Single- and multiple-dose pharmacokinetics, safety, and tolerability of Aripiprazole once-monthly, long-acting intramuscular injection for Chinese adults with schizophrenia

Abstract

Background

Aripiprazole once-monthly (AOM), a long-acting injectable antipsychotic, is increasingly used in managing schizophrenia. However, to date, there has been no disclosure of pharmacokinetic data for AOM long-acting injection in the Chinese population. The present study aimed to evaluate the pharmacokinetics of AOM of Chinese patients with schizophrenia.

Methods

The single-administration part of the study was single-center and multiple-dose, in which 300/400-mg AOM was administered to 24 patients with schizophrenia. In the multiple-administration part of the study, 400-mg of AOM was administered once every 4 weeks for 20 consecutive weeks to 12 subjects. Pharmacokinetic parameters (e.g., e.g., Cmax, tmax, AUC0-∞, t1/2, and CL/F) were derived via non-compartmental analysis using actual sampling times, with bootstrap-derived confidence intervals for non-normal data. Safety evaluation included monitoring of adverse events (AEs), physical examinations, vital signs, and clinical laboratory tests.

Results

Following single administration of AOM (300-mg or 400-mg), maximum plasma concentration (C_max) values of aripiprazole were 85.05 ± 42.11 and 175.25 ± 67.84 ng/mL, respectively; median times to achieve C_max (t_max) were 816.17 and 588.84 h, respectively; and elimination half-life (t_1/2) values were 647.18 ± 234.59 and 547.17 ± 258.48 h, respectively. Following multiple administration of AOM, the C_max of aripiprazole was 270.18 ± 113.37 ng/mL, the median t_max was118.83, and the t_1/2 was 1138.78 ± 998.77 h. In vivo exposure to aripiprazole increased with the AOM dose. No severe AEs were observed in single- or multiple-administration studies.

Conclusions

The pharmacokinetics of AOM support its clinical use as a 4-week injectable regimen, with favorable tolerability and safety profiles observed in Chinese patients with schizophrenia.

Trial registration

ClinicalTrials.gov Identifier: Single-administration NCT03287505 first submitted on 15 May 2017, Multiple-administration NCT03285503 first submitted on 11 Sep 2017.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12888-025-07407-w.

Background

Schizophrenia affects nearly 1% of the world population and is among the top 10 global causes of disability [1]. One of the most important cause of functional disability is the multiple relapses of this disease [2]. Continued administration of antipsychotic medications after recovery from a psychotic episode can effectively reduce the risk of a relapse of psychosis [3]. However, nonadherence to antipsychotic medication is the most common cause of psychotic relapse [4]. Long-acting injectable (LAI) antipsychotic medications relieve patients from the daily need to take medication, meaning they can potentially improve adherence [5]. Presumably due to improved medication adherence, the advantages of LAI antipsychotics include decreased risks of mortality or hospitalization, and decreased rates of treatment discontinuation, including discontinuation due to inefficacy [3].

Aripiprazole is an atypical antipsychotic with a unique pharmacodynamic profile, characterized by its partial agonism at dopamine D₂ receptors. This mechanism distinguishes it from most antipsychotics, which typically function as full D₂ antagonists, and underlies its favorable tolerability and broad therapeutic utility [6]. Clinical trials and years of post-marketing statistical data indicate that aripiprazole has good safety/tolerability, including low incidence of extrapyramidal side effects, low risk of elevated prolactin, low weight gain, and few impacts on blood glucose and lipid metabolism [7]. Aripiprazole is administered orally or intravenously. It is available in tablets, orally disintegrating tablets, oral solution and injection form [8]. Aripiprazole oral formulations are approved for schizophrenia and bipolar disorder globally, with additional indications (adjunctive major depressive disorder, Tourette’s disorder and irritability in autism) in some regions. The recommended dosage of aripiprazole for adult schizophrenia is 10–15 mg/day, with a maximum dose of 30 mg/day [9]. Given that LAI formulations can improve adherence and thereby reduce the risk of relapse in schizophrenia [10], and that aripiprazole has favorable tolerability and safety, the LAI formulation of aripiprazole is of significant importance in the maintenance treatment of schizophrenia. Two aripiprazole LAI formulations are approved for clinical use: aripiprazole monohydrate and aripiprazole lauroxil. This study utilized the aripiprazole monohydrate formulation (Abilify Maintena^®), which employs a nanocrystalline suspension technology for sustained drug release.

