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 (C max ) and trough concentration (C trough ) at steady-state of olaparib (OLA) in Caucasian, Japanese and Chinese. On top of that, the PBPK model was then combined with the mean and 95% confidence interval to predict optimal dosing regimens of OLA when co-administered with CYP3A4 modulators and administered in patients with hepatic impairment based on safety and efficacy PK threshold C max (< 12500 ng/mL) and C trough (772–2500 ng/mL). Here, the population PBPK model of OLA has been successfully developed and validated based on the prediction good consistent with the clinically observed data. The ratio of prediction to observation for C max and C trough was between 0.5 and 2.0. The dosing regimens of OLA should be reduced to 100 mg BID and 150 BID, respectively, when dosed with a strong or moderate CYP3A4 inhibitor. Additionally, the PBPK model also suggested that OLA should be permitted with CYP3A4 inducer (strong or moderate).The PBPK model also suggested that dosing regimens of OLA should be reduced to 200 mg BID and 150 mg BID in patients with moderate hepatic and renal impairment. In addition, in patients with severe hepatic and renal impairment, dosing regimens of OLA were suggested to be reduced to 100 mg BID by the PBPK model. Overall, the present PBPK model can identify the optimal dosing regimens in multiple clinical situations.