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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
Author(s) -
Bergman Arthur,
Bi Yian,
Mathialagan Sumathy,
Litchfield John,
Kazierad David J.,
Pfefferkorn Jeffrey A.,
Varma Manthena V.S.
Publication year - 2019
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.1419
Subject(s) - physiologically based pharmacokinetic modelling , organic anion transporter 1 , organic anion transporting polypeptide , pharmacokinetics , pharmacology , transporter , chemistry , kidney , renal function , renal physiology , medicine , area under the curve , endocrinology , biochemistry , gene
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 OATP 1B1/1B3 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 OATP s (~ 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.