M. Guidi (1) (2), C. Csajka (1) (2), A. Haouala (3), A. Ménétrey (3) and E. Rouits (3)
(1) School of Pharmaceutical Sciences, University of Geneva and University of Lausanne, Geneva, Switzerland; (2) Division of Clinical Pharmacology, Department of Laboratories, University Hospital Lausanne, Lausanne, Switzerland; (3) Debiopharm International, Lausanne, Switzerland.
Objectives: Debio 1143 (D-1143) is an orally administered antagonist of Inhibitors of Apoptosis Proteins (IAPs) currently in clinical development for cancer therapy. D-1143 and its major metabolite (D-1143-M) pharmacokinetics (PK) was investigated in three Phase I clinical studies as a single agent, in combination with cytarabine/daunorubicin (Cyt/Daun) and with carboplatin/paclitaxel (Carbo/Pac) [1-3]. The aim of the present study was to characterize D-1143 and D-1143-M PK and their variability in relation to potential influencing covariates and to drug/metabolite interaction.
Methods: Full PK profiles of D-1143 and D-1143-M in two occasions and several trough concentrations were available for the PK analysis (NONMEM®). Multi-compartment models with linear elimination and a variety of absorption models were compared to depict D-1143 PK. D-1143-M concentrations were described by assuming linear metabolism from D-1143 and by adding one or two compartments. Drug/metabolite interaction was evaluated through different inhibition models. Demographic characteristics, coadministered chemotherapy agents and biochemical parameters were tested as covariates.
Results: 94 oncologic patients provided 1717 D-1143 and 888 D-1143-M concentrations. D-1143 PK was best characterized by a two compartment model with sequential zero- and first-order absorption with one additional compartment for D-1143-M disposition. Assignment of distinct bioavailabilities to full profile occasions and trough concentrations allowed describing the non-linearity in drug PK. An important interindividual variability (IIV) was associated with the majority of the PK parameters. The D-1143/D-1143-M mutual interaction was best captured using AUCD and AUCM as covariates on metabolite (CLM) and drug clearance (CLD), respectively. A decrease of 22% in CLM and 13% in CLD was observed doubling AUCD and AUCM, respectively. Coadministration of Carbo/Pac lowered CLD by 35% compared to participants receiving Debio 1143 alone or in combination with Cyt/Daun. These covariates explained all together the totality of CLM IIV and 28% of CLD IIV.
Conclusions: D-1143 PK is characterized by non-linear kinetics. The large variability associated with drug and metabolite PK remains unexplained, despite the inclusion of D-1143/D-1143-M mutual interaction and of Carbo/Pac coadministration as covariates. The Carbo/Pac effect, however, is under investigation since it could not be disentangle from other study specificities.
References:
[1] Ascenta Therapuetics Inc., AT-406-CS-001: A phase I, open label, multi-center, dose escalation study of the safety, tolerability, pharmacodynamic and pharmacokinetic properties of orally administered AT-406 in patients with advanced solid tumors and lymphomas. 2013.
[2] Ascenta Therapuetics Inc., AT-406-CS-002: Phase I dose escalation study of the safety, tolerability, pharmacokinetics, and pharmacodynamic properties of oral AT-406 in combination with daunorubicin and cytarabine in patients with poor-risk, acute myelogenous leukemia (AML). 2013.
[3] Debiopharm International, Debio 1143: Investigator’s Drug Brochure. 2013.
Reference: PAGE 25 () Abstr 5702 [www.page-meeting.org/?abstract=5702]
Poster: Drug/Disease modeling - Oncology