Biopharmaceutic In Vitro In Vivo Extrapolation (IVIV_E) Informed Physiologically-Based Pharmacokinetic Model of Ritonavir Norvir Tablet Absorption in Humans Under Fasted and Fed State Conditions

Abstract

Ritonavir is a well-known CYP3A4 and CYP2D6 enzyme inhibitor, frequently used to assess the drug-drug interaction (DDI) liability of susceptible drugs. It is also used as a pharmacokinetic booster to increase exposure to CYP3A4 substrates. This study aimed to develop a mechanistic absorption and disposition model to describe exposure to ritonavir following oral dosing of the commercial amorphous solid dispersion tablet, Norvir®, under fasted and fed conditions. A mechanistic description of ritonavir absorption from Norvir® tablets may help to improve the design of DDI studies. Key parameters of amorphous ritonavir including free base solubility (solubility of the unbound, unionised species), bile micelle partition coefficients, formulation wetting/disintegration and in vivo precipitation parameters were either obtained from the literature or estimated by modelling in vitro biopharmaceutic experiments. Based upon a variety of in vitro evidence a main assumption of the model is that ritonavir does not form a crystalline precipitate while resident in the gastrointestinal tract. In the model, if simulated luminal concentration exceeds the amorphous solubility limit then precipitation to an amorphous form is immediate. Simulated and observed Cmax and AUC0-t parameters were well captured (within 1.5-fold) for both fasted and fed states in healthy volunteers. By accounting for luminal fluid viscosity differences in the different prandial states (affecting drug diffusivity) as well as the effect of drug free fraction on gut wall permeation rates, it was possible to explain the negative food effect observed for Norvir® tablets in humans. In summary, a biopharmaceutic In vitro In vivo Extrapolation (IVIV_E) approach provides confidence in (verification of) key input parameters of the Physiologically-Based Pharmacokinetic (PBPK) ritonavir model which resulted in successful simulation of observed plasma profiles.