Physiologically based pharmacokinetic framework for predicting CYP3A4-mediated drug-drug interactions of quetiapine with ketoconazole and carbamazepine.

Quetiapine is primarily metabolized by CYP3A4, and its coadministration with potent CYP3A4 inhibitors (eg, ketoconazole) or inducers (eg, carbamazepine) may substantially alter systemic and central nervous system exposure. Although clinical evidence supports these interactions, quantitative predictions of plasma and brain interstitial concentrations remain limited. This study aimed to develop an integrated physiologically based pharmacokinetic (PBPK) model to quantitatively predict drug-drug interactions (DDIs) among quetiapine, ketoconazole, and carbamazepine, and to propose model-based dose-adjustment strategies to mitigate exposure-related risks. Previously validated PBPK models for quetiapine, ketoconazole, and carbamazepine were incorporated. Clinical DDI data from previous reports were digitized for model calibration, and parameters related to CYP3A4 inhibition and induction were optimized. Model qualification included visual predictive checks, residual analysis, and fold-error evaluation. The final model simulated multiple DDI scenarios, including concurrent and sequential coadministration, and explored dose-adjustment strategies for all 3 drugs. The PBPK model accurately reproduced observed quetiapine-ketoconazole and quetiapine-carbamazepine interaction profiles in both plasma and brain. Ketoconazole coadministration markedly increased quetiapine exposure (approximately 6-fold to 8-fold), whereas carbamazepine reduced exposure by approximately 4-fold to 6-fold. Concurrent or sequential triple-drug combinations induced substantial quetiapine fluctuations, indicating potential clinical instability. Dose-adjustment simulations suggested that quetiapine reduction (eg, 200 mg daily) partially mitigates ketoconazole-mediated overexposure, whereas even high quetiapine doses could not fully compensate for carbamazepine-induced underexposure. This model provides a robust quantitative framework for predicting quetiapine exposure under clinically relevant DDI scenarios and highlights the substantial risks associated with coadministration of potent CYP3A4 modulators. SIGNIFICANCE STATEMENT: Physiologically based pharmacokinetic modeling was used to quantitatively predict CYP3A4-mediated drug-drug interactions of quetiapine with ketoconazole and carbamazepine, integrating both systemic and brain interstitial exposure. The model reveals how strong CYP3A4 inhibition or induction markedly alters quetiapine exposure and provides a mechanistic framework to evaluate clinically relevant drug-drug interaction scenarios and guide evidence-based dose-adjustment strategies in psychotropic polypharmacy.