Use of in vitro to in vivo extrapolation to predict the optimal strategy for patients switching from efavirenz to maraviroc or nevirapine.

Abstract

In clinical practice, antiretroviral regimens are often interrupted or modified for intolerance and toxicity. The objective of this study was to develop an in vitro to in vivo extrapolation (IVIVE) approach to describe the interaction when efavirenz is switched to either maraviroc or nevirapine and to test different switching scenarios to identify the best strategy. In vitro data describing the chemical and absorption, tissue distribution, metabolism and excretion (ADME) characteristics of efavirenz, maraviroc and nevirapine were obtained from the literature, and used to simulate plasma exposures of these drugs using the Simcyp Population-Based Simulator. The predicted maraviroc and nevirapine exposures were compared with data from clinical studies evaluating their exposures following a switch from efavirenz. Model predictions for maraviroc and nevirapine exposure were in agreement with observed data. The simulations suggest that the waning efavirenz induction effect following discontinuation necessitated increasing maraviroc to 600mg twice daily for 1week after efavirenz cessation. Alternatively, adequate exposure of maraviroc was shown with a dose of 450mg for 2weeks. Efavirenz waning induction did not affect nevirapine exposure. IVIVE modelling successfully predicted patient drug exposure. This modelling technique is able to inform the design of clinical studies, and allows assessment of pragmatic dosing strategies under complex therapeutic scenarios.