Quantitation of the impact of CYP3A5 A6986G polymorphism on quetiapine pharmacokinetics by simulation of target attainment.

PMID 27137148 | DOI 10.1002/cpdd.172 · Clinical pharmacology in drug development · 2015 · View on PubMed ↗

The aim of this study was to evaluate whether genetic polymorphisms in CYP3A5 and ABCB1 are responsible for the interindividual variability observed in quetiapine pharmacokinetics. Pharmacokinetic data from a randomized crossover study evaluating 2 quetiapine 25 mg immediate-release tablets after single oral dose were used to develop a population pharmacokinetic model. The single nucleotide polymorphisms (SNPs) evaluated for the genotype effects of quetiapine pharmacokinetics were CYP3A5 A6986G and ABCB1 C3435T, along with other demographic variables and formulations. A one-compartment distribution model with linear elimination plus four transit compartments for the delayed absorption adequately described quetiapine disposition. CYP3A5 *1/*1 individuals (n = 3) had 29% increased clearance compared to *1/*3 and *3/*3 individuals. The impact of an increased clearance was evaluated by simulations. By computing the probability of target attainment (PTA) of steady-state therapeutic goal at 1-hour and 12-hour time points after 50-400 mg twice-daily regimens, the results indicated that CYP3A5 genotype has minimal impact on the PTA of the 1-hour concentrations but a significant impact on the 12-hour concentrations. The interpretation based on the simulations does not call for a genotype-based dosing scheme and is consistent with consensus guidelines for quetiapine that therapeutic drug monitoring is considered useful. Clinical Pharmacology in Drug Development.