figure 2, the once-daily regimen results in achievement of aripiprazole therapeutic levels similar to those of the 21-day start regimen within 4 days.

[0111] As can be seen in Figure 2, the average concentration appears to be visibly lower in the 1-day start regimen group than in the 21-day start regimen group from approximately day 4 to day 14, and the error bars around the average plasma concentration show complete overlap of the concentration ranges across the treatment groups. As expected for the 21-day oral start regimen group, the aripiprazole concentration decreased after day 21 when active oral dosing was discontinued. In contrast, for the 1-day start regimen group, the plasma aripiprazole concentration showed no significant change until after day 30 after start when the average aripiprazole concentration began to decrease (Figure 6A, Figure 6B, Figure 6C). This indicates that the 1-day start regimen provides a continuous effective range over a longer period compared to the 21-day start regimen.

[0112] AUC 0~28 The values of were comparable across the four treatment groups (Figure 3, Table 2). Comparison of the range of values across the groups showed similar exposure within the first month of treatment regardless of the starting regimen used.

[0113] [Table 2]

[0114] When the aripiprazole concentrations obtained from this study were post hoc compared to those observed in a 12-week Phase 3 efficacy trial, consistent and reproducible results were shown across the trials using the 21-day oral aripiprazole start regimen (Figure 4). Importantly, the 1-day start regimen from this study resulted in aripiprazole concentrations within the concentration range observed with the 21-day oral aripiprazole supplementation used in the Phase 3 efficacy trial (Figure 5).

[0115] (Example 7) Adverse event Throughout the trial period, in each starting regimen group at all time points, a small similar mean change (≤0.1) from the baseline CGI-S score (score 3.0; mild) was observed, indicating no change in disease severity. All patients had a score of 0 (no suicidal behavior or ideation) for the C-SSRS throughout the trial.

[0116] In the AL 441 mg / day starting group and the AL 882 mg / day starting group, 26 patients (66.7%) and 28 patients (68.3%) experienced an AE, respectively, and 24 patients (60.0%) in the AL 441 mg / 21-day starting group and 28 patients (68.3%) in the AL 882 mg / 21-day starting group experienced an AE (Table 4). Most of the AEs were of mild or moderate intensity. Severe AEs were reported in 3 out of 6 patients in the once-daily starting regimen (traffic accident, status epilepticus, mental disorder, and schizoaffective disorder) and 6 out of 6 patients in the 21-day starting regimen group (upper gastrointestinal bleeding, cellulitis, traffic accident, and accidental overdose). Among these, schizoaffective disorder and status epilepticus were evaluated as "possibly related" to the treatment. A total of 5 patients, 3 in the once-daily starting regimen (traffic accident, extrapyramidal disorder, and status epilepticus) and 2 in the 21-day starting regimen (traffic accident and nausea), discontinued this trial due to an AE. One patient in the 21-day starting regimen group died as a result of an injury received in a traffic accident (considered not related to the investigational drug). Overall, the most commonly reported AEs were injection site pain (23.0%), headache (9.9%), weight gain (7.5%), insomnia (6.2%), dyspepsia (5.6%), and restlessness (5.0%). All other AEs occurred at an overall incidence of less than 5%.

[0117] ISR and akathisia are considered AEs of particular interest as they have been associated with the initiation of AL in previous trials. See, for example, Meltzer, H.Y. et al., J. Clin. Psychiatry, 2015, 76(8), 1085 - 1090; McEvoy, J.P. et al., J. Clin. Psychiatry, 2017, 78(8), 1103 - 1109.

[0118] Overall, AL NCD All injection site reactions (ISRs) associated with placebo IM, AL 441 mg, and AL 882 mg injections were of mild to moderate severity.

