E.Rouits(1), P. Olsson(2) , J.M. Sorensen(3) and V. Nicolas-Métral(1)
(1) Debiopharm S.A., Chemin Messidor 5-7, CP 5911, 1002 Lausanne – Switzerland (2) SGS Exprimo NV, Generaal De Wittelaan 19A b5, 2800 Mechelen – Belgium (3) Ascenta Therapeutics, Inc., 101 Lindenwood Drive, Malvern, PA 19380 – USA
Objectives: Debio 1143 is an orally available small molecule antagonist of the inhibitors of apoptosis proteins (IAPs), developed as a therapy for cancer. Debio 1143 pharmacokinetics (PK) were evaluated in two dose-escalating phase I studies; one in monotherapy and one in combination with cytarabine and daunorubicin.
Methods: A population PK model was developed using NONMEM 7.2, to fit the plasma concentration-time data (n=961) from 48 evaluable patients. The clinically relevant dose range (80 – 900 mg q5d21 in the monotherapy trial in patients with advanced cancer or lymphoma and 100/200/300 mg q5d21 in the combination trial in Acute Myelogenous Leukemia (AML) patients) was explored in the model.
Results: A two-compartment model proved sufficient to describe the distribution of Debio 1143. The absorption was best described by two sequential zero-first order absorption phases. Typically, the first absorption phase corresponded to 12% of the absorption, though this varied substantially between dosing occasions. The zero order absorption phases lasted for 31 and 52 minutes respectively, the second phase starting at the end of the first phase, though the duration of the phases varied considerably between individuals. Inter-individual variability was estimated for CL/F, LAG1, D1, Ka2 and D2. Parameters were estimated with good precision. Relative bioavailability was found to decrease by 22% for doses after the second dose. Residual error was modelled using a proportional model, with separate error terms for the two studies, as separate bioanalytical assays have been used.
Conclusions: The pharmacokinetics of Debio 1143 was well described by a two-compartment model with two absorption pathways. The bioavailability appeared to change after repeated administrations, suggesting a possible time-dependent PK, which is in line with what has been observed in vitro. The model will be updated with data from on-going studies using alternative schedules of administration to 1/ help designing optimal trials and 2/further explore PK/PD relationships.
Reference: PAGE 22 (2013) Abstr 2780 [www.page-meeting.org/?abstract=2780]
Poster: Oncology