Complete Substrate Inhibition of Cytochrome P450 2C8 by AZD9496, an Oral Selective Estrogen Receptor Degrader

AZD9496 is an oral selective estrogen receptor degrader currently in clinical development for treatment of estrogen receptor positive breast cancer. In a first-in-human Phase 1 study, AZD9496 exhibited dose non-linear pharmacokinetics whose mechanistic basis was investigated in this study. The metabolism kinetics of AZD9496 were studied using human liver microsomes (HLM), recombinant cytochrome P450s (rCYPs) and hepatocytes. In addition, modelling approaches were used to gain further mechanistic insights. CYP2C8 was predominantly responsible for biotransformation of AZD9496 to its two main metabolites whose rate of formation with increasing AZD9496 concentrations exhibited complete substrate inhibition in HLM, rCYP2C8 and hepatocytes. Total inhibition by AZD9496 of amodiaquine N-deethylation, a specific probe of CYP2C8 activity confirmed the completeness of this inhibition. The commonly used substrate inhibition model analogous to uncompetitive inhibition, fitted poorly to the data. However, using the same model but without constraints on the number of molecules occupying the inhibitory binding site (i.e. nS1ES) provided a significantly better fit (F test, P