[0119] Compared to 5 out of 81 (6.2%) patients who received placebo injections, a total of 14 out of 80 (17.5%) patients had an ISR associated with AL NCD injections (Table 3). The most common description of the ISR was injection site pain, which was reported in 12 out of 80 (15.0%) patients who received AL NCD injections compared to 4 out of 81 (4.9%) patients who received placebo IM injections. Whether the patient received the AL injection in the deltoid muscle (AL 441 mg; n = 7, 17.5%) or in the contralateral gluteal muscle (AL 882 mg; n = 5, 12.5%), the incidence of injection site pain associated with AL NCD was similar.

[0120] Overall, 18 out of 79 (22.8%) patients who received AL 441 mg in the deltoid muscle and 15 out of 82 (18.3%) patients who received AL 882 mg in the gluteal muscle had an ISR (Table 2). The most common description of the ISR was injection site pain, which was reported in 16 out of 79 (20.3%) patients who received AL 441 mg and 15 out of 82 (18.3%) patients who received AL 882 mg, respectively.

[0121] [Table 3]

[0122] The overall incidence of akathisia was low in all groups and was the total AE rate in 6 out of 140 patients (3.7%). Among the patients treated with the once-daily regimen, akathisia was reported in 4 out of 80 patients (5%). Two of these patients reported mild akathisia during the first week of treatment. One of the patients evaluated as having mild akathisia was probably not related to the investigational drug, while the other evaluated as having mild akathisia was definitely related to the investigational drug. The other two patients experienced akathisia in the third week of treatment. One of these was evaluated as mild and the other as moderate severity, and were evaluated as "probably related" and "definitely related" to the treatment, respectively. Among the patients treated with the 21-day oral regimen, mild akathisia was reported in 2 out of 81 patients (2.5%). One experienced the first akathisia event in the second week and the other in the third week of treatment, and were evaluated as "possibly" and "probably related" to the treatment, respectively.

[0123]

Table 4

[0124] (Example 8) Population pharmacokinetic (PK) model Three of these are being developed as starting regimens for AL for formulation development and AL (Hard et al CNS Drugs, submitted; Wehr et al in preparation) NCDData from four Phase 1 trials, which were important for the feasibility of using, were used to develop a PopPK model for aripiprazole. These trials (ALK9072-1, ALK9072-B102 and ALK9072-B103) are referred to herein as Trial 1, Trial 2 and Trial 3, respectively. The fourth trial was a Phase 1 pre-trial of AL administered alone (ALKS9072-A105, referred to as Trial 4). All trials enrolled adult patients with schizophrenia or schizoaffective disorder who were stable on first-choice antipsychotic medication (excluding aripiprazole); all patients with sufficient data on dosing, actual sampling times and aripiprazole concentration data were included in the PopPK analysis.

[0125] The mean patient age was 45.2 ± standard deviation (SD) 10.8 years; 73% were male; 78% were black or African American, and the mean weight was 89.1 ± 17.9 kg (Table 1). A total of 12,768 plasma aripiprazole concentrations from 343 patients (including 351 [3%] records below the lower limit of quantification) were included in the analysis. The dataset contained 2,536 dosing records (1,742 oral aripiprazole, 626 AL and 168 AL NCD dosing).

[0126] The model was developed using non-linear mixed effects modeling by the NONMEM® program version 7.3.0, and PDx-Pop version 5.1 was used as the NONMEM interface (complete details of the PopPK model development are provided in the supplementary materials). For modeling, the doses of AL and AL NCD were represented as 75, 150, 300, 450, 600 and 724 mg of aripiprazole equivalent (corresponding to 110, 221, 441, 662, 882 and 1064 mg of AL NCD or AL doses, respectively). A previously developed model for AL including an oral input function served as the starting point for model development and was extended to include an input function for AL NCD AL NCDFirst, a base model was selected that appropriately described the time course of aripiprazole plasma concentration in Study 1, which explained IM absorption and conversion to aripiprazole. Subsequently, the initial base model was expanded according to the incorporation of the final data from Study 3 (completed prior to Study 2), and this was used to re-estimate the model parameters. When the final data from Study 2 were received, the model was updated, the existing parameters were re-estimated, and a full covariance analysis was performed.

