2003
Verona, Italy
A PK-PD-disease model to support the design of clinical trials of drugs for the treatment of HIV
M. C. Rosario (1), P. Jacqmin (2), Pat Dorr(1), Manos Perro (1) & Elna van der Ryst (1)
(1) Pfizer Global Research and Development, Sandwich, Kent, UK; (2) Pharsight Corporation USA
Background: The viral dynamics of HIV infection have been widely studied and expressed as mathematical equations. For most of the registered anti-HIV drugs, the pharmacokinetics are well characterized and some relationships with the viral load-time profiles in patients have been established. These models are nonlinear which implies that simple assumptions can produce complex dynamics. The integration of these models in a PK-PD-disease model can help in better understanding the complexity of the interactions, and in the identification and clarification of the current assumptions.Methods: The present work describes the development of a generic PK-PD-disease model for a short-term (10-14 days) phase I/IIa study with an anti-HIV drug. The disease component is based on the model published by Bonhoeffer et al., which has been adapted for short-term treatment. It contains differential equations that describe the kinetics of the activated target cells, the actively infected cells, the latently infected cells and the virus. The parameters were derived from the literature, and from a model-based analysis of available phase I/IIa clinical data. The pharmacodynamic component that links the plasma concentrations of an anti-HIV drug to the inhibition of the virus growth is based on in-vitro measurements of drug potency. The links with the disease component take into account the mechanism of action of the drug (reverse transcriptase inhibition, protease inhibition, inhibition of entry), the difference in protein binding in-vitro and in-vivo and the uncertainties about the in-vitro in-vivo extrapolation. Finally, the pharmacokinetic component was based on information obtained from single and multiple dose escalation studies in volunteers as well as from clinical studies in patients.
Results and Conclusions: Simulations have been performed to better understand the complexity of the interactions and to support the design of Phase I/IIa clinical trials of new anti-HIV drugs. Finally, the model has aided the analysis and interpretation of the clinical data.