Influence of the pharmacokinetic profile on the plasma glucose lowering effect of the PPARγ agonist pioglitazone in Wistar fatty rats

Although the mechanism of action for peroxisome proliferator-activated receptor gamma (PPARγ) agonists has been extensively explored, the impact of the pharmacokinetic (PK) profile on the pharmacodynamic (PD) effects of PPARγ agonists has not been elucidated in detail. We evaluated the importance of the PK profile of PPARγ agonist for its PD effect based on population PK/PD analysis. Pioglitazone hydrochloride, the PPARγ agonist, was administered orally to Wistar fatty rats once a day (qd) or once every other day (q2d) as double the amount for the qd treatment. The plasma glucose lowering effect was selected as a surrogate PD effect for an anti-diabetic effect. The model fitting was conducted using non-linear mixed effect modeling (NONMEM) method. The indirect response model described well the plasma glucose concentration-time profile. The qd treatment showed a stronger impact on the plasma glucose lowering effect than did the q2d treatment. The results of PK/PD modeling suggested that the sensitivity (i.e. EC50) between each group was comparable. On the other hand, the time above the effective concentration in the qd treatment group was longer than that in the q2d treatment group. The simulation of various dose regimens suggested that the much longer exposure duration within the effective level showed a stronger plasma glucose lowering effect even with the identical exposure to pioglitazone in the plasma. The PK/PD analysis clarified that the PK profile affected the pharmacological response and that continuous exposure at an appropriate effective level would be efficient for the anti-diabetic effect of the PPARγ agonist.