A synergism model for PPARalpha and PXR agonist effects on HDL-cholesterol and apoA1

Synergism between gemfibrozil and CDD 3540, drugs used to elevate mouse serum HDL cholesterol and apoprotein A1, is modeled using nonlinear response surface techniques. This approach employs a common simple pharmacological model to describe the dose-response function. Its parameters are modeled as functions of drug mixture fractions using models borrowed from mixture experiment analysis methods. This study advances previous in vitro synergy studies in three key areas. First, it was in vivo, with the associated additional variability. Second, the sample size was much smaller than in previous studies. Finally, this was the first specially designed study with this type of statistical analysis in mind. The design consisted of replicated observations along each of five rays at combination amounts chosen employing the principles of D-optimality. Also, the observed in vivo synergism of the combined use of these drugs, elevated levels of HDL-C and apoA1, and the experimental results and statistical models may provide important clues regarding the biological mechanisms of action of the two compounds.