Use of nonlinear mixed effect modeling for the intestinal absorption data: Application to ritonavir in the rat

The aim of this study is to investigate in situ the mechanisms involved in the gastrointestinal absorption of ritonavir in the rat, as an animal model for preclinical studies of anti-HIV agents in vivo. Four ritonavir solutions (40, 27, 13 and 7 μM) in the presence of 1% dimethylsulfoxide (DMSO) were perfused in the small intestine of anaesthetised rats. Effects of DMSO on the intestinal permeability were investigated using solutions containing antipyrine 1.33 mM and ritonavir 7 μM with and without 1% of DMSO. Antipyrine and ritonavir transport was not modified in the presence of 1% of DMSO. The population pharmacokinetic parameters of the ritonavir intestinal transport were obtained by means of nonlinear mixed effect modelling approach according to a nonlinear absorption and nonlinear secretion. The absorption and secretion kinetic parameters for ritonavir were: Vm=47.6 μM/h; Km=8.77 μM; Vms=3.66 μM/h and Kms=0 μM. The interindividual variability found to ritonavir Vm 13.1%, and the residual variability was 8.98%. The Kms value support the saturation of the carrier at the range of concentrations of ritonavir assayed. The interindividual variability value of the Vm could explain, at least in part, the variability in absorption rate constants observed.