2006 - Brugge/Bruges - Belgium

PAGE 2006: Applications
Ken Kowalski

A Modeling and Simulation Case Study: Impact on an Early Clinical Development Program

Kowalski, Kenneth G., Stephen Olson, Ann Remmers

Pfizer Global Research and Development

PDF of presentation

A case study will be presented that illustrates the use of population modeling and clinical trial simulations for a compound (Drug X) in early clinical development.† A dose-ranging pain study using a capsule formulation of Drug X demonstrated analgesic activity relative to placebo, however, lower than expected pain relief relative to an active control (Drug Y) was observed.† Inspection of the Drug X plasma concentration profiles from this study revealed that the capsule formulation suffered from a slow and erratic rate of absorption as compared to an oral solution formulation used in the single dose tolerability (SDT) study.† A population pharmacokinetic/pharmacodynamic (PK/PD) model was developed and predicted that if the capsule formulation had resulted in exposures comparable to the oral solution that the highest dose studied (1x) of Drug X would have achieved a pain relief profile comparable to Drug Y.† Moreover, the population PK/PD model predicted that higher doses of Drug X might result in additional pain relief.† Clinical trial simulations (CTS) were performed using the population PK/PD model for a proposed oral solution pain study to explore higher doses of Drug X up to a 6x dose and to determine power and sample size to show a statistically significant improvement relative to an active comparator (Drug Z).† On the basis of the CTS results an oral solution pain study was conducted to test the hypothesis that a higher dose of Drug X could achieve a clinically relevant increase in pain relief relative to Drug Z.† Results of the study confirmed the predictive performance of the model.† The talk will conclude with a discussion regarding the impact this modeling and simulation effort had on the drug development program and the steps that were taken to garner the trust and confidence of the development team in employing this model-based approach.

Reference: PAGE 15 (2006) Abstr 939 [www.page-meeting.org/?abstract=939]
Oral Presentation: Applications