While aripiprazole LAI is widely used globally, its pharmacokinetics in Chinese populations remain poorly characterized. Asian populations exhibit distinct CYP2D6 polymorphism frequencies that may alter aripiprazole metabolism compared to Western cohorts [11]. The primary objective of this study was to characterize the pharmacokinetic profile of aripiprazole LAI in Chinese adults with schizophrenia. Secondarily, we aimed to evaluate the safety profile and preliminarily explore dose-exposure relationships to inform clinical use. This represents the first comprehensive pharmacokinetic analysis of aripiprazole LAI in Chinese adults with schizophrenia, addressing a critical gap in ethnic-specific PK data. The findings provide evidence-based support for optimizing therapeutic regimens in this patient population, including safety and tolerability verification, dose optimization and frequency determination.

Methods

The study was performed in Beijing Anding Hospital at Capital Medical University in China from August 2017 to October 2019. This trial was conducted in compliance with ethical standards of the Helsinki declaration, Good Clinical Practice guidelines, and all applicable local regulations. The protocol and its amendments, and informed consent forms were reviewed and approved by the Beijing Anding Hospital Ethics Review Board (Ethical Approval Number: 201717FS-2, 201718FS-2). Written informed consent was obtained from all participants after the nature of the procedures had been fully explained and prior to study participation.

Study design

This was a single-center, open-label, two-part (single-administration first, multiple-administration second) study in Chinese adults with schizophrenia that assessed the PK, safety, and tolerability of AOM. In the single-administration part of the study, the first 12 subjects received 300-mg of AOM, while the following 12 subjects received 400-mg of AOM (See Figure S1). In the multiple-administration part of the study, 400-mg of AOM was administered once every 4 weeks for 20 consecutive weeks (five intramuscular injections per subject) to 12 subjects (See Figure S2).

Subject selection

Male and female subjects were aged 18–64 years; had a diagnosis of schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria; and a body mass index of 18.5 (inclusive) to 35 kg/m². Patients displaying any evidence of organ dysfunction or who had a medically significant abnormal physical examination, laboratory test, or electrocardiogram were excluded. Subjects with any psychiatric diagnoses other than schizophrenia according to DSM-IV-TR were excluded. Patients who took any CYP3A4 or CYP2D6 inhibitors, or inducers or foods prohibited by both protocol within the 28 days (single-administration) or 14 days (multiple-administration) before the AOM administration were also excluded.

Study drug and usage

For the single-administration study, successfully selected subjects without a medication history of aripiprazole were orally administered a 10-mg aripiprazole tablet once to ensure that the subjects did not experience any hypersensitivity reaction. After a 35-day wash-out period, a single intramuscular injection of 300-mg/400-mg was administered deep into the buttock by a designee before or after breakfast on the morning of day 1 of the trial. For subjects with a history of aripiprazole administration who confirmed that they did not experience any hypersensitivity reaction to aripiprazole and had not been administered this drug in at least 35 days, a single dose of 300-mg/400-mg AOM was injected into the gluteal muscle. After AOM was administered, subjects were hospitalized for at least 35 days. Subsequently, follow-up visits could be completed in outpatient clinics. Other antipsychotics that do not inhibit or induce CYP3A4 and CYP2D6 could be combined during the trial. The therapeutic drugs in use at the time of signing the informed consent varied in dosage and manner of administration depending on the patient’s situation. The addition of new antipsychotics was allowed when unavoidable, such as when symptoms worsened.

For the multiple-administration study, all enrolled patients had demonstrated ≥ 28 days of stable antipsychotic monotherapy, with aripiprazole-treated subjects maintained at 10–20 mg/day. For subjects receiving non-aripiprazole antipsychotics at screening, a 14-day transition to fixed-dose oral aripiprazole monotherapy (10–20 mg/day) was required, followed by a minimum 14-day stabilization period at this target dose prior to baseline. To bridge the pharmacokinetic gap after initial LAI administration, participants continued their pre-existing oral aripiprazole regimen (10–20 mg/day) for 14 days. Subsequently, each subject was administered 400-mg of AOM by intramuscular injection deep into the buttock before or after breakfast every 4 weeks until they received a total of five intramuscular injections. The post-treatment observation period was 4 weeks after the last administration. Subjects were hospitalized for at least 14 days after the first AOM was administered. Other antipsychotics were forbidden during the trial until the post-treatment observation period.

