1. 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
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David J. Kazierad, Arthur Bergman, Manthena V.S. Varma, Jeffrey A. Pfefferkorn, John Litchfield, Yi-an Bi, and Sumathy Mathialagan
- Subjects
Drug ,Physiologically based pharmacokinetic modelling ,Organic anion transporter 1 ,media_common.quotation_subject ,Pharmacology ,Kidney ,030226 pharmacology & pharmacy ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Glucokinase ,Humans ,Medicine ,Drug Interactions ,Tissue Distribution ,Pharmacology (medical) ,Enzyme Inhibitors ,Renal Insufficiency, Chronic ,media_common ,biology ,Liver-Specific Organic Anion Transporter 1 ,business.industry ,Imidazoles ,Nicotinic Acids ,Membrane Transport Proteins ,Kidney metabolism ,Biological Transport ,medicine.disease ,Hypoglycemia ,Organic anion-transporting polypeptide ,HEK293 Cells ,Nicotinic agonist ,Liver ,Area Under Curve ,030220 oncology & carcinogenesis ,Cyclosporine ,biology.protein ,business ,Kidney disease - Abstract
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.
- Published
- 2019