Pharmacokinetic Profile of a 2-Month Dose Regimen of Aripiprazole Lauroxil: A Phase I Study and a Population Pharmacokinetic Model
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BACKGROUND: Aripiprazole lauroxil (AL) is a long-acting injectable medication approved for the treatment of schizophrenia. Current AL regimens are 441 mg, 662 mg, and 882 mg administered monthly (every 4 weeks [q4wk]), or 882 mg administered every 6 weeks (q6wk). OBJECTIVE: We examined the feasibility of a 2-month (every 8 weeks [q8wk]) dosing interval of AL in a phase I open-label pharmacokinetic study investigating AL 1064 mg administered q8wk for 24 weeks, followed by 20 weeks of safety and pharmacokinetic measurements (ClinicalTrials.gov ID: NCT02320032). Second, a population pharmacokinetic model (referred to as the 2MPopPK model) was generated using data collected from the present trial, as well as data obtained from earlier studies. METHODS: The phase I study included patients with schizophrenia or schizoaffective disorder maintained on an oral antipsychotic (n = 140) who were assigned to one of three groups: AL 441 mg q4wk, AL 882 mg q6wk, or AL 1064 mg q8wk, with a total of seven, five, or four injections administered, respectively. No oral aripiprazole lead-in supplementation was administered and patients continued on maintenance oral antipsychotics. Pharmacokinetic samples were collected at various time points during the 24-week study period and the 20-week follow-up period. Plasma concentrations obtained from the phase I study were analyzed using non-compartmental methods. Additionally, the data were combined with data collected from prior studies to develop the 2MPopPK model. RESULTS: values were 125.8 ng/ml, 131.1 ng/ml, and 140.7 ng/ml for the 441 mg q4wk, 882 mg q6wk, and 1064 mg q8wk doses, respectively. The mean elimination half-life of aripiprazole following the last dose was 53.9 days for the 1064 mg dose, 55.1 days for the 882 mg dose, and 57.2 days for the 441 mg dose. The 2MPopPK dataset included 14,524 aripiprazole concentrations from 700 patients with schizophrenia. The duration of absorption of aripiprazole was estimated as 43 days (95% confidence interval [CI] 42-45 days), which was preceded by a 3.2-day lag time (95% CI 3.0-3.5 days) for a total duration of input into the systemic circulation of 46 days following intramuscular administration of AL. Multiple-dose simulations showed that the 1064 mg q8wk regimen provides aripiprazole concentrations within the concentration range associated with 441 mg and 882 mg q4wk doses previously demonstrated to be efficacious in a phase III study. CONCLUSION: These data from the phase I study and the 2MPopPK model support the suitability of using the AL 1064 mg dose as a 2-month (q8wk) dose interval option for the treatment of schizophrenia.
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Using data after tmax (41 days) estimates the elimination half-life of aripiprazole lauroxil at 53.9-57.2 days.
“Using data after tmax (41 days) estimates the elimination half-life of aripiprazole lauroxil at 53.9–57.2 days [66].”
From Pharmacokinetic Characteristics of Long-Acting Injectable Antipsychotics for Schizophrenia: An Overview (2021) · cites this paper as [66]
The Results (Phase I Pharmacokinetics; page unavailable) report a mean elimination half-life of 53.9–57.2 days for aripiprazole after the last aripiprazole lauroxil injection. They place maximum aripiprazole concentrations at 24.4–35.2 days, not a tmax of 41 days. The paper does not say the half-life was estimated using data only after day 41, and the reported half-life is for aripiprazole rather than the prodrug. (LLM, conf=0.88)
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- Authors
- Hard, M. L., Mills, R. J., Sadler, B. M., Wehr, A. Y., Weiden, P. J., & von Moltke, L.
- Affiliations
- Alkermes (United States) (US)
- Icon (United Kingdom) (GB)
- ORCID
- Weiden, Peter J.
- Venue
- CNS Drugs
- Published
- 2017-06-08
- Volume
- 31
- Issue
- 7
- Pages
- 617-624
- ISSN
- 1172-7047 (ISSN-L)
- 1179-1934
- PMC
- PMC5511303
- OpenAlex
- W2621768849
- Cited by
- 44
- References
- 11
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 5 · 2023: 10 · 2022: 5 · 2021: 8 · 2020: 3 · 2019: 3 · 2018: 3 · 2017: 3
- FWCI
- 2.70
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- CNS Drugs (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- Alkermes, Inc.
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- aripiprazole lauroxil, long-acting injectable antipsychotics, dosing interval, population pharmacokinetic model, elimination half-life, schizophrenia, schizoaffective disorder, plasma concentration, dose proportionality, pharmacokinetic variability, drug safety and tolerability, adverse events
- MeSH terms
- Aripiprazole, Administration, Oral, Adult, Drug Administration Schedule, Drug Therapy, Combination, Feasibility Studies, Female, Follow-Up Studies, Humans, Injections, Male, Middle Aged, Models, Biological, Psychotic Disorders, Schizophrenia, Antipsychotic Agents
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