Simbiology v 5

The model was designed using Simbiology^® v.5.8.2, a product of MATLAB^® v.R2019a (MathWorks, Natick, MA, USA; 2019). Some of the key assumptions considered in the simulations were first-order kinetics, blood flow-limited distribution, no drug reabsorption from the colon, and instant distribution of the drug in tissues and organs (well-stirred model), except in the liver where the distribution of ATV was refined by a mechanistic transport-based model that included active efflux (P-gp) and uptake mediated transport of the drug. For ATV and RTV, a full PBPK model was applied, while RIF was applied in a three-compartment PBPK model (absorption, distribution, and elimination).

A PBPK model was developed for ISL in Simbiology v5.8, a product of Matlab 2018a (MathWorks, Natick, MA, USA). Drug distribution in the intradermal MAP compartments was described using permeability-limited, first-order kinetics. The drug distribution in the remaining whole-body PBPK model was described using blood-flow-limited, first-order kinetics with well-stirred compartments that assumed instant distribution of the drug. Furthermore, it was assumed that there was no absorption of orally dosed drug from the large intestine. Physicochemical, pharmacokinetic, in vitro, and in vivo data for ISL and ISL-TP were sourced from the literature or, if unavailable, were estimated via curve fitting to the observed clinical data. Where applicable, concentration–time profile data were extracted from graphs using the Plot Digitizer Tool v4.5 (WebPlotDigitizer, Pacifica, California, USA). The PBPK model was verified against observed clinical data for both ISL and ISL-TP. Specifically, clinical data for ISL 0.5–30 mg single oral dose and ISL 60 mg and 120 mg once-monthly oral dose regimens were used. For model verification and application, virtual cohorts consisting of 50 male and 50 female patients aged 18–60 years were simulated.