Methods for dose initiation of aripiprazole treatments

Abstract

The present disclosure is directed to a method of dose initiation for an aripiprazole treatment to a patient in need thereof; the patient is administered two, separate 100 to 500 mg injections of an aripiprazole intramuscular (IM) depot formulation at separate gluteal and / or deltoid injection sites, and a single dose of oral aripiprazole. The administration occurs on a first day of the treatment.

Description

[0095] Simulation Results

[0096] The final combined model was utilized to simulate aripiprazole plasma concentration-time profiles following oral, gluteal, and / or deltoid administration of aripiprazole. To compare simulated PK profiles, a virtual population consisting of 817 subjects with similar demographic characteristics to the subjects enrolled in the clinical trials in the final analysis dataset (provided under “popPK Model”) was used to ensure only the dosing regimen changed across simulations. Individual PK parameters for subjects in the final analysis dataset (all assigned as CYP2D6 extensive metabolizers (EM) except for simulation of CYP2D6 poor metabolizers [PM] subjects) were generated from the final combined PK model and its final parameter estimates. Individual PK profiles following oral, gluteal, and deltoid administration of aripiprazole were simulated using a 2-hour sampling interval for 24 hours post the preceding oral dose and every 24-hour sampling post the preceding IM Depot dose. A full listing of all simulations performed is provided in Figures 3A-3C.

[0097] Alternative Initiation Regimen Without Prior Oral Aripiprazole Stabilization

[0098] Several scenarios for dose initiation were simulated to assess the time to achieve concentrations within the therapeutic window as provided above under the heading entitled “Therapeutic Window and Aripiprazole Plasma Concentrations During Dose Initiation with Alternative Initiation Regimen.” The median and 5th to 95th percentile of concentration of simulated aripiprazole plasma PK profiles for the currently approved initiation regimen (400 mg with 14 days of 10 to 20 mg oral dosing) and the alternative initiation regimen (2 x 400 mg with 1 day of 20 mg oral dosing) administered as two separate injections in the gluteal and / or deltoid sites are shown in Figures 4A - 4D. In Figures 4A - 4D, approved initiation regimen was 10 to 20 mg oral (14 days) and 400 mg IM depot (day 1).

[0099] Based on the simulations, in Figures 4A - 4D, the median and 5th to 95th percentile of concentration of the aripiprazole PK profile following administration of the proposed alternative initiation regimen is comparable to the approved initiation regimen of 400 mg aripiprazole IM on Day 1 + 10 mg to 20 mg oral aripiprazole for 14 days, for example:

[0100] - Median aripiprazole PK profiles following the alternative initiation regimen reach therapeutic levels (10 mg daily aripiprazole Cmin,ss of 94.0 ng / mL) on the first day and remain above the lower threshold of the therapeutic window thereafter.

[0101] - The 95th percentile of simulated concentrations following the proposed alternative initiation regimen are comparable to, or lower than, the 95th percentile of the currently approved regimen and within the upper bound of the therapeutic window, as discussed above.

[0102] - Plasma concentrations for all regimens exceed the previously used conservative upper bound of the 75th percentile of simulated Cmax,ss following daily administration of 541 ng / mL but remain below the 95th percentile of the simulated 30 mg oral Cmax,ss (741 ng / mL).

[0103] - The alternative initiation regimen has no impact on steady state maintenance con centration.

[0104] Alternative Initiation Regimen With Prior Oral Aripiprazole Stabilization

[0105] In the approved label for Abilify Maintena(R), the first dose is administered with concomitant oral aripiprazole (10 to 20 mg) for 14 consecutive days to adult patients stabilized with oral aripiprazole. Thus, simulations were performed to predict and compare plasma concentrations during the 28 days following administration of the currently approved and the alternative initiation regimen to patients stabilized with 20 mg aripiprazole, which is the highest typical oral dose a patient would be receiving prior to initiating treatment with IM depot of aripirazole. The median, 5th, 25th to 75th, and 95th percentile of simulated aripiprazole plasma PK profiles for the currently approved and the alternative initiation regimen administered as two separate injections in the gluteal or deltoid sites of subjects with prior stabilization on an oral aripiprazole dose of 20 mg are presented in Figures 5A and 5B. In Figures 5A and 5B, the approved initiation regimen was 10 to 20 mg oral (14 days) and 400 mg IM depot (Day 1). The starting concentration at time zero is the average concentration at steady state for subjects stabilized on 20 mg oral aripiprazole.

