Abstract
The phosphatidylinositol-3-kinase/Akt/mTOR (PI3K/Akt/mTOR) pathway is a critical intracellular signaling pathway directly related to cell proliferation, metabolism, survival, and growth, and dysregulation of the pathway is a driver of cancer progression and tumor development that is implicated in a number of other human diseases as well. Apitolisib (GDC-0980) is a dual class I PI3K/mTOR inhibitor developed by Genentech that has been evaluated as an anticancer agent. Although the ADME and pharmacokinetic properties of Apitolisib have been previously characterized, this project independently evaluated key in vitro ADME (Absorption, Distribution, Metabolism, and Excretion) properties and used these experimentally obtained values in PK-Sim to further investigate its pharmacokinetic behavior. The resulting physiologically based pharmacokinetic (PBPK) model was used to examine how variation in gastric emptying time may influence predicted Apitolisib exposure in a virtual human population. Lipophilicity assays were performed to determine Apitolisib’s lipid or water phase preference; plasma protein binding assays were conducted to determine the fraction/percentage bound/unbound to proteins in blood/plasma; and hepatic microsomal stability assays were performed to determine how quickly Apitolisib is metabolized by liver enzymes. An average LogP value of 1.28±0.204 (n=4) was obtained for Apitolisib from lipophilicity assay, 51.3% (n=4) was observed to be bound to plasma proteins, and an average intrinsic clearance (Clint) value of 30.7 µl/min/mg (n=2) was obtained microsomal stability assay. The lab obtained ADME values were input into the PK-Sim software for PBPK modeling of Apitolisib. Using a virtual European population, differences in exposure parameters including maximum plasma concentration (Cmax), time to maximum concentration (Tmax), and area under the concentration-time curve (AUC), were observed with changes in gastric emptying time.