Slimano Florian, Djerada Zoubir, Bouchene Salim, Van Gulick Laurence, Brassart-Pasco Sylvie, Dukic Sylvain
MEDyC Research Unit, UMR CNRS/URCA n(o) 7369, SFR CAP-Santé, Reims University, 51, rue Cognacq-Jay, 51100 Reims, France; Department of Pharmacy, University Hospital Reims, Avenue du General Koenig, 51100 Reims, France.
Department of Pharmacology and Toxicology, EA3801, SFR CAP-Santé, University Hospital Reims, 51, rue Cognacq-Jay, 51100 Reims, France.
Eur J Pharm Sci. 2017 Jul 15;105:178-187. doi: 10.1016/j.ejps.2017.05.016. Epub 2017 May 13.
The YSNSG peptide is a synthetic peptide targeting αβ integrin. This peptide exhibits promising activity in vitro and in vivo against melanoma. To determine pharmacokinetic parameters and predictive active doses in the central nervous system (CNS) and subcutaneous tissue (SC), we conducted microdialysis coupled with pharmacokinetic modeling and Monte Carlo simulation. After a recovery period of surgical procedures, a microdialysis probe was inserted in the caudate and in subcutaneous tissue. Plasma samples and dialysates collected 5h after YSNSG intravenous administration (10mg/kg) were analyzed by UPLC-MS/MS. A nonlinear mixed-effect modeling approach implemented in Monolix® 2016R1 was performed. Model selection and evaluation were based on the usual diagnostic plot, precision and information criteria. The primary plasma and tissue pharmacokinetic parameters were comparable with those of other integrin antagonists, such as cilengitide or ATN-161. Tissue/plasma and brain/plasma area under the curve (AUC) ratio were 66.2±21.6% and 3.6±4.7%, respectively. Two models of 2-compartments with an additional microdialysis compartment, parameterized as rate constants (k for elimination, k12/k21 and k13/k31 for distribution) and volumes (central V1 and peripheral microdialysis compartment V3) with zero-order input were selected to describe the dialysate concentrations in CNS and SC. The inter-individual variability (IIV) was described by exponential terms, and residual variability was described by a combined additive and proportional error model. Individual AUC (plasma and tissues) values were derived for each animal using the Empirical-Bayes-Estimates of the individual parameters. The regimens needed to achieve an in vitro predetermined target concentration in tissues were studied by Monte Carlo simulations using Monolix® 2016R1. YSNSG pharmacokinetic parameters show promising results in terms of subcutaneous disposition. Further investigations into such processes as encapsulation and intratumoral disposition are currently being conducted.