[0106] Based on the simulations, the median and 5th to 95th percentile of concentration of the aripiprazole PK profile following administration of the alternative initiation regimen is comparable to the approved initiation regimen when administered to subjects already stabilized on 20 mg oral aripiprazole:

[0107] - The 95th percentile of simulated concentrations following the alternative initiation regimen are comparable to, or lower than, the 95th percentile of the approved regimen.

[0108] - The alternative initiation regimen has no impact on steady state maintenance con centration.

[0109] Subjects who are CYP2D6 Poor Metabolizers

[0110] In subjects who are known to be cytochrome P450 2D6 poor metabolizers (CYP2D6 PM), the currently approved IM depot initiation dose should be reduced from 400 to 300 mg due to an approximately 50% lower apparent clearance of aripiprazole. Simulations were thus performed to predict aripiprazole concentrations following administration of the alternative initiation regimen to CYP2D6 extensive metabolizers (EM) and PM subjects. A comparison of the simulated median concentration time profiles and boxplots of maximum aripiprazole plasma concentrations (Cmax) following a single dose of 20 mg oral aripiprazole along with two administrations of either 400 mg (CYP2D6 EM and PM subjects) or 300 mg (only CYP2D6 PM subjects) Abilify Maintena(R) in the gluteal or deltoid sites is presented in Figures 6A and 6B. In Figures 6A and 6B, the approved initiation regimen was 10 to 20 mg oral (14 days) and 400 mg IM depot (Day 1).

[0111] Simulations of plasma concentrations were performed to also allow comparison of the simulated median concentration time profiles and boxplots of aripiprazole Cmax following a single dose of 20 mg oral aripiprazole along with two administrations of either 400 mg (CYP2D6 EM and PM subjects) or 300 mg (CYP2D6 PM subjects only) IM depot aripiprazole formulation in the gluteal or deltoid sites of subjects or patients with prior stabilization on 20 mg (EM) or 10 mg (PM) oral aripiprazole. These simulations are presented in Figures 7A and 7B. In Figures 7A and 7B, the approved initiation regimen is 10 to 20 mg oral (14 days) + 400 mg IM depot (Day 1). The starting concentration at time zero is the average concentration at steady state for CYP2D6 EM stabilized on 20 mg oral aripiprazole and PM subjects stabilized on 10 mg oral aripiprazole. For PMs, prior oral dose was reduced by half (10 mg instead of 20 mg).

[0112] As expected, simulations resulted in CYP2D6 PM subjects exhibiting higher aripiprazole Cmax and exposure compared to CYP2D6 EM subjects when both receive two administrations of 400 mg IM depot aripiprazole formulation. Thus, a dose reduction of the proposed regimen from two 400 mg IM depot aripiprazole formulation administrations to two 300 mg IM depot aripiprazole formulation administrations along with a single dose of 20 mg oral aripiprazole is recommended for known CYP2D6 PM subjects or patients to ensure concentrations following the alternative initiation regimen are comparable to the currently approved regimen and remain within or slightly above the therapeutic window.

[0113] Missed Maintenance IM Depot Dose

[0114] Simulations were performed to assess aripiprazole concentrations following a missed second, third, fourth, or steady-state dose of IM depot aripiprazole formulation to determine whether the alternative initiation regimen could be applicable to situations when the currently approved initiation regimen requires concurrent oral administration of aripiprazole for 2 weeks with a single IM depot aripiprazole formulation injection.

