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Combining biorelevant in vitro and in silico tools to investigate the in vivo performance of the amorphous solid dispersion formulation of etravirine in the fed state

: Litou, C.; Turner, D.B.; Holmstock, N.; Ceulemans, J.; Box, K.J.; Kostewicz, E.; Kuentz, M.; Holm, R.; Dressman, J.


European journal of pharmaceutical sciences : EUFEPS 149 (2020), Art.105297
ISSN: 0928-0987
ISSN: 1879-0720
Fraunhofer IME ()

Introduction: In the development of bio-enabling formulations, innovative in vivo predictive tools to understand and predict the in vivo performance of such formulations are needed. Etravirine, a non-nucleoside reverse transcriptase inhibitor, is currently marketed as an amorphous solid dispersion (Intelence® tablets). The aims of this study were 1) to investigate and discuss the advantages of using biorelevant in vitro setups to simulate the in vivo performance of Intelence® 100 mg and 200 mg tablets in the fed state, 2) to build a Physiologically Based Pharmacokinetic (PBPK) model by combining experimental data and literature information with the commercially available in silico software Simcyp® Simulator V17.1 (Certara UK Ltd.), and 3) to discuss the challenges of predicting the in vivo performance of an amorphous solid dispersion and identify the parameters which influence the pharmacokinetics of etravirine most. Methods: Solubility, dissolution and transfer experiments were performed in various biorelevant media simulating the fasted and fed state environment in the gastrointestinal tract. An in silico PBPK model for etravirine in healthy volunteers was developed in the Simcyp® Simulator, using in vitro results and data available from the literature as input. The impact of pre- and post-absorptive parameters on the pharmacokinetics of etravirine was investigated by simulating various scenarios. Results: In vitro experiments indicated a large effect of naturally occurring solubilizing agents on the solubility of etravirine. Interestingly, supersaturated concentrations of etravirine were observed over the entire duration of dissolution experiments on Intelence® tablets. Coupling the in vitro results with the PBPK model provided the opportunity to investigate two possible absorption scenarios, i.e. with or without implementation of precipitation. The results from the simulations suggested that a scenario in which etravirine does not precipitate is more representative of the in vivo data. On the post-absorptive side, it appears that the concentration dependency of the unbound fraction of etravirine in plasma has a significant effect on etravirine pharmacokinetics. Conclusions: The present study underlines the importance of combining in vitro and in silico biopharmaceutical tools to advance our knowledge in the field of bio-enabling formulations. Future studies on other bio-enabling formulations can be used to further explore this approach to support rational formulation design as well as robust prediction of clinical outcomes.