Study assessments

Safety evaluation indicators included adverse events (AEs), vital signs (blood pressure, pulse, and body temperature), physical examination, laboratory tests (including prolactin), 12-lead echocardiogram (ECG), reactions at the injection site (redness, swelling, induration, and pain), Simpson-Angus Scale (SAS), Abnormal Involuntary Movement Scale (AIMS), Barnes Akathisia Rating Scale (BARS), Columbian Suicide Severity Rating Scale (C-SSRS), and weight. In addition, Positive and Negative Symptom Scale (PANSS), Clinical Global Impression Severity Scale (CGI-S), and Clinical Global Impression-Improvement (CGI-I, only in multiple-dose part) were evaluated. AEs and safety assessments were reported for all subjects who received at least one injection of AOM.

In the single-administration part of the study, the indices above were evaluated during the screening period and at Day 23, Day 56, Day 84, Day 112, and Day 140. In the multiple-administration part, PANSS and CGI were evaluated during the screening period and at Week 4, Week 8, Week 12, Week 16, and Week 20; in addition, SAS, AIMS, BARS, and C-SSRS were evaluated at Week 24.

Bioanalytical method

Plasma concentrations of aripiprazole and its major metabolite dehydro-aripiprazole were quantified by a fully validated ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) assay, with a lower limit of quantification (LLOQ) of 0.5 ng/mL for both analytes.

Pharmacokinetic (PK) analysis

Subjects that received at least one plasma drug concentration measurement were included in the PK analysis set. The non-compartmental analysis method (Linear Up Log Down) with Phoenix WinNonlin version 8.2 (Certara LP, Princeton, NJ, USA) software was used to calculate PK parameters of the original drug aripiprazole and its main metabolite dehydro-aripiprazole. All parameters were calculated based on the actual sampling time. Analysis is performed only on observed data, excluding missing or dropped values.For point estimates of PK parameters, the nonparametric bootstrap method (with 1000 resamples) was used to calculate 95% confidence intervals (CIs) to account for non-normally distributed data. If the data followed a normal distribution, the parametric method (based on the t-distribution) was employed for CI computation. The coefficient of variation (CV%) is calculated as: (Standard Deviation/Mean) × 100%.

In the single-administration part of the study, the maximum plasma concentration (C_max), time to maximum plasma concentration (t_max), area under the curve from time 0 to infinity (AUC_0−∞ or AUC_inf), area under the curve from time 0 to last measurable concentration (AUC_0−t or AUC_last), area under the curve from time 0 to day 140 (AUC_140d), elimination rate constant (ke), elimination half-life (t_1/2), percentage of extrapolated AUC in AUC_0−∞ (AUC_%_Extrap or %AUC_ex), apparent clearance rate (CL/F*), apparent volume of distribution (V_z/F*, *only for aripiprazole as unchanged), and time to last measurable concentration (t_last) were calculated for aripiprazole and dehydro-aripiprazole.

In the multiple-administration part of the study, C_672h values of aripiprazole and dehydro-aripiprazole were calculated before the first administration and after all subsequent administrations of AOM. In addition, the following PK parameters of aripiprazole and dehydro-aripiprazolewere calculated after the fifth administration: C_max, t_max, AUC_672h, Ke, t_1/2, CLss/F*, Vz/F*, Cavg, and DF (*only calculated for aripiprazole).

Statistical analysis

PK parameters and safety data are summarized using descriptive statistics. Mean changes from baseline were recorded at each visit for the PANSS total score and CGI-S score, and compared using an analysis of covariance.

Results

Subjects distribution

In the single-administration study, 24 subjects were enrolled (12 each in 300-mg AOM and 400-mg AOM cohorts), received treatment with AOM and underwent at least one plasma drug concentration measurement. All 24 subjects were included in the safety analysis set (SS) and PK analysis set. All 24 subjects completed the trial without any premature discontinuation (See Figure S3).