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

[0116] A comparison of the simulated median aripiprazole plasma concentrations following administration of the alternative initiation regimen or the currently approved initiation regimen in the gluteal or deltoid site when the 4th or 5th (steady-state) dose is administered 6 weeks after the previous injection are provided in Figures 9A - 9D. In Figures 9A - 9D, the approved initiation regimen was 10 to 20 mg oral (14 days) and 400 mg IM depot (Day 1).

[0117] In all simulations, administration of the alternative initiation regimen following a missed maintenance IM depot resulted in median aripiprazole concentrations above the lower threshold of the therapeutic window and similar to those following the approved initiation regimen.

[0118] Based on the results of the simulations, the alternative initiation regimen may be administered in place of concomitant oral aripiprazole for 14 days together with a single IM depot formulation of aripiprazole injection on Day 1 when a maintenance IM depot dose is missed. Such a treatment strategy following a missed dose is consistent with that in the Abilify Maintena(R) label.

[0119] Comparison and Analyses of Results Across Trials

[0120] An analysis was performed to evaluate observed safety outcomes from a subset of 17 subjects from the phase I clinical trial describe below with plasma concentration time profiles that fall within the 5th to 95th percentile of simulated concentrations following administration of the alternative initiation regimen and are consistently above the mean PK profile following a single gluteal administration of 400 mg Abilify Maintena(R). A graphical comparison of all aripiprazole concentration time profiles following a single dose of 780 mg (N = 18) or 1200 mg (N = 13) aripiprazole LAI to the gluteal muscle (from a previous clinical trial), with aripiprazole concentration time profiles from the subset of 17 subjects highlighted in red, is presented in Figure 11. In Figure 11, the N equals the number of subjects; the subset of 17 subjects from a trial with plasma concentration time profiles that fall within the 5th to 95th percentile of simulated concentration following administration of the alternative initiation regimen and are consistently above the mean PK profile following a single gluteal administration of 400 mg Abilify Maintena(R); and lower limit of quantitation of aripiprazole was 0.500 ng / mL.

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

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

[0123] Conclusions

[0124] Simulations indicated that the two-injection start regimen of two administrations of aripiprazole once-monthly at separate gluteal and / or deltoid injection sites with a single 20 mg dose of oral aripiprazole on the first day of treatment regimen would: (1) achieve therapeutic aripiprazole plasma concentrations on the first day of treatment; (2) support consistent clinical effectiveness over the entire dosing interval; (3) result in comparable aripiprazole plasma concentrations thus, safety profile, to the currently approved (traditional) initiation regimen; and (4) provide a new initiation option which obviates the need for the 14-day oral tablet supplementation, potentially reducing compliance related undertreatment during the initiation phase of treatment.

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

[0126] This trial was an open-label, single ascending dose, parallel-arm, multiple-center trial to determine the PK, safety, and tolerability of single-dose administration of 780 mg (Cohort 1) and 1200 mg (Cohort 2) of a high dose formulation of aripiprazole LAI that is in the gluteal muscle of adult subjects with schizophrenia. Data from this trial is supportive information, as it was evaluated for instances in which aripiprazole plasma concentrations increased at a similar rate and reached levels predicted in simulations for the alternative initiation regimen. Overall, aripiprazole LAI was well tolerated when administered IM as a single dose of 780 mg and 1200 mg to adult subjects with schizophrenia. In a subset of 17 subjects, the administration of aripiprazole LAI resulted in higher aripiprazole plasma concentrations as well as faster absorption rates, resulting in aripiprazole plasma concentration time profiles that fell within the 5th to 95th percentile of simulated concentrations following administration of the proposed alternative initiation regimen and were consistently above the mean PK profile following a single gluteal administration of 400 mg Abilify Maintena(R) (Figure 1). Safety data from this subset of subjects was evaluated and compared to the known safety profile of Abilify Maintena(R). Further details of this analysis are provided under the section entitled “Comparison and Analyses of Results Across Trials.”

