Population pharmacokinetics of ipatasertib and its metabolite in cancer patients

This study was undertaken to characterize pharmacokinetics profiles of ipatasertib and its metabolite M1 (G-037720), and to understand the sources of variability. Population pharmacokinetic models of ipatasertib and M1 were developed separately using data from 342 individuals with cancer from five Phase I and II studies. The final population pharmacokinetic models for ipatasertib and M1 were three-compartmental, with first-order elimination and sequential zero- and first-order absorption. Ipatasertib bioavailability and M1 formation increased after multiple dosing resulting in an increase in exposure beyond that expected from accumulation alone. Covariate effects of ipatasertib include decreased oral clearance with increasing age and with coadministration of abiraterone, as well as decreased bioavailability with increasing weight. For ages of 37 and 80 years, steady-state area under the curve (AUCss ) were predicted to be 81% and 109% of the typical population value (64 years), respectively. For body weights of 49 and 111 kg, AUCss were predicted to be 132% and 78% of the typical population value (75 kg), respectively. The small magnitude of changes in ipatasertib exposure is not likely to be clinically relevant. For M1, the peripheral distribution volume and intercompartmental clearance increased with increasing weight. Coadministration of abiraterone was estimated to increase M1 exposure by 61% at steady-state. Mild and moderate renal impairment, mild hepatic impairment and...
Source: Clinical Prostate Cancer - Category: Cancer & Oncology Authors: Source Type: research