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, un-ionized species), bile micelle partition coefficients, formulation wetting/disintegration, and in vivo precipitation parameters were either obtained from the literature or estimated by modeling in vitro biopharmaceutic experiments. Based on 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 C max 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 approach provides confidence in (verification of) key input parameters of the physiologically-based pharmacokinetic ritonavir model which resulted in successful simulation of observed plasma profiles.

Bottom-Up Physiologically Based Oral Absorption Modeling of Free Weak Base Drugs

“…Physiologically based pharmacokinetic (PBPK) modeling has been anticipated to be a powerful tool to improve the productivity of drug discovery and development [ 11 ]. There have been many case studies of oral absorption PBPK modeling [ 12 , 13 , 14 , 15 , 16 ]. However, case studies are prone to publication bias.…”

Guide to development of compound files for PBPK modeling in the Simcyp population‐based simulator

“…Details into modeling of such drugs are outside the scope of this tutorial, but readers are herein referred to more relevant publications describing the modeling of complex oral drug formulations. 10 , 11 , 12 For compounds with poor intrinsic solubility, it can be extremely important to include low basic p K a (s) when present to account for drug dissolution at gastric pH, which is much lower than the physiological pH of 7.4.…”

“…To account for formulation effects, additional input parameters are required to describe the dissolution of the drug in the GI tract, including intrinsic solubility, solubilization factor, p K a , particle size, micelle partition (log K m:w ), effective diffusion coefficient ( D eff ), effective diffusion layer thickness ( h eff ), and parameters describing super‐saturation and precipitation. Details into modeling of such drugs are outside the scope of this tutorial, but readers are herein referred to more relevant publications describing the modeling of complex oral drug formulations 10–12 . For compounds with poor intrinsic solubility, it can be extremely important to include low basic p K a (s) when present to account for drug dissolution at gastric pH, which is much lower than the physiological pH of 7.4.…”

Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling to Support Waivers of In Vivo Clinical Studies: Current Status, Challenges, and Opportunities

“…Pepin et al have proposed the use of fitted particle size distribution (PSD) to simulate in vivo dissolution in cases where the absorption is dissolution limited . Others have recommended a stepwise in vitro - in vivo extrapolation of biopharmaceutic parameters approach as promising and more mechanistic. ,,, In any case, further research on establishing and validating the in vitro - in vivo link and development of more mechanistic dissolution models will be needed to further increase confidence in PBBM.…”

“…21 Others have recommended a stepwise in vitro-in vivo extrapolation of biopharmaceutic parameters approach as promising and more mechanistic. 17,20,162,163 In any case, further research on establishing and validating the in vitro-in vivo link and development of more mechanistic dissolution models will be needed to further increase confidence in PBBM.…”