[0127] Covariates available for evaluation were as follows: for continuous covariates, age (years) at baseline and weight (WT) (kg) at baseline, and for categorical covariates, injection site (buttock or deltoid), formulation, CYP2D6 genotype, ethnicity, gender, and race. Weight, formulation, and CYP2D6 genotype were evaluated as part of the initial base model development in Study 1. After receiving data from Studies 3 and 2, the covariate model was re-evaluated. The effects of weight on the clearance (CL) and volume (V) terms were incorporated using fixed allometric exponents of 0.75 and 1, respectively, and scaled to 70 kg (7). Background deletion was performed by deleting the background from the full model on an individual basis until the final model was identified, to evaluate the relative impact of each covariate by adding all relevant covariates to the model (full model).

[0128] Thereafter, data from Study 4 were added (to include data from AL-only administration), and the parameters of the final model were updated based on data from all four studies. The model was evaluated by creating a predicted value-corrected visual predictive performance assessment (pcVPC) using goodness-of-fit analysis.

[0129] Initial simulations for oral aripiprazole administered for 21 days at 15 mg suggested that the final PopPK model may overpredict exposure to aripiprazole with multiple oral doses. The investigation showed that the variability in aripiprazole concentrations associated with the 21-day oral regimen in Study 2 was high but consistent with that previously observed in key Phase 3 trials, and that there appears to be a subgroup of individuals whose profile reflects low exposure following multiple oral aripiprazole doses. To determine whether the subpopulation could be formally identified, a mixed model for oral aripiprazole was evaluated.

[0130] Monte Carlo simulations were performed using the final PopPK model and a mixed model for oral aripiprazole appropriately, using Pharsight Trial Simulator version 2.2.2 (Certara USA, Inc, Princeton, NJ). Without incorporating the residuals from the final PopPK model, 500 individual concentration-time profiles were simulated for each scenario, for a total of 500. The simulations were conducted for the following purposes: · To evaluate the effect on aripiprazole concentrations of co-administering a 1-day start regimen with AL on the same day, compared to administering AL several days later. With the administration of a 1-day start regimen (single-dose AL NCD and a single 30-mg dose of oral aripiprazole) on the same day, simulations were performed for a total of five approved AL dose strengths and dosing intervals (441, 662, and 882 mg q4w, 882 mg q6w, and 1064 mg q8w). Additionally, simulations were performed for administering AL (all approved doses) 1, 3, 7, 10, or 14 days after the 1-day start regimen. AL treatment was continued at the prescribed dosing interval from the first dosing time point. · To evaluate the use of AL as an alternative to the current recommendation for daily oral aripiprazole supplementation to re-establish therapeutic aripiprazole plasma concentrations after a missed dose of AL NCD To evaluate the use of AL as an alternative to the current recommendation for daily oral aripiprazole supplementation to re-establish therapeutic aripiprazole plasma concentrations after a missed dose of AL NCD The "re-establishment" regimen (ALNCD Simulations were conducted to predict the likely alpiprazole concentration-time profiles following subsequent AL administrations, with and without supplementation, according to a multiple-dose scenario to determine the likely effects. Five dosing regimens were simulated at steady state (441, 662, and 882 mg q4wk, 882 mg q6wk, and 1064 mg q8wk). A fixed dose of AL was administered alone or supplemented with oral alpiprazole or AL NCD after 1, 2, 3, 4, or 6 weeks.

[0131] AL NCD The base model was parameterized to describe alpiprazole after single IM administration of AL, single IM administration of AL, and oral alpiprazole administration from Trials 1, 2, and 3. The model contained a central and a peripheral compartment for alpiprazole and 16 structural parameters.

