Pharmacokinetic Profile of a 2-Month Dose Regimen of Aripiprazole Lauroxil: A Phase I Study and a Population Pharmacokinetic ModelReportar como inadecuado




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CNS Drugs

, Volume 31, Issue 7, pp 617–624

First Online: 08 June 2017

Abstract

BackgroundAripiprazole 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.

ObjectiveWe 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.

MethodsThe 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.

ResultsFollowing the final injection of AL in the phase I study, maximum aripiprazole concentrations were achieved 24.4–35.2 days after the last dose and persisted for the duration of the study. The mean Cavg,ss 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.

ConclusionThese 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.

Electronic supplementary materialThe online version of this article doi:10.1007-s40263-017-0447-7 contains supplementary material, which is available to authorized users.

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Autor: Marjie L. Hard - Richard J. Mills - Brian M. Sadler - Angela Y. Wehr - Peter J. Weiden - Lisa von Moltke

Fuente: https://link.springer.com/



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