Clinical pharmacokinetic (PK)/pharmacodynamic (PD) model for Debio 1143, a novel antagonist of IAPs in cancer treatment.

Abstract

2585 Background: Inhibitors of apoptosis proteins (IAPs) modulate multiple processes, including caspase activation and NF-kB signaling. Expression and/or overexpression of IAPs have been reported for a variety of tumor types and are correlated with tumor growth and resistance to apoptosis induced by standard chemo and radiation therapies. The small molecule Debio 1143 is an orally-active IAP antagonist able to promote apoptosis in tumor cells. Methods: In a first-in-human Phase I study in patients with advanced cancer, Debio 1143 was given orally once daily on days 1-5 every 2 or 3 weeks. Ten dose levels ranging from 5 mg to 900 mg were explored. Blood samples were taken on days 1-5 for PK (Debio 1143) and PD assessments (IAPs levels, blood markers of apoptosis and inflammation) with rich sampling at day 1 and day 5. A population PK model was built within NONMEM 7.2. Further to a graphical PK vs PD check, population PK/PD models were explored. Results: The PK of Debio 1143 was well described by a two-compartment model with two absorption pathways. Debio 1143 bioavailability appeared to decrease after repeated administrations, suggesting a possible time-dependent PK. Graphically, markers of target engagement (cIAP1 PBMCs levels) and apoptosis (caspase-3 generated cytokeratine-18 fragments plasma levels [CK18-M30]) showed changes with Debio 1143 PK. cIAP1 levels could be fitted using an indirect response model where the elimination of cIAP1 was stimulated by Debio 1143. The CK18-M30 data was best fitted by a model with a delayed effect, onsetting after the first day. Simulations of d14q21 treatment predicted a clear decrease in cIAP1, with small differences between 100 mg and 200 mg dosing. A CK18-M30 increase ranging from 20 to 200% is predicted at day 14 after 200 mg qd. Conclusions: Debio 1143PK is compatible with oral administration q5d21. A clear relationship between PK and markers of target engagement or apoptosis was evidenced over the dose range explored. Findings from the q14d21 simulations indicate a promising PK/PD relationship for such schedule. Results from ongoing studies including PK/safety and PK/efficacy exploration will also feed the model to support Debio 1143 treatment optimization.