[0127] The aripiprazole LAI was an extended release presentation for dosing every 2 months at the dose levels evaluated. The extension of the dosing interval for the aripiprazole LAI was primarily through an increase in the dose while maintaining minimum aripiprazole concentrations that are comparable to Abilify Maintena(R) after multiple doses. The aripiprazole LAI was engineered with higher aripiprazole concentrations in the drug product (300 mg / mL vs 200 mg / mL) and minor changes to the vehicle compared to currently marketed / approved Abilify Maintena(R). The mean aripiprazole particle size distribution and the dissolution profile for the aripiprazole LAI formulation were comparable with the Abilify Maintena(R) formulation and the formulation was expected to have a similar extended release profile compared with the approved Abilify Maintena(R) formulation. Mean (standard deviation [SD]) aripiprazole plasma concentration time profiles following administration of a single dose of 780 mg or 1200 mg aripiprazole to the gluteal muscle in subjects with schizophrenia are presented in Figure 12.

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

[0129] [Table 2] TABLES Mean (SD) Aripiprazole Pharmacokinetic Parameters Following MministHiwofaSmgteDcmM ■ AsOgdnjectafifetoW PK Parameter ArippsdBZMRTO. W Wo mg ■ Aripipi^oteW : 'lit" ' lO(rng-: CffiaxfngBiy 27T (157) 391 / (200) 25.1(40-76.0) AUCt (ng dawr<j 126® 23800^(7520) AIJO» (ng<iay^ 24700 (6080)" 22.^ 20«:®2)e CLF (mL / dsy / kg) '763^ 596 (207F 0326(0.167) AUCt / Oose ([ng-da^mLp'mg) 16.1 p.75) 19®(R35) 17.2(5.90^

[0130] From Table 2, it is noted that AUCoo is area under the concentration-time curve calculated from time zero to infinity; AUCt is area under the concentration-time curve calculated to the last observable concentration at time t; CL / F is apparent clearance of drug from plasma after extravascular administration; RTU is ready to use; tmax is time to maximum (peak) plasma concentration; 11 / 2 is elimination half-life. Additionally,a Median (minimum-maximum); bn = 14; and cn = 11.

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

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

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

[0134] - Single-dose administration of 780 or 1200 mg aripiprazole LAI to the gluteal muscle resulted in a slightly less than proportional increase in aripiprazole Cmax and a slightly more than dose proportional increase in exposure (AUCt and AUCoo) based on mean values corrected for dose.

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

[0136] - Following administration of 780 or 1200 mg aripiprazole LAI to the gluteal muscle, mean terminal elimination half-life (tl / 2) values for aripiprazole (22.1 and 20.0 days, respectively) were comparable, and similar to the median tl / 2 following single-dose administration of 400 mg Abilify Maintena(R) to the gluteal muscle (24.0 days).

[0137] - A consistent increase in aripiprazole concentrations followed by a decline and a secondary peak in concentrations were observed following administration of 780 or 1200 mg aripiprazole LAI to the gluteal muscle based on examination of mean, median, and individual concentration-time profiles.

[0138] - Additionally, this Phase I trial supports the use of the present disclosure of a method of dose initiation for an aripiprazole treatment to a patient in need thereof comprising: administering two, separate injections of an aripiprazole intramuscular (IM) depot formulation ranging from about 10 mg to about 500 mg of aripiprazole to the patient at separate gluteal and / or deltoid injection sites, and a single dose of oral aripiprazole, wherein administration occurs on a first day of the treatment. That is, the use of two injections ranging from about 10 mg to about 500 mg of aripiprazole did not result in any unexpected AEs and the safety profile was in accordance with the known safety profile of Ability Maintena(R).

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

[0140] Claims or descriptions that include “or” or “and / or” between at least one members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The disclosure includes embodiments in which more than one, or all the group members are present in, employed in, or otherwise relevant to a given product or process.

