M. C. Rosario (1), P. Jacqmin (2), P. Dorr (3), M. Westby (3), E. van der Ryst (3) C. Hitchcock (3) & S. Felstead (3)
(1) Pfizer Global Research and Development, Groton, USA (2) Exprimo LLP, Colchester, UK, (3) Pfizer Global Research and Development, Sandwich, UK.
Introduction: Maraviroc (UK-427,857) is an antiretroviral drug with a new mechanism of action. It is a CCR5 antagonist. Currently, maraviroc is entering phase 2B/3 clinical development. Throughout the development of this compound, it was decided to implement a model-based decision making approach. Modeling and simulation activities started during the pre-clinical development with the design of the proof-of-concept (POC) trial (1). Being the first in class, little information was available at that time. So an integrated semi-mechanistic PK-PD-disease model was developed based on prior knowledge in the field of HIV. On an ongoing basis relevant pre-clinical and clinical information generated during the development were implemented in the model. At each step of the development, the updated model was used to guide decisions.
Methods: A disease mechanistic model was developed to incorporate information from several sources (2). When clinical data from maraviroc POC trial became available (3), the model was updated and used to assess the impact of food and dosing regimens on viral load decline. These predictions were in agreement with the one measured in the trial (4). Simulations were performed to assess the ability of a study with maraviroc given as combination therapy to provide information to select phase 3 doses. Based on simulation results, we have decided not to do a stand-alone phase 2B and go straight to phase 2b/3. Compliance and trial outcome components were added to the PK-PD-disease model to simulate long-term outcome. The outcome of several doses, along with several scenarios was simulated to aid in the selection of doses for phase 2B/3. Doses were selected based on trade-off analysis carried out on predicted efficacy and adverse events profile from phase 1 studies.
Conclusions: The impact of uncertainties on dose-response curve was identified early in the development of maraviroc. A trial strategy was selected to cover for the uncertainties detected and characterize dose-response curve with reasonable precision.
Modeling allowed prediction of the effect on viral load of different maraviroc doses as monotherapy in this patient population. The use of a model-based approach for selecting doses can accelerate drug development, by predicting long-term response from short-term data and by replacing some arms or trials with simulations.
References:
(1) Rosario, M. C., et al. 12th PAGE meeting, Verona, Italy, 2003 (Abstract) http://www.page-meeting.org/
(2) Funk, G. A., et al. J Acquir Immune Defic Syndr 26 397-404.
(3) Pozniak, A., et al. 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Illinois, USA, 2003 (Abstract H-443)
(4) Fatkenheuer, G., et al. XV International AIDS Conference, Bangkok, Thailand, 2004 (Abstract TuPeB4489) http://www.aids2004.org/
Reference: PAGE 14 (2005) Abstr 701 [www.page-meeting.org/?abstract=701]
Poster: poster