Ortega, I.(1), Ganza, A.(1), Arteche, J.(1), Berisa, A.(1), Ledo, F.(1), Gonzalo, A.(1)
(1) Research, Development and Innovation Department, FAES FARMA, S.A. 48940 Leioa-Bizkaia (Spain).
Objectives: F10503LO1, a small molecule of FAES FARMA R&D portfolio, is an antitumoral drug under preclinical development. At this stage, information from PK in different species was gathered and analyzed in an allometric exercise to estimate the PK parameters of F10503LO1 in humans.
Methods: Three animal species (mouse, rat and dog) and a total of 294 plasmatic samples from different studies were included in this exercise. All data were fitted to a pharmacokinetic model using non-linear mixed effect modelling implemented in NONMEM 7.2. This approach estimates coefficients and exponents that characterize the relationship between pharmacokinetic parameters and species features in a single step. Non-parametric bootstrap and VPC were conducted to evaluate the adequacy of the model to describe the plasmatic observations.
Results: A two-compartment PK model with first-order elimination from central compartment was selected as the best model, describing F10503LO1 pharmacokinetics after intravenous administration in the 3 evaluated species. The coefficient and exponents estimated by the model have been applied to simulate PK parameters of F10503LO1 in man in different scenarios.
Conclusions: The model selected describes plasmatic observations in the 3 evaluated species correctly, and allows the extrapolation of PK parameters to humans. These parameters in combination with information of in vitro efficacy and pharmacology security will be applied for simulation of different scenarios and to select first-in-man dose.
References:
[1] Beal SL, Sheiner LB, Boeckmann AJ & Bauer RJ (Eds.) NONMEM Users Guides. 1989-2011. Icon Development Solutions, Ellicott City, Maryland, USA.
[2] Cosson VF, Fuseau E, Efthymiopoulos C, Bye A. Mixed effect modeling of sumatriptan pharmacokinetics during drug development. I: Interspecies allometric scaling. J Pharmacokinet Biopharm. 1997; 25: 149-67.
[3] Jolling K, Perez Ruixo JJ, Hemeryck A, Vermeulen A, Greway T. Mixed-effects modelling of the interspecies pharmacokinetic scaling of pegylated human erythropoietin. Eur J Pharm Sci. 2005; 24: 465-75.
Reference: PAGE 22 (2013) Abstr 2833 [www.page-meeting.org/?abstract=2833]
Poster: Oncology