Time-dependent inhibition and induction of human cytochrome P450A4/5 by an oral IAP antagonist, LCL161, in vitro and in vivo in healthy subjects

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 uM 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

A Phase I dose-escalation study of LCL161, an oral IAP inhibitor, in patients with advanced solid tumors

Purpose LCL161 antagonizes the function of inhibitor of apoptosis proteins (IAPs), thereby promoting cancer cell death. This first-in-human, dose-escalation study assessed the maximum tolerated dose (MTD), safety, pharmacokinetics, and pharmacodynamics of LCL161 in patients with advanced solid tumors. Patients and Methods LCL161 was administered orally once-weekly on a 21-day cycle to adult patients with advanced solid tumors. An adaptive Bayesian Logistic Regression Model with overdose control guided dose escalation. A second part of the study assessed the relative bioavailability of tablet versus solution formulation. Results Fifty-three patients received at least one dose of LCL161 (range 10–3000 mg). LCL161 was well tolerated at doses up to 1800 mg, with cytokine release syndrome (CRS) the only dose-limiting toxicity (3/53; 6%) and most common grade 3/4 event (5/53; 9%). Although the MTD was not reached, a dose of 1800 mg was selected for further study given the occurrence of CRS at higher doses and evidence of pharmacodynamic activity at lower doses. LCL161 was rapidly absorbed. The tablet formulation of LCL161 was better tolerated than the solution with similar exposure, and the solution was discontinued. No patient had an objective response. LCL161 induced degradation of cellular IAP1 protein in the blood, skin, and tumor, and increased circulating cytokine levels consistent with LCL161’s mechanism of action. Conclusion Single-agent LCL161 administered in tablet formulation at a dose of 1800 mg once-weekly was well tolerated, with significant pharmacodynamic activity, warranting further investigation in future studies