Laurence Del Frari (1), Eric Didier (1)
(1) Pierre Fabre Médicament, Centre de R&D, Toulouse, France
Objectives: F50067 is a CXCR4 receptor antagonist humanised monoclonal antibody developed by Pierre Fabre Laboratories for the treatment of Acute Myeloid Lymphoma (AML) and Multiple Myeloma (MM). In order to support the dose and dosing selection in human patients, a pharmacokinetic (PK) model was developed using PK data collected in monkeys (NHP).
Methods: Data were obtained from 4 studies in NHP after single IV administration in the range from 1 to 120 mg/kg involving 50 animals and 353 concentrations. The population PK analysis was performed by non linear mixed effects modelling approach using NONMEM 7.2 with FOCE + interaction estimation. The model building and the selection of the best model was conducted using differences in Objective Function Values, Visual inspection of Goodness Of Fit Plots and Visual Predictive Checks (VPC). Then translational approach to predict the PK in human was done through allometric scaling of the clearance and volume of distribution, with allometric coefficients tested between 0.75 and 1 in order to provide an adequate range of predictions for the PK in human [1,2].
Results: The developed PK model in NHP displayed a dual clearance, with a non linear component and a linear component allowing to take into account the observed target mediated disposition [3]. VPC showed that the model described adequately the observations and allowed simulations. In MM and AML patients, it appears that the observed PK is accurately predicted with a PK model using allometric scaling of 1 on the volume of distribution and the clearance.
Conclusions: In spite of its target mediated disposition behaviour, which could have been a source of imprecision in the estimates, allometric scaling from NHP to human allowed to accurately predict the PK in human of a monoclonal antibody targeting a membrane bound receptor such as CXCR4. This allometric translation of a PK model allowed to appropriately select a once weekly dosing regimen in the clinical program.
References:
[1] Dong J. Q. et al. Quantitative prediction of human pharmacokinetics for monoclonal antibodies – retrospective analysis of monkey as a single species dor first-in-human prediction. Clin Pharmacokinet (2011) 50:131-142.
[2] Lobo E. L. et al. Antibody pharmacokinetics and pharmacodynamics. J Pharm Sci (2004) 93:2645-2668.
[3] Gibianski L. et al. Approximations of the target-mediated drug disposition model and identifiability of model parameters. Journal Pharmacokinet Pharmacodyn (2008) 35:573-91.
Reference: PAGE 25 (2016) Abstr 5740 [www.page-meeting.org/?abstract=5740]
Poster: Drug/Disease modeling - Oncology