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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.
Lee et al. (Tue,) studied this question.