title: Time-dependent inhibition and induction of human cytochrome P4503A4/5 by an oral IAP antagonist, LCL161, in vitro and in vivo in healthy subjects.
abstract: Tumor cells can evade programmed cell death via up-regulation of inhibitor of apoptosis proteins (IAPs). LCL161 is a small molecule oral IAP antagonist in development for use in combination with cytotoxic agents. The effect of LCL161 on CYP3A4/5 (CYP3A) activity was investigated in vitro and in a clinical study. Results in human liver microsomes indicated LCL161 inhibited CYP3A in a concentration- and time-dependent manner (KI of 0.797 µM and kinact of 0.0803 min(-1) ). LCL161 activated human PXR in a reporter gene assay and induced CYP3A4 mRNA up to ∼5-fold in human hepatocytes. In healthy subjects, the dual inhibitor and inductive effects of a single dose of LCL161 were characterized using single midazolam doses, given before and at three time points after the LCL161 dose. Midazolam Cmax increased 3.22-fold and AUC(0-inf) increased 9.32-fold when administered four hours after LCL161. Three days later, midazolam Cmax decreased by 27% and AUC(0-inf) decreased by 30%. No drug interaction remained one week later. The strong CYP3A inhibition by LCL161 was accurately predicted using dynamic physiologically-based pharmacokinetic (PBPK) modeling approaches in Simcyp. However, the observed induction effect after the LCL161 dose could not be modeled; suggesting direct enzyme induction by LCL161 was not the underlying mechanism.
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936, USA. shyeilla.dhuria@novartis.com
authors.forename: Shyeilla
authors.initials: S
authors.lastname: Dhuria
authors.forename: Heidi
authors.initials: H
authors.lastname: Einolf
authors.forename: James
authors.initials: J
authors.lastname: Mangold
authors.forename: Suman
authors.initials: S
authors.lastname: Sen
authors.forename: Helen
authors.initials: H
authors.lastname: Gu
authors.forename: Lai
authors.initials: L
authors.lastname: Wang
authors.forename: Scott
authors.initials: S
authors.lastname: Cameron
mesh_terms: D000328:Adult; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008874:Midazolam / Q000493:pharmacokinetics; D008875:Middle Aged; D008954:Models, Biological; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000378:metabolism; D011987:Receptors, Steroid / Q000187:drug effects / Q000378:metabolism; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors; D055815:Young Adult
chemical_list: D004791:Enzyme Inhibitors; D051034:Inhibitor of Apoptosis Proteins; C574246:LCL161; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D011987:Receptors, Steroid; D013844:Thiazoles; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam