A pharmacokinetic-pharmacodynamic disease model to predict in vivo antiviral activity of maraviroc

Abstract

The viral dynamics of human immunodeficiency virus (HIV) infection has been widely studied and expressed as mathematic equations. For most of the current registered antiretroviral drugs, the pharmacokinetics is well characterized and some relationships with the viral load-time profiles in plasma from HIV patients have been established. The integration of these models in a pharmacokinetic (PK)-pharmacodynamic (PD)-disease model can help toward a better understanding of the complexity of the interactions, as well as in the identification and clarification of the current model assumptions. This work describes the development of a generic PK-PD disease model for a short-term (10 days) monotherapy phase IIa study with a novel anti-HIV drug, maraviroc (UK-427,857). The disease component of the model was based on the model published by Bonhoeffer et al, which was adapted for short-term treatment and for the new mechanism of action, CCR5-receptor antagonism. The model parameters were derived from the literature, as well as from a model-based analysis of available phase IIa clinical data from another investigational antiretroviral drug. The PD component that links the plasma concentrations of maraviroc to the inhibition of virus replication was based on in vitro measurements of drug potency and took into account the difference in the in vitro and in vivo protein binding and the uncertainties regarding the interpretation of the in vitro to in vivo extrapolation of the 50% inhibitory concentration. Finally, the PK component was based on information obtained from a single-dose study in healthy volunteers. The integrated PK-PD disease modeling allowed prediction of the effect on viral load of different maraviroc doses given as monotherapy to drug-naive patients. By making use of the available PK-PD disease model, the possible range of active oral doses for maraviroc in HIV-positive patients was estimated by simulation before any clinical trials were taking place. The use of a model-based approach for selecting doses for clinical phase IIa has improved and accelerated the drug's development. This model was a powerful tool for assisting in the design of clinical studies on new agents for treating HIV/acquired immunodeficiency syndrome.