Population pharmacokinetics of aripiprazole and its active metabolite dehydroaripiprazole in subjects receiving once-monthly intramuscular aripiprazole.
Enrique Bandín-Vilar (1,2,3), Francisco Toja-Camba (1,2,3), María Vidal-Millares (4), María José Durán-Maseda (4), Ana Castro-Balado (1,2,3), Irene Zarra-Ferro (1,2), Dolors Soy (5,6), Anxo Fernández-Ferreiro (1,2), Víctor Mangas-Sanjuan (7,8), Cristina Mondelo-García (1,2)
(1) Pharmacy Department, University Clinical Hospital of Santiago de Compostela, Santiago de Compostela, Spain, (2) Clinical Pharmacology Group, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain, (3) Pharmacology, Pharmacy and Pharmaceutical Technology Department, Faculty of Pharmacy, University of Santiago de Compostela (USC), Santiago de Compostela, Spain, (4) Psychiatry Department, University Clinical Hospital of Santiago de Compostela, Spain, (5) Pharmacy Department, Division of Medicines, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain, (6) Department of Pharmacology, Toxicology and Chemical Therapeutics, School of Pharmacy, University of Barcelona, Barcelona, Spain, (7) Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, Valencia, Spain, (8) Interuniversity Research Institute for Molecular Recognition and Technological Development, Polytechnic University of Valencia - University of Valencia, Valencia, Spain.
Introduction: Aripiprazole is an antipsychotic whose systemic metabolism is mainly carried out by hepatic biotransformation, mediated by CYP2D6 and, to a lesser extent, by CYP3A4. Dehydroaripiprazole is the main active metabolite of aripiprazole and accounts for 40% of its plasma exposure (1). Long-acting injectable (LAI) antipsychotics are a resource to ensure treatment adherence in patients with psychiatric pathologies. Aripiprazole once-monthly (AOM) is an extended-release drug for intramuscular injection. A target Ctrough of 100-350 ng/mL for aripiprazole and 150-500 ng/mL for active moiety (aripiprazole plus dehydroaripiprazole) at steady-state conditions has been proposed (2). Given the complex pharmacokinetics of LAI antipsychotics, population modelling to characterize the pharmacokinetics of AOM is a useful method to fully understand their pharmacokinetic properties (3).
Objectives: The aims of this work were (i) to build a non-linear mixed effects model of aripiprazole and its active metabolite dehydroaripiprazole and (ii) to identify the sources of inter-individual variability in these subjects.
Methods: Blood samples were collected from subjects who received at least 5 doses of AOM immediately before the administration and 2, 4, 6, 14, 25 and 28 days later. Concentrations of aripiprazole and dehydroaripiprazole were measured by a validated ultra-high performance liquid chromatography-tandem mass spectroscopy (UHPLC-MS/MS) method. Age, gender, weight, height, body mass index, serum creatinine, glomerular filtration, AST, ALT, GGT, bilirubin and site of injection (gluteal or deltoid) were collected. CYP2D6 and CYP3A4 metabolizer status was assessed after pharmacogenetic analysis. Concomitant treatment with strong inhibitors/inducers of CYP2D6/CYP3A4 was also registered.
Modelling was performed using NONMEM® (version 7.5) with the first-order conditional estimation with interaction method (FOCE-I). Different base structural models were tested and selected based on the difference of the objective function value (dOFV), the Akaike Information Criterion (AIC) and the goodness-of-fit (GOF) plots. Subsequently, a stepwise covariate modelling (scm) was performed applying a forward inclusion (p<0.1), followed by a backward elimination (p<0.05) procedure. The final PK model was evaluated using the visual predictive check (VPC) method and the bootstrapping technique.
Results: A total of 258 observations from 22 subjects were included. A one-compartment model for both aripiprazole and dehydroaripiprazole with linear absorption and elimination, adequately described the concentration-time profiles. Inter-individual variability (IIV) was assumed to follow a log-normal distribution.
Covariate analysis identified a statistically significant relationship of CYP2D6 (both metabolizing status and concomitant treatment with CYP2D6 inhibitors) on apparent parent clearance (CLP/F) and body weight on aripiprazole absorption rate constant (Ka). The final parameter values (CV%) were the following: Ka = 0.000525 h-1 (18.8%). CLP/F = 0.977, 1.35 and 1.58 L/h (29.4%) for poor, intermediate, and normal CYP2D6 metabolizers, respectively. Aripiprazole apparent volume of distribution (V2/F) was 275 L (170.2%). Dehydroaripiprazole apparent clearance (CLM/fm) was 3.54 L/h (27%) and dehydroaripiprazole apparent volume of distribution (V3/fm) was 28.6 L, where fm is the unknown fraction metabolized. The proportional error was 23.5%.
Conclusions: The present population pharmacokinetic model of aripiprazole and its active metabolite dehydroaripiprazole successfully characterized longitudinal data for both molecules simultaneously in psychiatric patients receiving once-monthly aripiprazole. The impact of body weight (95.8% higher Ka in a subject weighting 40 kg vs 140 kg), CYP2D6 metabolizer status (14% and 39% lower CLP for intermediate and poor vs normal metabolizers) and concomitant treatment with CYP2D6 inhibitors (59.4% lower CLP) showed a relevant impact on the pharmacokinetics of aripiprazole and dehydroaripiprazole. Further evaluation of dosing regimens is required to assess whether alternative dosing regimens may be necessary in clinical practice.
References:
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