[0132] Previous PopPK models for alpiprazole after administration of AL and oral alpiprazole included covariates describing a decrease in CL / F for the CYP2D6 poor metabolizer group and an increase in VC / F for body weight (power model fixed with an allometric exponent of 1.0). However, this dataset did not contain any poor metabolizer groups; as a result, CYP2D6 phenotype was not evaluated for this dataset. Based on eta for the covariate plots, WT was tested for VC / F (power model fixed with an allometric exponent of 1.0), CL / F, D, and ALAG for AL. Additionally, age for CL / F, AL for FRAC NCD injection site, and potential effects of the AL injection site on D and ALAG. For injection site effects, changes in parameters after administration in the deltoid were estimated in the gluteal as a reference. Ethnicity was not included in the covariate analysis because the number of Hispanic or Latin American patients was limited (5%). Race and sex were not included because there were no apparent differences in model parameter estimates.

[0133] The base model was updated to include eight covariate effects to form a full covariate model. The parameters related to AL administration were consistent with the previous analysis. Of the eight effects in the model, two of the estimated injection site effects included null values (AL of FRAC NCD injection site and AL injection site of ALAG), so they were removed. Slight changes in OFV were obtained by removing age of CL / F, WT of ALAG, WT of input D, AL injection site of D, and WT of CL / F. Thus, the model obtained from backward elimination contained only the single covariate effect of VC / F increasing with WT.

[0134] Adding the data from Study 4 (to include data from AL administration only), a final PopPK model was developed. A two-compartment model with a central compartment and a peripheral compartment for aripiprazole, and the conversion of IM AL to aripiprazole described by a zero-order process due to the estimated conversion of D and first-order absorption from the dosing depot defined as 1 / D1 were used. Further, ALAG was present from the IM AL depot to the appearance of aripiprazole in the central compartment. The first-order process described the absorption of aripiprazole after oral administration and the movement between the central and peripheral compartments as in all previous models. However, the previous model was updated here to include a double Weibull function that describes the conversion of IM AL NCD of IM AL NCD to aripiprazole in plasma after administration.

[0135] By goodness-of-fit analysis, it was demonstrated that the observed concentrations were well described by model predictions without using obvious tests, routes of administration, or observed dose-effect biases. pcVPC plots were created by the tests and regimens within Tests 2 and 4. pcVPC showed that for Tests 1 and 3, within and across tests, and by the regimens within Tests 2 and 4, most of the observed concentrations were contained within the final PopPK model prediction 90% PI. The final PopPK model was considered adequate to conduct simulations to evaluate various dosing and administration scenarios.

[0136] A mixed model was applied to patients who received the 21-day start regimen in Test 2 to account for a subgroup of patients with low exposure after multiple oral aripiprazole administrations over the first 28 days of dosing. The mixed model estimated that there was a subpopulation of patients (37.4%; 95% CI 22.3% - 55.4%) in the 21-day start regimen group of Test 2 with a 44.6% lower FPO (95% CI: 40.9 - 48.3%). These estimates of the decrease in FPO from the mixed model and the proportion of patients in the subpopulation were applied to the final PopPK model in a formal simulation.

[0137] The results observed in Study 2 demonstrated that co - administration of a once - daily starting regimen with 441 mg and 882 mg of AL achieved therapeutic concentrations of aripiprazole within 4 days, similar to those achieved with the 21 - day starting regimen administered in conjunction with the first AL dose (Hard et al., CNS Drugs, submitted; Aristada USPI, 2017). Simulations were performed for all approved AL dose strengths and dosing intervals (441, 662, and 882 mg q4w, 882 mg q6w, and 1064 mg q8w) with a once - daily starting regimen given on the same day as the initial AL dose. In all cases, same - day administration of AL and the once - daily starting regimen was predicted to provide rapid and sustained levels of aripiprazole within 4 days of treatment initiation for all regimens. Aripiprazole concentrations remained equivalent across all 5 AL doses over the first 2 weeks. After the first 2 weeks, differences in aripiprazole concentrations related to AL dosing began to become apparent as expected.

