Influence of CYP2D6 Phenotypes on the Pharmacokinetics of Aripiprazole and Dehydro-Aripiprazole Using a Physiologically Based Pharmacokinetic Approach
Open Access
- 14 June 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Clinical Pharmacokinetics
- Vol. 60 (12), 1569-1582
- https://doi.org/10.1007/s40262-021-01041-x
Abstract
Background and Objectives Aripiprazole is an atypical antipsychotic drug that is metabolized by cytochrome P450 (CYP) 2D6 and CYP3A4, which mainly form its active metabolite dehydro-aripiprazole. Because of the genetic polymorphism of CYP2D6, plasma concentrations are highly variable between different phenotypes. In this study, phenotype-related physiologically based pharmacokinetic models were developed and evaluated to suggest phenotype-guided dose adjustments. Methods Physiologically based pharmacokinetic models for single dose (oral and orodispersible formulation), multiple dose, and steady-state condition were built using trial data from genotyped healthy volunteers. Based on evaluated models, dose adjustments were simulated to compensate for genetically caused differences. Results Physiologically based pharmacokinetic models were able to accurately predict the pharmacokinetics of aripiprazole and dehydro-aripiprazole according to CYP2D6 phenotypes, illustrated by a minimal bias and a good precision. For single-dose administration, 92.5% (oral formulation) and 79.3% (orodispersible formulation) of the plasma concentrations of aripiprazole were within the 1.25-fold error range. In addition, physiologically based pharmacokinetic steady-state simulations demonstrate that the daily dose for poor metabolizer should be adjusted, resulting in a maximum recommended dose of 10 mg, but no adjustment is necessary for intermediate and ultra-rapid metabolizers. Conclusions In clinical practice, CYP2D6 genotyping in combination with therapeutic drug monitoring should be considered to personalize aripiprazole dosing, especially in CYP2D6 poor metabolizers, to ensure therapy effectiveness and safety.Keywords
Funding Information
- H2020 Marie Skłodowska-Curie Actions (721236 grant)
- Westfälische Wilhelms-Universität Münster
This publication has 37 references indexed in Scilit:
- A Computational Systems Biology Software Platform for Multiscale Modeling and Simulation: Integrating Whole-Body Physiology, Disease Biology, and Molecular Reaction NetworksFrontiers in Physiology, 2011
- Aripiprazole in schizophrenia and schizoaffective disorder: A reviewClinical Therapeutics, 2010
- Polymorphism of Human Cytochrome P450 2D6 and Its Clinical SignificanceClinical Pharmacokinetics, 2009
- Effects of Hepatic or Renal Impairment on the Pharmacokinetics of AripiprazoleClinical Pharmacokinetics, 2008
- Serum levels of aripiprazole and dehydroaripiprazole, clinical response and side effectsThe World Journal of Biological Psychiatry, 2008
- Pharmacokinetic Variability of Aripiprazole and the Active Metabolite Dehydroaripiprazole in Psychiatric PatientsTherapeutic Drug Monitoring, 2006
- Aripiprazole and its human metabolite are partial agonists at the human dopamine D2 receptor, but the rodent metabolite displays antagonist propertiesEuropean Journal of Pharmacology, 2006
- PM Frequencies of Major CYPs in Asians and CaucasiansDrug Metabolism Reviews, 2003
- AripiprazoleCNS Drugs, 2002
- Interactions of the Novel Antipsychotic Aripiprazole (OPC-14597) with Dopamine and Serotonin Receptor SubtypesNeuropsychopharmacology, 1999