Influence of the pharmacokinetic profile on the plasma glucose lowering effect of the PPARγ agonist pioglitazone in Wistar fatty rats. (28th May 2017)

• Record Type: Journal Article
• Authors: Goto, Akihiko; Tagawa, Yoshihiko; Kimura, Yoshiaki; Kogame, Akifumi; Moriya, Yuu; Amano, Nobuyuki
• Is Part Of: Biopharmaceutics & drug disposition. Volume 38:Number 6(2017:Sep.)
• Page Start: 381
• Page End: 388
• Publication Date: 2017-05-28
• Subjects: diabetes -- modeling and simulation -- PK profile -- PK/PD -- PPAR; Biopharmaceutics -- Periodicals; Drugs -- Metabolism -- Periodicals; Pharmacology -- Periodicals; Biopharmaceutics -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; 615.19
• DOI: 10.1002/bdd.2076
• Languages: English
• ISSNs: 0142-2782

Abstract

Abstract: 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. The importance of the PK profile of PPARγ agonist was evaluated 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 (q.d.) or once every other day (q.2d.) as double the amount for the q.d. treatment. The plasma glucose lowering effect was selected as a surrogate PD effect for an anti‐diabetic effect. The model fitting was conducted using the non‐linear mixed effect modeling (NONMEM) method. The indirect response model described well the plasma glucose concentration–time profile. The q.d. treatment showed a stronger impact on the plasma glucose lowering effect than did the q.2d. treatment. The results of PK/PD modeling suggested that the sensitivity (i.e. EC 50 ) between each group was comparable. On the other hand, the time above the effective concentration in the q.d. treatment group was longer than that in the q.2d. 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 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.