ESTABLISHING THE DOSE-RESPONSE CURVE FOR METABOLIC CONTROL WITH TROGLITAZONE, AN INSULIN ACTION ENHANCER, IN TYPE-2 DIABETES PATIENTS

Troglitazone is a novel once-daily oral antidiabetic agent for the tre atment of type 2 diabetes patients. Here, we report the overall dose r esponse characteristics of troglitazone, with respect to effects on me tabolic control, using a pharmacodynamic model. Data from week 12 from two previously reported double-blind, randomized, parallel-group, pla cebo-controlled, dose-ranging multicentre studies examining once-daily doses of 10, 30, 100, 200, 400, 600 and 800 mg of troglitazone were c ombined for the analyses. The pharmacodynamic relationships for releva nt parameters of metabolic control were modelled using a nonlinear reg ression modelling programme. The troglitazone dose-concentration relat ionship was linear over 10-800 mg. Using an inhibitory sigmoid E-max m odel, ED50 values of approximately 100 mg and 200 mg were found for fa sting serum glucose and triglycerides, respectively. The 200 mg dose f or HbA(1c) showed an inconsistent reduction compared with placebo betw een the two studies; this illustrates the difficulties associated with comparing results from different assay techniques. Insulin and nonest erified fatty acid reductions compared with placebo were not consisten t between studies, and no pharmacodynamic modelling was possible. No c hanges in body weight were observed at any dose. Troglitazone was as w ell tolerated as placebo across the dose range investigated. This phar macodynamic analysis has established that 200-600 mg once daily can be considered the therapeutic dose range of troglitazone that significan tly improves metabolic control in type 2 diabetes patients.