In the multiple-administration study, a total of 12 subjects were successfully screened and received at least one AOM administration and plasma concentration quantification. These 12 subjects were included in SS and PK analysis sets. Among the 12 subjects included in the PK analysis, 11 completed the trial per protocol. One subject discontinued after the third administration due to an adverse event but contributed trough concentration data up to the scheduled pre-fourth-administration timepoint. Trough concentrations before the first four administrations were analyzed for all 12 subjects, whereas the fifth pre-administration trough concentration and steady-state PK parameters were calculated using data from the 11 subjects who completed the study (See Figure S4).

Baseline demographic characteristics and psychiatric histories of the study cohort are summarized in Table 1.

Table 1.

Baseline demographic and psychiatric characteristics (Safety Set)

Variables	Single administration study		Multiple administration study
	Aripiprazole IMD 300 mg (N = 12)	Aripiprazole IMD 400 mg (N = 12)	(N = 12)
Sex male
n (%)	11 (91.7)	11 (91.7)	11 (91.7)
Race, Han nationality
n (%)	12 (100)	10 (83.3)	11 (91.7)
Age, years
mean (SD)	41.3 (12.48)	35.3 (13.21)	32.4 (6.30)
BMI, kg/m2
mean (SD)	26.53 (3.22)	24.38 (4.51)	23.91 (4.14)
Baseline disease characteristics
Age at first diagnosis of schizophrenia (years), mean (SD)	29.3 (10.46)	27.1 (9.39)	32.4(6.30)
PANSS total score, mean (SD)	73.3 (10.4)	80.0 (8.2)	65.5 (14.5)
CGI-S score, mean (SD)	4.6 (1.0)	5.0 (0.7)	3.9 (0.9)

SD standard deviation, BMI body mass index, PANSS Positive and Negative Syndrome Scale, CGI-S Clinical Global Impressions-Severity

Pharmacokinetics

Concentration-time profiles of aripiprazole in the single-administration study are shown in Fig. 1, while concentration-time profiles of the aripiprazole metabolite dehydro-aripiprazole are shown in Fig. 2. Administration of a single dose of AOM (300-mg or 400-mg) resulted in dose-dependent increases in plasma exposure (AUC and Cmax) for both aripiprazole and dehydro-aripiprazole, although their concentration-time curves displayed comparable shapes across doses (e.g., similar T_max and elimination half-lives). Aripiprazole was slowly absorbed into the blood, as indicated by the plasma concentration reaching a plateau around 5 days after the first administration. Importantly, this plateau was maintained for nearly 40 days and only started to gradually decrease around 42 days. The plasma concentration of the aripiprazole metabolite dehydro-aripiprazole generally reached a plateau around 11 days after the first administration. Plateau levels of this metabolite were maintained for nearly 30 days and also started to gradually decrease around 42 days.

Fig. 1.

Mean (± Standard Deviation) Plasma Concentration-Time Curves of aripiprazole After Single Administration

Fig. 2.

Mean (± Standard Deviation) Plasma Concentration-Time Curves of dehydro-aripiprazole After Single Administration

Detailed PK parameters for aripiprazole and its metabolite dehydro-aripiprazole following administration of a single dose of AOM (300-mg or 400-mg) are listed in Table 2.

Table 2.

PK parameters of Aripiprazole and dehydro-aripiprazole in the Single-Administration study

PK parameter	Aripiprazole		Dehydro-aripiprazole
	300 mg	400 mg	300 mg	400 mg
Cmax, ng/mL, mean ± SD (CV%)	85.05 ± 42.11 (49.51%)	175.25 ± 67.84 (38.71%)	25.93 ± 11.40 (43.97%)	57.88 ± 16.28 (28.12%)
tmax, h, median (min, max)	816.17 (167.87, 1632.82) (58.31%)	588.84 (120.17, 1321.47) (65.06%)	986.76 (264.57, 1658.73) (48.04%)	732.73 (168.03, 1633.80) (61.00%)
AUC0−t, ng·h/mL, mean ± SD (CV%)	135542.84 ± 43956.57 (32.43%)	207885.47 ± 54465.08 (26.20%)	42102.25 ± 13069.80 (31.04%)	77636.85 ± 26683.83 (34.37%)
AUC0−∞, ng·h/mL, mean ± SD (CV%)	150488.55 ± 48560.28 (32.27%)a	216425.11 ± 53373.24 (24.66%)	51698.14 ± 12922.30 (25.00%)b	82958.21 ± 29875.91 (36.01%)
AUC140d, ng·h/mL, mean ± SD (CV%)	135625.12 ± 43810.12 (32.30%)	208328.10 ± 54354.52 (26.09%)	42140.49 ± 13120.06 (31.13%)	77881.32 ± 26694.50 (34.28%)
t1/2, h, mean ± SD (CV%)	647.18 ± 234.59 (36.25%)a	547.17 ± 258.48 (47.24%)	712.62 ± 328.87 (46.15%)b	607.04 ± 285.09 (46.96%)
Vz/F, L, mean ± SD (CV%)	1990.12 ± 894.47 (44.95%)a	1588.52 ± 878.54 (55.31%)	——	——
CL/F, L/h, mean ± SD (CV%)	2.14 ± 0.52 (24.30%)a	1.99 ± 0.68 (34.36%)	——	——