[0141] Furthermore, the disclosure encompasses all variations, combinations, and permutations in which at least one limitation, element, clause, and descriptive term from at least one of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include at least one limitation found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should be understood that, in general, where the disclosure, or aspects of the disclosure, is / are referred to as comprising particular elements and / or features, embodiments of the disclosure or aspects of the disclosure consist, or consist essentially of, such elements and / or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub range within the stated ranges in different embodiments of the disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0142] Those of ordinary skill in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the disclosure described herein. Such equivalents are intended to be encompassed by the following claims. 26833299.1:DCC-3 / 11 / 2025 2021245713  11 Mar 2025

[0143] Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

[0144] The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Claims

1. A method of dose initiation for an aripiprazole treatment to a patient in needthereof, the method comprising:administering two, separate injections of an aripiprazole intramuscular (IM) depot formulation, wherein each injection comprises 300 mg or 400 mg of aripiprazole, to the patient at an injection site chosen from a gluteal site, a deltoid site, and combinations thereof, and a single dose of oral aripiprazole,wherein the step of administering the two separate injections and the single oral dose occurs on a first day of the treatment.

2. The method according to claim 1, wherein the patient in need of the aripiprazoletreatment is a patient with or without prior stabilization on oral aripiprazole.

3. The method according to claim 1, wherein the patient in need of the aripiprazoletreatment is a patient with prior stabilization on oral aripiprazole.

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

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

6. The method according to any one of claims 1 to 5, wherein the aripiprazoletreatment further comprises after the first day of the treatment, administering single monthly, maintenance injections of the aripiprazole IM depot formulation comprising 400 mg of aripiprazole.

7. The method according to any one of claims 1 to 5, wherein the aripiprazoletreatment further comprises after the first day of the treatment, administering single monthly, maintenance injections of the aripiprazole IM depot formulation comprising 300 mg of aripiprazole.2021245713   18 Aug 20268.     The method according to any one of claims 1 to 5, wherein when the patient is aCYP2D6 poor metabolizer or is taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors for greater than 14 days, and the aripiprazole treatment comprises administering single monthly, maintenance injections chosen from 160 mg and 200 mg of aripiprazole in the aripiprazole IM depot formulation.

9. The method according to any one of claims 6 to 8, wherein each maintenanceinjection is administered no sooner than 26 days after the previous injection.

10. The method according to any one of claims 1 to 9, wherein the two, separate injections of the aripiprazole IM depot formulation are administered at separate gluteal and / or deltoid injection sites of the patient.

11. The method according to claim 10, wherein the two, separate injections of the aripiprazole IM depot formulation are administered at separate gluteal injection sites of the patient.

12. The method according to claim 10, wherein the two, separate injections of the aripiprazole IM depot formulation are administered at gluteal and deltoid injection sites of the patient.

13. The method according to claim 10, wherein the two, separate injections of the aripiprazole IM depot formulation are administered at separate deltoid injection sites of the patient.

14. The method according to any one of claims 1 to 13, wherein the patient has schizophrenia.

15. The method according to any one of claims 1 to 13, wherein the patient has bipolar I disorder.2021245713   18 Aug 202616. The method according to any one of claims 1 to 15, wherein the single dose of oral aripiprazole ranges from about 2 mg to about 30 mg of aripiprazole.

17. The method according to claim 16, wherein the single dose of oral aripiprazole ranges from about 10 mg to about 30 mg.

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

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

20. The method according to claim 1, wherein when the patient is a CYP2D6 poor metabolizer, each of the two, separate injections comprise about 300 mg of aripiprazole and the single dose of oral aripiprazole is about 20 mg.

21. The method according to any one of claims 1 to 20, wherein the aripiprazole is in the form of a salt.

22. The method according to any one of claims 1 to 21, wherein the single dose of oral aripiprazole is administered along with the two, separate injections on the first day.

