Physiologically-based pharmacokinetic modeling for optimal dosage prediction of olaparib when co-administered with CYP3A4 modulators and in patients with hepatic/renal impairment

Abstract

This study aimed to develop a physiologically-based pharmacokinetic (PBPK) model to predict the maximum plasma concentration (Cmax) and trough concentration (Ctrough) at steady-state of olaparib (OLA) in Caucasian, Japanese and Chinese. Furthermore, the PBPK model was combined with mean and 95% confidence interval to predict optimal dosing regimens of OLA when co-administered with CYP3A4 modulators and administered to patients with hepatic/renal impairment. The dosing regimens were determined based on safety and efficacy PK threshold Cmax (< 12,500 ng/mL) and Ctrough (772–2500 ng/mL). The population PBPK model for OLA was successfully developed and validated, demonstrating good consistency with clinically observed data. The ratios of predicted to observed values for Cmax and Ctrough fell within the range of 0.5 to 2.0. When OLA was co-administered with a strong or moderate CYP3A4 inhibitor, the recommended dosing regimens should be reduced to 100 mg BID and 150 mg BID, respectively. Additionally, the PBPK model also suggested that OLA could be not recommended with a strong or moderate CYP3A4 inducer. For patients with moderate hepatic and renal impairment, the dosing regimens of OLA were recommended to be reduced to 200 mg BID and 150 mg BID, respectively. In cases of severe hepatic and renal impairment, the PBPK model suggested a dosing regimen of 100 mg BID for OLA. Overall, this present PBPK model can determine the optimal dosing regimens for various clinical scenarios involving OLA.