 Vz/F apparent volume of distribution during terminal phase after non-intravenous administration

CL/F apparent total clearance of the drug from plasma after administration

PK pharmacokinetic, SD standard deviation, CV coefficient of variation, AUC area under the curve 

All other parameters n = 12

^an = 9

^bn = 8

The concentration-time profiles of aripiprazole and its metabolite in the multiple-administration study are shown in Fig. 3. It can be seen from the mean trough concentration-time curve of aripiprazole and dehydro-aripiprazole, as well as the individual trough concentration-time curves after five consecutive administrations, that both of plasma concentrations reached a steady state before the fourth intramuscular injection of AOM with administration once every 4 weeks. Moreover, there was little variation in the trough concentration-time curve of each subject.

Fig. 3.

Mean Minimum Concentration (± Standard Deviation)-Time Curve of aripiprazole and dehydro-aripiprazole After the First Administration in the Multiple-Administration Study

The concentration-time profiles of aripiprazole and its metabolite dehydro-aripiprazole after the last administration (Day 113) are shown in Fig. 4. The results indicate that aripiprazole was slowly absorbed, as the plasma drug concentration in the body gradually increased, peaked at about 118.83 h, and then gradually decreased. Similarly, the plasma concentration of dehydro-aripiprazole slowly increased after administration, peaked around 167.27 h after administration, and then slowly decreased.

Fig. 4.

Mean Minimum Concentration (± Standard Deviation)-Time Curve of aripiprazole and dehydro-aripiprazole After the Fifth Administration in the Multiple-Administration Study

Detailed PK parameters for aripiprazole and its metabolite dehydro-aripiprazole in the multiple-administration study are listed in Table 3.

Table 3.

PK parameters of Aripiprazole and dehydro-aripiprazole in the multiple-administration study

PK parameter	aripiprazole	Dehydro-aripiprazole
Cmax, ng/Ml, mean ± SD (CV%)	270.18 ± 113.37a (41.96%)	101.13 ± 39.88a (39.43%)
tmax, h, median (min, max) (CV%)	118.83 (70.73, 262.8)a (44.61%)	167.27 (1, 263.98)a (53.54%)
AUC0−t, ng·h/mL, mean ± SD (CV%)	239457.41 ± 101552.26a (42.41%)	97788.92 ± 45809.44a (46.85%)
AUC672h, ng·h/mL, mean ± SD (CV%)	138113.19 ± 58821.46a (42.59%)	55217.76 ± 24685.29a (44.71%)
t1/2, h, mean ± SD (CV%)	1138.78 ± 998.77b (87.71%)	1057.19 ± 909.14b (86%)
Vz/F, L, mean ± SD (CV%)	4623.94 ± 4051.37b (87.62%)	——
CL/F, L/h, mean ± SD (CV%)	3.49 ± 1.71a (49.01%)	——

Vz/F apparent volume of distribution during terminal phase after non-intravenous administration

CL/F apparent total clearance of the drug from plasma after administration

PK pharmacokinetic, SD standard deviation, CV coefficient of variation, AUC area under the curve 

^an = 11 

^bn = 10

Safety and tolerability

Treatment-emergent adverse events (TEAEs) at an incidence of ≥ 10% are summarized in Table 4. Most TEAEs were classified as mild or moderate in severity. No subject discontinued with treatment due to TEAEs in the single-administration study, although one discontinuation (8.3%) occurred in the multiple-administration study (due to worsening of schizophrenia).

Table 4.

