Goto Akihiko, Tagawa Yoshihiko, Kimura Yoshiaki, Kogame Akifumi, Moriya Yuu, Amano Nobuyuki
Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Co. Ltd, Fujisawa, Japan.
Biopharm Drug Dispos. 2017 Sep;38(6):381-388. doi: 10.1002/bdd.2076. Epub 2017 May 28.
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.
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.
The results of PK/PD modeling suggested that the sensitivity (i.e. EC ) 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.
尽管过氧化物酶体增殖物激活受体γ（PPARγ）激动剂的作用机制已得到广泛研究，但药代动力学（PK）特征对PPARγ激动剂药效动力学（PD）效应的影响尚未得到详细阐明。基于群体PK/PD分析，评估了PPARγ激动剂的PK特征对其PD效应的重要性。将PPARγ激动剂盐酸吡格列酮以每日一次（q.d.）或隔日一次（q.2d.）的方式口服给予Wistar肥胖大鼠，q.2d.的剂量为q.d.的两倍。
选择血浆葡萄糖降低效应作为抗糖尿病效应的替代PD效应。使用非线性混合效应建模（NONMEM）方法进行模型拟合。间接反应模型很好地描述了血浆葡萄糖浓度-时间曲线。q.d.治疗对血浆葡萄糖降低效应的影响比q.2d.更强。
PK/PD建模结果表明，各组之间的敏感性（即EC）相当。另一方面，q.d.治疗组中高于有效浓度的时间比q.2d.治疗组长。各种给药方案的模拟表明，即使血浆中吡格列酮的暴露量相同，在有效水平内更长的暴露持续时间也显示出更强的血浆葡萄糖降低效应。PK/PD分析表明，PK特征影响药理反应，并且在适当的有效水平持续暴露对PPARγ激动剂的抗糖尿病效应是有效的。
