Effect of Hepatic Organic Anion-Transporting Polypeptide 1B Inhibition and Chronic Kidney Disease on the Pharmacokinetics of a Liver-Targeted Glucokinase Activator: A Model-Based Evaluation
Effect of Hepatic Organic Anion-Transporting Polypeptide 1B Inhibition and Chronic Kidney Disease on the Pharmacokinetics of a Liver-Targeted Glucokinase Activator: A Model-Based Evaluation
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DOI：
10.1002/cpt.1419
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发表时间：
2019-10-01
影响因子：
6.7
通讯作者：
Varma, Manthena V. S.
中科院分区：
文献类型：
--
作者：
Bergman, Arthur;Bi, Yi-an;Varma, Manthena V. S.
PF-04991532(((S)-6-(3-Cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)丙氨基)烟酸)是一种葡糖激活剂，旨在通过有机阴离子转运多肽S来实现肝脏选择性，从而将全身降血糖作用降至最低。本研究探讨OATP1B1/1B3抑制和肾损害对PF-04991532口服药代动力学的影响。在健康受试者中，环孢素(6 0 0 mg单次剂量)使PF-04991532的血浆曲线下平均面积(AUC)增加约3倍。在一项肾损害研究中，与健康受试者相比，轻度、中度和重度肾功能障碍患者的PF-04991532 AUC值增加了~2.3%。基于生理的药代动力学(PBPK)模型以体外输入为基础，将肝和肾转运体介导的处置参数化，并使用首例人类数据进行验证，表明OATP介导的肝脏摄取在PF-04991532的系统性和靶向组织暴露中起着关键作用。临床数据的机械性评估表明，肝脏OATPs(~35%)和肾脏有机阴离子转运体(OAT)3(80%-90%)功能降低，并伴有肾脏损害。这项研究说明了PBPK方法在评估药物相互作用和肾功能障碍对转运蛋白介导的处置的影响方面的充分性和有效性。
PF-04991532 ((S)-6-(3-Cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl) propanamido) nicotinic acid) is a glucokinase activator designed to achieve hepato-selectivity via organic anion-transporting polypeptides (OATP)s, so as to minimize systemic hypoglycemic effects. This study investigated the effect of OATP1B1/1B3 inhibition and renal impairment on PF-04991532 oral pharmacokinetics. Cyclosporine (600 mg single dose) increased mean area under the plasma curve (AUC) of PF-04991532 by approximately threefold in healthy subjects. In a renal impairment study, PF-04991532 AUC values were ~ 2.3-fold greater in subjects with mild, moderate, and severe kidney dysfunction, compared with healthy subjects. Physiologically-based pharmacokinetic (PBPK) model parameterizing hepatic and renal transporter-mediated disposition based on in vitro inputs, and verified using first-in-human data, indicated the key role of OATP-mediated hepatic uptake in the systematic and target-tissue exposure of PF-04991532. Mechanistic evaluation of the clinical data suggest reduced hepatic OATPs (~ 35%) and renal organic anion transporter (OAT)3 (80-90%) function with renal impairment. This study illustrates the adequacy and utility of the PBPK approach in assessing the impact of drug interactions and kidney dysfunction on transporter-mediated disposition.