[0138] Simulations were performed to evaluate whether the once - daily starting regimen could be administered before and on a different day than the first dose of AL. As before, all 5 AL dosing regimens were simulated (441, 662, and 882 mg q4wk, 882 mg q6wk, and 1064 mg q8wk). For all scenarios, the once - daily starting regimen was administered on Day 1, and the first AL dose was given on the same day as the once - daily starting regimen, or 1, 3, 7, 10, or 14 days after the once - daily starting regimen (i.e., AL was started on Days 2, 4, 8, 11, and 15). AL was then continued at the specified dosing intervals from the previous time point.

[0139] Delaying the start of AL relative to the start of the once-daily regimen resulted in a decrease in the median aripiprazole concentration over the first two dosing intervals of AL compared to simultaneous treatment initiation, and the magnitude of this effect was determined by the length of the delay. When AL was administered 1 or 3 days after the once-daily regimen, a negligible decrease in aripiprazole concentration was observed at the end of the AL dosing interval (Ct) compared to when AL was administered on the same day as the once-daily regimen. Delays in the first AL injection of more than 1 week from the once-daily regimen were also evaluated. When AL was administered 7, 10, or 14 days later, the median C T was 8%–16%, 9%–23%, and 14%–31% lower, respectively, compared to administration on the same day as the once-daily regimen. When AL administration was 10 days after the once-daily regimen, C T was decreased by 23% or less compared to when both were administered on day 1.

[0140] Simulations were conducted to evaluate the use of AL as an alternative to the current recommendation of using 7 days of oral supplementation after a missed AL injection. At steady state, all approved AL dosing regimens were simulated (441, 662, and 882 mg q4wk, 882 mg q6wk, and 1064 mg q8wk). A fixed dose of AL was administered alone, with 7 days of supplemental oral aripiprazole, or with a single injection of AL NCD (without a single oral aripiprazole dose) 1, 2, 3, 4, or 6 weeks later (depending on the dosing regimen). NCD For the dosing scenarios selected for 5 approved AL regimens (with and without the re-establishment regimen), the simulated median aripiprazole concentrations currently require 7 days of oral aripiprazole supplementation with a subsequent dose to restore therapeutic aripiprazole concentrations (Aristada US PI 2017). In these simulations, subsequent dosing of AL resulted in lower predicted median concentrations after the subsequent dose compared to when AL dosing was not delayed. AL

[0141] The simulated median aripiprazole concentrations for the dosing scenarios selected for 5 approved AL regimens (including and not including the re-establishment regimen) currently require 7 days of oral aripiprazole supplementation with a subsequent dose to restore therapeutic aripiprazole concentrations (Aristada US PI 2017). In these simulations, subsequent dosing of AL resulted in lower predicted median concentrations after the subsequent dose compared to when AL dosing was not delayed. AL NCDWhen used in combination with AL after a missed dose, the aripiprazole concentration increases and reaches a C similar to that achieved with 7 days of oral aripiprazole, covering the maximum concentration range related to the approved dosing range of AL. max The value reaches and covers the maximum concentration range related to the approved dosing range of AL.

[0142] When the AL dose was not missed, the aripiprazole C max ranged from 153 to 310 ng / mL. Both re - establishment regimens resulted in C max values within a range comparable to that of C max for AL at steady state, so it was sufficient to return the concentration to the therapeutic level. These simulations demonstrate that when the AL dose is missed, the aripiprazole concentration can be returned to the therapeutic range using 7 days of oral aripiprazole or AL NCD .

[0143] Therefore, AL NCD is a suitable alternative to daily oral aripiprazole supplementation to restore aripiprazole concentration after a missed AL dose. Further simulations showed that a longer delay (requiring 21 days of oral aripiprazole supplementation according to current prescribing information [Aristada PI, 2017]) would require restarting AL treatment with a combination of AL NCD and 30 mg of oral aripiprazole.

