RT Journal Article
SR Electronic
T1 Complete Substrate Inhibition of Cytochrome P450 2C8 by AZD9496, an Oral Selective Estrogen Receptor Degrader
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1268
OP 1276
DO 10.1124/dmd.118.081539
VO 46
IS 9
A1 Tashinga E. Bapiro
A1 Andy Sykes
A1 Scott Martin
A1 Michael Davies
A1 James W. T. Yates
A1 Matthias Hoch
A1 Helen E. Rollison
A1 Barry Jones
YR 2018
UL http://dmd.aspetjournals.org/content/46/9/1268.abstract
AB AZD9496 ((E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid) 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 nonlinear pharmacokinetics, the mechanistic basis of which was investigated in this study. The metabolism kinetics of AZD9496 were studied using human liver microsomes (HLMs), recombinant cytochrome P450s (rP450s), and hepatocytes. In addition, modeling 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 fit 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 < 0.005). With the improved model, up to three AZD9496 molecules were predicted to bind the inhibitory site of CYP2C8. In contrast to previous studies showing substrate inhibition of P450s to be partial, our results demonstrate complete substrate inhibition of CYP2C8 via binding of more than one molecule of AZD9496 to the inhibitory site. As CYP2C8 appears to be the sole isoform catalyzing formation of the main metabolites, the substrate inhibition might explain the observed dose nonlinearity in the clinic at higher doses.