Summary of TEAEs with an incidence ≥ 10% (Safety Set)

TEAE, n (%)	Single Administration of Arip IMD 300 mg	Single Administration of Arip IMD 400 mg	Multiple Administration of Arip IMD 400 mg
Weight gaina	3 (25.0)	4 (33.3)	4 (33.3)
Weight increaseb			2 (16.7)
Blood pressured increased	1 (8.3)	2 (16.7)	2 (16.7)
Anxiety	2 (16.7)	4 (33.3)
Constipation	3 (25.0)	2 (16.7)
Injection site pain	5 (41.7)	2 (16.7)
Nasopharyngitis			4 (33.3)
Extrapyramidal disorder			2 (16.7)
Sinus bradycardia			2 (16.7)
White blood cell count decrease			3 (25.0)
γ-glutamyl transpeptidase abnormal	3 (25.0%)
triglyceride abnormal		2 (16.7%)

TEAE Treatment-emergent adverse event

^aEvents with a weight gain of ≥ 7% increase from baseline were analyzed

^bEvents with a weight decrease of ≥ 7% increase from baseline were analyzed

No subject experienced redness, swelling, or induration at the injection site after injection of the study drug. In the single-administration study, increasing numbers of subjects in both 300-mg and 400-mg AOM cohorts experienced pain at the injection site from 1 h to 12 h after injection of the study drug. However, 24 h after injection, the number of subjects reporting injection-site pain decreased progressively over time. Three days after injection, no subject experienced pain at the injection site at any visit. In the multiple-administration study, one subject (8.3%) experienced mild pain at the injection site 1 h after the first injection of the investigational drug, and no subject experienced any pain at the injection site at other time points. All injection site reaction TEAEs were considered mild in intensity and resolved without sequelae.

Based on the SS, at 4 weeks after the first administration in the multiple-administration study, one subject (8.3%) had suicidal ideation (Active Suicidal Ideation with Any Methods without Intent to Act). At sixteen weeks after the first administration, one subject (8.3%) had suicidal ideation (Wish to Be Dead).

Mean changes in objective rating movement scales from baseline to last visit were minimal and not considered to be clinically meaningful. No significant changes in SAS, AIMS, or BARS scores occurred for any cohort.

In the single-administration study, mean scores of PANSS and CGI-S in both 300-mg and 400-mg AOM cohorts were decreased from baseline at 23 days, 8 weeks, 12 weeks, 16 weeks, and 20 weeks post-treatment; moreover, the score-reduction rate gradually increased with prolonged administration time. At 20 weeks, mean PANSS and CGI-S scored in the 400-mg AOM cohort were slightly more decreased compared with the 300-mg AOM cohort (PANSS: −16.90 ± 10.03 and − 19.30 ± 16.63; CGI-S: −1.3 ± 1.37 and − 1.0 ± 0.85). The same decreasing trend for PANSS and CGI-S scores was observed in the multiple-administration study. Twenty weeks after the first administration, mean values of PANSS and CGI-S score changes from baseline were − 16.0 ± 12.30 and − 1.0 ± 1.10, respectively (See Table S1).

Clinically relevant changes from baseline were observed for hematology results, urinalysis, prolactin levels, and serum chemistry laboratory tests, as listed in Table 4. No clinically relevant changes were observed for vital signs in the single-administration study. In the multiple-administration administration study, 1 subject (8.3%) with a systolic pressure ≤ 90 mmHg and a change from baseline ≤−20 mmHg; 1 subject (8.3%) with a diastolic blood pressure ≥ 105 mmHg and a change from baseline ≥ 15 mmHg; 1 subject (8.3%) with a heart rate ≤ 50 bpm and a change from baseline ≤−15 bp.

Discussion

This is the first study conducted in Chinese subjects to characterize the PK, safety, and tolerability of AOM following single and multiple administration.