[0144] The disclosed subject matter is not limited in scope by the specific embodiments and examples described herein. Indeed, various modifications of the disclosure in addition to those described will become apparent to those skilled in the art from the description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims.

[0145] All references (e.g., publications or patents or patent applications) cited in this specification are hereby incorporated by reference in their entirety for all purposes as if each individual reference (e.g., publication or patent or patent application) had been specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Other embodiments are within the scope of the following claims.

Claims

1. A kit for treating schizophrenia comprising a therapeutically effective amount of a first ingredient comprising aripiprazole; AL NCD and a second component comprising: Aripiprazole with a third ingredient, lauroxyl Including, The kit further comprising instructions for administration, the instructions specifying oral administration of the first component, intramuscular administration of the second component, and intramuscular administration of the third component.

2. The kit of claim 1, wherein the therapeutically effective amount of the first component is about 5 to 50 mg.

3. 3. The kit of claim 1 or 2, wherein the therapeutically effective amount of the first component is about 30 mg.

4. 3. The kit of claim 1 or 2, wherein the therapeutically effective amount of the first component is about 15 mg.

5. The kit of any one of claims 1 to 4, wherein the therapeutically effective amount of the second component is about 629 to 695 mg.

6. 6. The kit of claim 1, wherein the therapeutically effective amount of the second component is about 675 mg.

7. The kit of any one of claims 1 to 5, wherein the therapeutically effective amount of the third component is about 300 to 1500 mg.

8. 8. The kit of claim 1, wherein the therapeutically effective amount of the third component is 441, 662, 882 or 1064 mg.

9. AL NCD 9. The kit of claim 1, comprising a population of particles of polysorbate 20, sodium citrate, sodium chloride, an aqueous buffer and aripiprazole lauroxyl.

10. 10. The kit of claim 9, wherein the population of particles of aripiprazole lauroxyl has a volume-based particle distribution diameter (Dv50) between about 175 nm and about 350 nm.

11. AL NCD 11. The kit of claim 1, wherein the ratio of the particles to polysorbate 20 is 17:

1.

12. 12. The kit of any one of claims 1 to 11, wherein all components of the method are administered substantially simultaneously.

13. 13. The kit of any one of claims 1 to 12, wherein the method comprises a regimen in which the first, second and third components are administered substantially simultaneously, and the first component is not administered again within 21 days of the first administration.

14. 14. The kit of any one of claims 1 to 13, wherein the method comprises a regimen in which the first, second and third components are administered substantially simultaneously, with the second administration of the components occurring no later than 21 days after the initial treatment.

15. 15. The kit of any one of claims 1 to 14, wherein the method comprises a regimen in which the first, second and third components are administered substantially simultaneously, followed by a second treatment comprising administering only the third component.

16. 16. The kit of claim 15, wherein the second treatment is administered no later than 21 days after the first treatment.

17. 17. The kit of any one of claims 1 to 16, wherein the first component is administered only once during the treatment period.

18. 18. The kit of any one of claims 1 to 17, wherein the first component is not administered again within 21 days after the initial treatment.

19. 13. The kit of any one of claims 1 to 12, wherein the method comprises a regimen in which the first component is administered only on the first and / or second day of treatment, the second component is administered only on the first day of treatment, and the third component is administered only once within the first 10 days of treatment.

20. 20. The kit of claim 19, wherein the regimen further comprises a second administration of only the third component.

21. 20. The kit of claim 19, wherein the third component is administered on day 1 of treatment.

22. 20. The kit of claim 19, wherein the third component is administered on the second day of treatment.

23. 20. The kit of claim 19, wherein the third component is administered 7 to 10 days after the start of the treatment regimen.

24. 24. The kit of any one of claims 19 to 23, wherein the first component is administered only on days 1 and 2 of treatment.

25. 25. The kit of any one of claims 19 to 24, wherein the first component is administered only on the first day of treatment.

