Rasmus Vestergaard Juul (1), Martha Kampp Nøhr (2), Carsten Uhd Nielsen (2), Rene Holm (3) and Mads Kreilgaard (1)
(1) Department of Drug Design and Pharmacology and (2) Department of Pharmacy, University of Copenhagen, Denmark, (3) Biologics and Pharmaceutical Science, H. Lundbeck A/S, Valby, Denmark
Objectives: Vigabatrin is an anti-epileptic drug used for the treatment of infantile spams. Vigabatrin has been identified as a substrate of the human proton-coupled amino acid transporter, hPAT1 [1], and in vitro studies suggest that PAT1 mediates the transepithelial transport [2]. The aim of this study was to develop a population-based pharmacokinetic (PK) model of the oral absorption of vigabatrin and to assess the potential involvement of PAT1.
Methods: Vigabatrin plasma concentration-time profiles were obtained from 78 rats dosed either orally (0.3mg/kg, 1mg/kg, 3mg/kg or 30mg/kg) or intravenously (i.v.) (1mg/kg). The involvement of PAT1 was investigated by co-administration of the hPAT1 substrate and inhibitor, proline (100mg/kg) and tryptophan (100mg/kg). PK models were fitted to data using non-linear mixed-effects modelling implemented in NONMEM (V7.2.0.). One to three compartment models with 1st order elimination were investigated to describe disposition of vigabatrin. Oral absorption of vigabatrin was investigated among zero-order, 1st order and saturable (Michaelis-Menten) absorption models encompassing lag-time or transit compartments [2,3]. Models were selected and evaluated based on objective function value, visual goodness of fit, parameter precision, visual predictive checks and bootstraps.
Results: A two-compartment model best described the disposition of vigabatrin after oral and i.v. administration. A transit compartment model with estimated 1.4 compartments and a population mean transit time (MTT) of 4.5 min best described the oral absorption of vigabatrin. An apparent dose dependent absorption was observed, as the MTT of 0.3mg/kg doses were lower (3.0 min) than for other doses. Administration of proline and tryptophan resulted in significantly prolonged MTT of 9.2 min.
Conclusions: The oral absorption of vigabatrin in rat was successfully described by a population PK model with dose-dependent transit that could be prolonged by the PAT1 inhibitors proline/tryptophan. These findings are the first in vivo evidence suggesting that PAT1 could be involved in intestinal vigabatrin absorption.
References:
[1] Abbot, E.L., et al., Vigabatrin transport across the human intestinal epithelial (Caco-2) brush-border membrane is via the H+ -coupled amino-acid transporter hPAT1. Br J Pharmacol, 2006. 147(3): p. 298-306.
[2] Nøhr, M.K. et al., The absorptive transport of the anti-epileptic drug substance vigabatrin across Caco-2 cell monolayers is carrier-mediated, submitted, Eur J Pharm Biopharm, 2013.
[3] Holford, N.H. et al., Models for describing absorption rate and estimating extent of bioavailability: application to cefetamet pivoxil. J Pharmacokinet Biopharm, 1992. 20(5): p. 421-42.
[4] Savic, R.M., et al., Implementation of a transit compartment model for describing drug absorption in pharmacokinetic studies. J Pharmacokinet Pharmacodyn, 2007. 34(5): p. 711-26.
Reference: PAGE 22 () Abstr 2860 [www.page-meeting.org/?abstract=2860]
Poster: Absorption and Physiology-Based PK