Following single administration of AOM (300-mg or 400-mg), the mean concentration-time curve showed a similar trend for the two dose cohorts, and the plasma drug exposure level increased with dose in a proportionate manner. Figure 1 demonstrates a delay in peak attainment during the absorption phase. Both dose cohorts exhibit a slow-rising sigmoidal curve. The peak time of the 400-mg cohort is approximately 588.84 h (24.5 days), and that of the 300-mg cohort is 816.17 h (34.0 days), which is consistent with the expected characteristics of nanocrystal sustained-release formulations. The 400-mg cohort has a faster absorption rate (steeper slope), possibly related to the increased local concentration gradient caused by the higher dose [13]. The plateau phase is stable with a bimodal pattern, consistent with the characteristics of long-acting injectables. The elimination phase shows a biexponential elimination pattern, and the terminal slopes of the two dose cohorts are parallel, suggesting linear pharmacokinetics. The concentration-time curve trend of aripiprazole following administration in this study was similar to that of a previous single-administration study in Japan [13]. Median t_max values for subjects in 300-mg and 400-mg AOM cohorts were also similar to the Japanese study (816.17 h vs. 648.20 h, and 588.84 h vs. 840.75 h, respectively). In addition, mean t_1/2 (647.18 h vs. 351 h, and 547.17 h vs. 727.30 h, respectively), C_max (85.05 ng/mL vs. 259.00 ng/mL, and 175.25 ng/mL vs. 113.10 ng/mL, respectively), and AUC (135.54 µg·h/mL vs. 190.00 µg·h/mL, and 207.89 µg·h/mL vs. 155.70 µg·h/mL, respectively) were similar between these two studies.

After multiple administrations of AOM (400-mg), the systemic concentration of aripiprazole increased to the C_max in 118.83 h (about 5 days) after the last administration on Day 112 and the mean terminal elimination half-life was 47.5 days. In a previous study [14], the aripiprazole C_max occurred 5.0 to 7.1 days after 400-mg injection of AOM, and the average terminal t_1/2 of aripiprazole was 46.5 days. In another study [15], t_max and t_1/2 values were 95.7 h (about 4 days) and 55.8 days. The mean plasma concentration of aripiprazole reached a steady state in all subjects before the fourth injection. Therefore, the PK characteristics of AOM (400-mg) elicited by multiple administration in this study are consistent with the conclusions of previous studies. The engineered low solubility of aripiprazole nanocrystals dictates prolonged drug release from the intramuscular depot, where nanocrystal dissolution becomes the rate-limiting step for systemic absorption [16]. Accordingly, after intramuscular injection, the drug was slowly absorbed into the blood, yielding the PK characteristics of a long-acting formulation.

The observed sigmoidal pharmacokinetic profile of aripiprazole long-acting injectable formulation reflects the unique release characteristics of its nanocrystalline suspension system [17]. Following intramuscular administration, the initial lag phase (0–3 days) corresponds to the hydration and structural reorganization of the drug depot, resulting in minimal drug release and consequently low plasma concentrations during this period. As the hydration layer surrounding individual nanocrystals thickens over time, it facilitates the development of a nanoporous network through which accelerated drug release occurs. This process generates the steep ascending curve that reaches the first peak concentration (day7). The rapid dissolution of surface-localized drug nanocrystals within the depot leads to transient release rate reduction upon exhaustion of this immediately available fraction. Concurrently, the post-peak concentration decline reflects the distribution phase, characterized by drug redistribution from the central compartment (plasma) to peripheral tissues [18]. Therefore, the drug concentration decreases after 7 days and rises again after 14 days. Thus, in clinical use, oral aripiprazole can be reduced in dosage on day 7 but should continue to be used until day 14. The biexponential elimination of aripiprazole long-acting injectable stems from its microcrystalline depot release properties, high lipophilicity, and in vivo processes [18]. In the first phase, the rapid drop in plasma concentration results from both the termination of rapid surface drug release and the drug’s fast transfer to peripheral compartments (accelerated by high lipophilicity). In the second phase, with surface “easily released” drug exhausted, slow inner depot release and balanced drug distribution between compartments lead to a slower concentration decline, dominated by metabolism and excretion.

Psychopathological symptoms remained stable during the study period. PANSS and CGI scores demonstrated progressive reductions across all cohorts. In the AOM single-dose administration cohort, most participants had recently completed acute-phase treatment and entered consolidation therapy, with baseline PANSS scores reflecting residual symptoms (300-mg cohort: 73.3 ± 10.41; 400-mg cohort: 80 ± 8.21). The observed symptom improvement likely reflects the therapeutic progression inherent to this treatment phase rather than specific effects of the study drug. In the AOM multiple-dose cohort, symptom stability improved over time with long-acting injection therapy. However, based solely on the current study design, without an oral aripiprazole medication control, we cannot determine whether the observed clinical improvement resulted from superior efficacy of the LAI formulation or simply reflected disease modification over prolonged treatment duration. A meta-analysis [19] comparing aripiprazole tablets and AMO for maintenance treatment in schizophrenia showed no difference in terms of efficacy. However, the all-cause discontinuation rate was significantly lower with the LAI than with oral medication, while the discontinuation rate due to adverse events was comparable. These findings highlight that the core clinical value of the long-acting injectable formulation lies in its ability to improve treatment continuity.

