Meta‐Analysis of Steady‐State Pharmacokinetics of Troglitazone and Its Metabolites

Abstract

The object of this study is to evaluate the effects of age, gender, age‐by‐gender interaction, Type II diabetes, body weight, race, smoking, and formulation on steady‐state pharmacokinetics of troglitazone, Metabolite 1 (sulfate conjugate), and Metabolite 3 (quinone metabolite) following multiple‐dose oral administration of troglitazone. Pharmacokinetic parameter estimates [Cl/F (apparent oral clearance), AUC_0–24 (area under plasma concentration—time curve), and ratio of AUC for troglitazone to Metabolite 1 and to Metabolite 3] obtained from 84 healthy volunteers and 171 patients with Type II diabetes in 8 studies were analyzed using a graphical method (for race and smoking) or a weighted ANCOVA model incorporating gender, health status (healthy vs Type II diabetes), and formulation as main effects; age, age‐by‐gender interaction, and body weight as continuous covariates. Ratio of AUC for troglitazone to metabolites was also examined by inspection of log‐probit plots. Age, gender, age‐by‐gender, Type II diabetes, and formulation had negligible effects on troglitazone Cl/F, AUC_0–24 (all analytes), and AUC ratio of troglitazone to metabolites. Race and smoking did not appear to influence steady‐state pharmacokinetics of troglitazone and its metabolites. Although body weight was a significant covariate for AUC_0–24 and Cl/F, the explanatory power of the overall model was weak (R² < 0.2). Log‐probit plots did not reveal a polymorphic distribution in AUC ratio of troglitazone to Metabolite 1 or Metabolite 3. Based on pharmacokinetics, dose adjustment for troglitazone in relation to the demographic factors examined is not required due to their poor predictive ability on steady‐state pharmacokinetics of troglitazone and its metabolites.