26. 1. A method of treating schizophrenia in a subject in need thereof, comprising: a first component comprising about 5-50 mg of aripiprazole; Approximately 629-695 mg of AL NCD and a second component comprising: a third ingredient comprising a therapeutically effective amount of aripiprazole lauroxyl; The method comprises administering to a subject.

27. AL NCD 27. The method of claim 26, wherein the population of particles of polysorbate 20, sodium citrate, sodium chloride, an aqueous buffer and aripiprazole lauroxyl.

28. 28. The method of claim 26 or 27, wherein the population of aripiprazole lauroxyl particles has a volume-based particle distribution diameter (Dv50) between about 175 nm and about 350 nm.

29. AL NCD 29. The method of any one of claims 26 to 28, wherein the ratio of particles to polysorbate 20 is 17:

1.

30. 30. The method of any one of claims 26 to 29, wherein the first component is administered in a dosage of about 30 mg.

31. 30. The method of any one of claims 26 to 29, wherein the first component is administered in a dosage of about 15 mg.

32. 32. The method of any one of claims 26 to 31, wherein the second component is administered in a dosage of about 675 mg of active ingredient.

33. 33. The method of any one of claims 26 to 32, wherein the third component is administered in a dosage of about 300 to 1500 mg.

34. 33. The method of any one of claims 26 to 32, wherein the third component is administered in a dosage of 441, 662, 882 or 1064 mg.

35. 35. The method of any one of claims 26 to 34, wherein all components of the method are administered substantially simultaneously.

36. 35. The method of any one of claims 26 to 34, comprising a regimen in which the first, second and third components are administered substantially simultaneously, and the first component is not administered again within 21 days of the first administration.

37. 35. The method of any one of claims 26 to 34, comprising a regimen in which the first, second and third components are administered substantially simultaneously, with the second administration of the components occurring no later than 21 days after the initial treatment.

38. 36. The method of any one of claims 26 to 35, comprising a regimen in which the first, second and third components are administered substantially simultaneously, followed by a second treatment comprising administering only the third component.

39. 37. The method of claim 36, wherein the second treatment is administered no later than 21 days after the first treatment.

40. 38. The method of any one of claims 26 to 37, wherein the first component is administered only once during the treatment period.

41. 39. The method of any one of claims 26 to 38, wherein the first component is not administered again within 21 days after the initial treatment.

42. 33. The method of any one of claims 26 to 32, comprising a regimen in which the first component is administered only on the first and / or second days of treatment, the second component is administered only on the first day of treatment, and the third component is administered only once within the first 10 days of treatment.

43. 41. The method of claim 40, wherein the regimen further comprises a second administration of only the third component.

44. 41. The method of claim 40, wherein the third component is administered on day 1 of treatment.

45. 41. The method of claim 40, wherein the third component is administered on the second day of treatment.

46. 41. The method of claim 40, wherein the third component is administered 7 to 10 days after initiation of the therapeutic regimen.

47. 45. The method of any one of claims 40 to 44, wherein the first component is administered only on days 1 and 2 of treatment.

48. 45. The method of any one of claims 40 to 44, wherein the first component is administered only on the first day of treatment.

49. 49. The method of any one of claims 26 to 48, wherein the first component is administered orally.

50. 50. The method of any one of claims 26 to 49, wherein the second component is administered intramuscularly.

51. 51. The method of any one of claims 26 to 50, wherein the second component is administered intramuscularly to the deltoid or gluteus muscle.

52. 52. The method of any one of claims 26 to 51, wherein the second component is administered intramuscularly in the deltoid muscle.

53. 53. The method of any one of claims 26 to 52, wherein the third component is administered intramuscularly.

54. 54. The method of any one of claims 26 to 53, wherein the third component is administered intramuscularly to the deltoid or gluteus muscle.