The majority of TEAEs reported were mild or moderate. In the single-dose cohort, common TEAEs included weight increase (16.7%), injection site pain (25.0%), and constipation (16.7%), with slight dose-related variations in incidence. In the multiple-dose cohort, TEAEs such as weight change (increase: 33.3%; decrease: 16.7%), decreased white blood cell count (16.7%), sinus bradycardia (16.7%), and extrapyramidal symptoms (16.7%) were observed. Other drug-related TEAEs occurred in < 10% of subjects. Notably, this safety profile is consistent with historical data from previous AOM trials, showing comparable patterns of adverse reactions, which supports the reproducibility of AOM’s safety profile across studies [20]. Abnormalities in hematology, biochemical tests, or urinalysis that were judged by the investigators to be clinically significant were observed in some individual subjects. However, these findings were not considered indicative of a new safety signal related to AOM, and the overall safety and tolerability profile remained consistent with expectations, revealing no new safety concerns.

A limitation of this study is that all subjects were physically healthy adults, which may restrict the generalizability of the derived pharmacokinetic characteristics and tolerability profiles to other age groups and populations with comorbidities.

Metabolism of aripiprazole primarily occurs through the liver via CYP2D6 and CYP3A4 [21]. Approximately 8% of Caucasians, 3–8% of Black/African Americans, and up to 2% of Asians cannot metabolize CYP2D6 substrates and are therefore classified as “poor metabolizers” [22]. Compared with “normal metabolizers”, “intermediate” and “poor” metabolizers exhibited 50.4% and 59.3% higher serum concentrations of aripiprazole, respectively [23]. As a direction for future research, well-powered studies should characterize aripiprazole exposure differences across CYP2D6 phenotypes, particularly in underrepresented Asian populations where genotypic prevalence remains understudied.

Conclusions

In this study, the pharmacokinetic profile of AOM supports its clinical use as a monthly injectable regimen, with favorable safety and tolerability demonstrated in Chinese schizophrenia patients. The evidence establishes AOM as a viable monthly antipsychotic option for Chinese schizophrenia patients.

Abbreviations

AEs

Adverse events

AIMS

Abnormal involuntary movement scale

AOM

Aripiprazole once-monthly

AUC

Area under the curve

AUC_0-∞ or AUC_inf

Area under the curve from time 0 to infinity

AUC_0-t or AUC_last

Area under the curve from time 0 to last measurable concentration 

AUC_140d

Area under the curve from time 0 to day 140

AUC_%_Extrap or %AUC_ex

Percentage of extrapolated AUC in AUC_0-∞

BARS

Barnes akathisia rating scale

C_max

Maximum plasma concentration

C-SSRS

Columbian suicide severity rating scale

CGI-I

Clinical global impression-improvement

CGI-S

Clinical global impression severity scale

CV

Coefficient of variation

DSM-IV-TR

Diagnostic and statistical manual of mental disorders, fourth edition, text revision

ECG

Echocardiogram

ke

elimination rate constant

LAI

Long-acting injectable

PANSS

Positive and negative symptom scale

PK

Pharmacokinetics

SAS

Simpson-angus scale

SD

Standard deviation

SS

Safety analysis set

t_1/2

Elimination half-life

TEAEs

Treatment-emergent adverse event

t_last

Time to last measurable concentration

t_max

Time to maximum plasma concentration

V_z/F

Apparent volume of distribution

Authors’ contributions

FD and AL had full access to all of the data in the study and took responsibility for the integrity of the data and the accuracy of the data analysis. FD, AL and TJ were involved in the study concepts and design. All authors (FD, FW, XY, YZ, MU, TJ, AL) were involved in the acquisition, analysis and interpretation of data. FD, AL and TJ supervised the analysis. FD, AL and MU were involved in the draft of the manuscript. All authors read, critically revised and approved the manuscript.

Funding

Not applicable.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

This study was approved by the ethics committee of The Beijing Anding Hospital Ethics. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Written informed consent was obtained from individual participants.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.