Intramuscular (IM) long acting (LA) antiretrovirals can provide pharmacological options to simplify regimens and improve adherence. Currently, two IM LA drugs have been developed, rilpivirine (RPV) and cabotegravir (CBV), however the impact of liver impairment on their pharmacokinetics (PK) has not been fully elucidated. The aim of this project was to predict the PK of IM LA CBV in patients with liver impairment conditions using physiologically-based pharmacokinetic (PBPK) modelling.
A whole-body IM PBPK model was designed in Simbiology v.5.8.1 (MATLAB R2018b) and used to simulate 100 healthy and liver impaired adults aged 18-60 years. The model was assumed to be qualified if the simulated values were within 2-fold of the mean reported values, using the absolute average fold error (AAFE) approach as per convention. The model was validated using both oral (30mg QD) and IM administration (800mg followed by maintenance dose of 800mg 3 months later) clinical data on CBV. The PBPK model used first order kinetics to describe the IM LA drug release process. Virtual liver impaired patients were classified following the Child-Pugh (CP) score. Equations describing organ and tissue blood flows, plasma protein concentrations and hepatic metabolic enzyme changes were optimised according to each CP score.
The CBV PBPK model successfully passed the validation criteria, as shown in Table 1. Predictions for the IM dose of CBV showed a decrease of 8, 23 and 50% for AUC, Ctrough and Cmax compared to healthy condition, respectively in CP-A, B and C conditions. A portion of the patients with CP-C liver impairment are predicted to have total plasma Ctrough below the PAIC90 (660 ng/mL). However, the unbound CBV concentrations are predicted to be comparable to healthy individuals for all patients with liver impairment due to the increase of free drug fraction.
These data suggest that IM LA CBV may be used safely in patients with liver impairment, considering the overall steady-state and increment in unbound plasma concentrations. This approach could also be utilised for the prediction of risk related to altered PK for IM LA therapy in liver impaired patients as well as supporting the design of future clinical trials.