55. 1. A method of treating schizophrenia in a subject in need thereof, comprising: a first ingredient comprising aripiprazole; AL NCD and a second component comprising: Aripiprazole with a third ingredient, lauroxyl administering to a subject the combined dosage of the first, second and third components is sufficient to maintain a therapeutically effective mean plasma level of aripiprazole in the subject; method.

56. 56. The method of claim 55, wherein the therapeutically effective mean plasma level of aripiprazole is about 102 to 435 ng / mL at steady state plasma levels.

57. 57. The method of claim 55 or 56, wherein the therapeutically effective mean plasma level of aripiprazole is greater than about 102 ng / mL at steady state plasma levels.

58. 58. The method of claim 55 or 57, wherein the therapeutically effective mean plasma level of aripiprazole is less than about 435 ng / mL at steady state plasma levels.

59. AL NCD 59. The method of any one of claims 55 to 58, wherein the population of particles of polysorbate 20, sodium citrate, sodium chloride, an aqueous buffer and aripiprazole lauroxyl.

60. 60. The method of claim 59, wherein the population of particles of aripiprazole lauroxyl has a volume-based particle distribution diameter (Dv50) between about 175 nm and about 350 nm.

61. AL NCD 61. The method of any one of claims 55 to 60, wherein the particle size is 17:1 to polysorbate 20 ratio.

62. 62. The method of any one of claims 55 to 61, wherein a therapeutically effective mean plasma level of aripiprazole is reached within 24 hours of the first treatment.

63. 63. The method of any one of claims 55 to 62, wherein the therapeutically effective mean plasma level of aripiprazole is maintained for 21 days or more.

64. 64. The method of any one of claims 55 to 63, wherein all components of the method are administered substantially simultaneously.

65. 65. The method of any one of claims 55 to 64, comprising a regimen in which the first, second and third components are administered substantially simultaneously, and the first component is not administered again within 21 days of a first administration.

66. 66. The method of any one of claims 55 to 65, comprising a regimen in which the first, second and third components are administered substantially simultaneously, with the second administration of the components occurring no later than 21 days after the initial treatment.

67. 67. The method of any one of claims 55 to 66, comprising a regimen in which the first, second and third components are administered substantially simultaneously, followed by a second treatment comprising administering only the third component.

68. 66. The method of claim 65, wherein the second treatment is administered no later than 21 days after the first treatment.

69. 69. The method of any one of claims 55 to 68, wherein the first component is administered only once during the treatment period.

70. 70. The method of any one of claims 55 to 69, wherein the first component is not administered again within 21 days after the initial treatment.

71. 64. The method of any one of claims 55 to 63, comprising a regimen in which the first component is administered only on the first and / or second days of treatment, the second component is administered only on the first day of treatment, and the third component is administered only once within the first 10 days of treatment.

72. 72. The method of claim 71, wherein the regimen further comprises a second administration of only the third component.

73. 72. The method of claim 71, wherein the third component is administered on day 1 of treatment.

74. 72. The method of claim 71, wherein the third component is administered on the second day of treatment.

75. 72. The method of claim 71, wherein the third component is administered 7 to 10 days after initiation of the therapeutic regimen.

76. 76. The method of any one of claims 71 to 75, wherein the first component is administered only on days 1 and 2 of treatment.

77. 76. The method of any one of claims 71 to 75, wherein the first component is administered only on the first day of treatment.

78. 78. The method of any one of claims 55 to 77, wherein the first component is administered orally.

79. 79. The method of any one of claims 55 to 78, wherein the second component is administered intramuscularly.

80. 80. The method of any one of claims 55 to 79, wherein the second component is administered intramuscularly to the deltoid or gluteus muscle.

81. 81. The method of any one of claims 55 to 80, wherein the second component is administered intramuscularly in the deltoid muscle.

82. 82. The method of any one of claims 55 to 81, wherein the third component is administered intramuscularly.

83. 83. The method of any one of claims 55 to 82, wherein the third component is administered intramuscularly to the deltoid or gluteus muscle.

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