2019 PharmSci 360
This study aimed to develop a mechanistic absorption and disposition model to describe exposure to ritonavir from the commercial amorphous solid dispersion tablet, Norvir®, under fasted and fed conditions using the Simcyp Population PBPK Simulator (v18). Key parameters of amorphous ritonavir such as intrinsic solubility, bile-micelle partition coefficients, formulation wetting and in vivo precipitation parameters were either obtained from the literature or estimated by modeling in vitro biopharmaceutics experiments using the Simcyp In Vitro Data Analysis Toolkit (SIVA 3). In vitro studies suggest that crystallisation is unlikely to occur during absorption timeframes and any precipitation in the simulations was assumed to be to the amorphous form; the modelling results support this approach. Predicted and Observed Cmax and AUC0-t parameters were predicted within 1.5 fold for both the fasted and fed states in healthy volunteers. Viscosity differences in prandial states as well as the effect of free fraction of drug on gut wall permeation rate (using the ‘MechPeff’ mechanistic permeability model) were found able to explain the negative food effect observed for Norvir® tablets in humans. The model also successfully predicted clinical drug-drug interactions with several CYP3A4 substrates providing further verification of the ritonavir PBPK model. In summary, a biopharmaceutic IVIV_E approach provided confidence in the key input parameters of the ritonavir PBPK model which was able to capture fasted and fed conditions as well as CYP3A4-mediated DDIs. The IVIVE informed PBPK model can be used to simulate untested scenarios such as with patient populations.