23. Use of aripiprazole in the manufacture of a medicament for dose initiation for an aripiprazole treatment to a patient in need thereof,wherein the treatment comprises administering two, separate injections of an aripiprazole intramuscular (IM) depot formulation, wherein each injection comprises 300 mg or 400 mg of aripiprazole, to the patient at an injection site chosen from a gluteal site, a deltoid site, and combinations thereof, and a single dose of oral aripiprazole,and wherein the treatment comprises the step of administering the two separate injections and the single oral dose on a first day of the treatment.2021245713   18 Aug 202624. The use according to claim 23, wherein the medicament is an aripiprazole intramuscular (IM) depot formulation comprising 300 mg or 400 mg of aripiprazole.

25. The use according to claim 23, wherein the medicament is a single oral dose of aripiprazole.

26. The use according to any one of claims 23 to 25, wherein the patient in need of the aripiprazole treatment is a patient with or without prior stabilization on oral aripiprazole.

27. The use according to any one of claims 23 to 25, wherein the patient in need of the aripiprazole treatment is a patient with prior stabilization on oral aripiprazole.

28. The use according to any one of claims 23 to 27, wherein each of the two, separate injections comprise 400 mg of aripiprazole.

29. The use according to any one of claims 23 to 27, wherein each of the two, separate injections comprise 300 mg of aripiprazole.

30. The use according to any one of claims 23 to 27, wherein the aripiprazole treatment further comprises after the first day of the treatment, administering single monthly, maintenance injections of the aripiprazole IM depot formulation comprising 400 mg of aripiprazole.

31. The use according to any one of claims 23 to 29, wherein the aripiprazole treatment further comprises after the first day of the treatment, administering single monthly, maintenance injections of the aripiprazole IM depot formulation comprising 300 mg of aripiprazole.

32. The use according to any one of claims 23 to 29, wherein when the patient is a CYP2D6 poor metabolizer or is taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors for greater than 14 days, and the aripiprazole treatment comprises2021245713   18 Aug 2026administering single monthly, maintenance injections chosen from 160 mg and 200 mg of aripiprazole in the aripiprazole IM depot formulation.

33. The use according to any one of claims 30 to 32, wherein each maintenance injection is to be administered no sooner than 26 days after the previous injection.

34. The use according to any one of claims 23 to 33, wherein the two, separate injections of the aripiprazole IM depot formulation are to be administered at separate gluteal and / or deltoid injection sites of the patient.

35. The use according to claim 34, wherein the two, separate injections of the aripiprazole IM depot formulation are to be administered at gluteal and deltoid injection sites of the patient.

36. The use according to claim 34, wherein the two, separate injections of the aripiprazole IM depot formulation are to be administered at gluteal and deltoid injection sites of the patient37. The use according to claim 34, wherein the two, separate injections of the aripiprazole IM depot formulation are to be administered at separate deltoid injection sites of the patient.

38. The use according to any one of claims 23 to 37, wherein the patient has schizophrenia39. The use according to any one of claims 23 to 37, wherein the patient has bipolar I disorder.

40. The use according to any one of claims 23 to 39, wherein the single dose of oral aripiprazole ranges from about 2 mg to about 30 mg of aripiprazole41. The use according to claim 40, wherein the single dose of oral aripiprazole ranges2021245713   18 Aug 2026from about 10 mg to about 30 mg42.    The use according to claim 40, wherein the single dose of oral aripiprazole is 20 mg.

43. The use according to claim 40, wherein the single dose of oral aripiprazole is 10 mg44. The use according to any one of claims 23 to 25, wherein when the patient is a CYP2D6 poor metabolizer, each of the two, separate injections comprise about 300 mg of aripiprazole and the single dose of oral aripiprazole is about 20 mg45. The use according to any one of claims 23 to 44, wherein the aripiprazole is in the form of a salt46. The use according to any one of claims 23 to 45, wherein the single dose of oral aripiprazole is administered along with the two, separate injections on the first day

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