Precision Pharmacokinetics of Quetiapine: A Physiologically Based Model Incorporating Liver Cirrhosis and CYP3A4 Polymorphisms

Quetiapine, an atypical antipsychotic primarily metabolized by CYP3A4, exhibits altered pharmacokinetics (PK) in patients with liver cirrhosis and individuals with CYP3A4 polymorphisms. This study aimed to develop and validate a physiologically based pharmacokinetic (PBPK) model to predict the effects of hepatic impairment and CYP3A4*22 variants on quetiapine PK. A model was developed using data from healthy individuals administered a single 25 mg dose and validated against 19 independent clinical datasets. Subsequently, the model was adapted to simulate PK in patients with liver cirrhosis (Child-Pugh A, B, and C) and those with CYP3A4*1/*22 and *22/*22 genotypes. Simulation results showed a significant increase in systemic exposure and a corresponding decrease in apparent clearance as hepatic impairment worsened or in the presence of CYP3A4*22 alleles. Model-based dose adjustments were proposed and validated, effectively aligning drug exposure levels in specific populations with those observed in healthy controls. In severe cases (Child-Pugh C with CYP3A4*22/*22), only 5% of the standard dose was required to achieve reference exposure levels. This study demonstrates that PBPK modeling is a valuable tool for optimizing individualized dosing in patients with hepatic impairment or genetic variability. These findings offer clinically relevant insights for safer and more effective quetiapine therapy through evidence-based dose adjustments.