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.
Area Under Curve
Biological Transport
Cyclosporine
/ pharmacokinetics
Drug Interactions
Enzyme Inhibitors
/ pharmacokinetics
Glucokinase
/ metabolism
HEK293 Cells
Humans
Hypoglycemia
/ chemically induced
Imidazoles
/ pharmacokinetics
Kidney
/ metabolism
Liver
/ metabolism
Liver-Specific Organic Anion Transporter 1
/ antagonists & inhibitors
Membrane Transport Proteins
/ metabolism
Nicotinic Acids
/ pharmacokinetics
Renal Insufficiency, Chronic
/ metabolism
Tissue Distribution
Journal
Clinical pharmacology and therapeutics
ISSN: 1532-6535
Titre abrégé: Clin Pharmacol Ther
Pays: United States
ID NLM: 0372741
Informations de publication
Date de publication:
10 2019
10 2019
Historique:
received:
17
12
2018
accepted:
22
02
2019
pubmed:
29
3
2019
medline:
14
5
2020
entrez:
29
3
2019
Statut:
ppublish
Résumé
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.
Substances chimiques
Enzyme Inhibitors
0
Imidazoles
0
Liver-Specific Organic Anion Transporter 1
0
Membrane Transport Proteins
0
Nicotinic Acids
0
Cyclosporine
83HN0GTJ6D
6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic acid
AJ212MS2O2
Glucokinase
EC 2.7.1.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
792-802Informations de copyright
© 2019 Pfizer Inc. Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics.
Références
Matschinsky, F.M., Glaser, B. & Magnuson, M.A. Pancreatic beta-cell glucokinase: closing the gap between theoretical concepts and experimental realities. Diabetes 47, 307-315 (1998).
Agius, L. Glucokinase and molecular aspects of liver glycogen metabolism. Biochem. J. 414, 1-18 (2008).
Iynedjian, P. Molecular physiology of mammalian glucokinase. Cell. Mol. Life Sci. 66, 27 (2009).
Haynes, N.-E. et al. Discovery, structure−activity relationships, pharmacokinetics, and efficacy of glucokinase activator (2 R)-3-cyclopentyl-2-(4-methanesulfonylphenyl)-N-thiazol-2-yl-propionamide (RO0281675). J. Med. Chem. 53, 3618-3625 (2010).
Bertram, L.S. et al. SAR, pharmacokinetics, safety, and efficacy of glucokinase activating 2-(4-sulfonylphenyl)-N-thiazol-2-ylacetamides: discovery of PSN-GK1. J. Med. Chem. 51, 4340-4345 (2008).
Waring, M.J., Johnstone, C., McKerrecher, D., Pike, K.G. & Robb, G. Matrix-based multiparameter optimisation of glucokinase activators: the discovery of AZD1092. MedChemComm 2, 775-779 (2011).
Grimsby, J. et al. Allosteric activators of glucokinase: potential role in diabetes therapy. Science 301, 370-373 (2003).
Matschinsky, F.M. GKAs for diabetes therapy: why no clinically useful drug after two decades of trying? Trends Pharmacol. Sci. 34, 90-99 (2013).
Sarabu, R., Berthel, S.J., Kester, R.F. & Tilley, J.W. Novel glucokinase activators: a patent review (2008-2010). Expert Opin. Ther. Pat. 21, 13-33 (2011).
Bebernitz, G.R. et al. Investigation of functionally liver selective glucokinase activators for the treatment of type 2 diabetes. J. Med. Chem. 52, 6142-6152 (2009).
Pfefferkorn, J.A. et al. Discovery of (S)-6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1 H-imidazol-1-yl) propanamido) nicotinic acid as a hepatoselective glucokinase activator clinical candidate for treating type 2 diabetes mellitus. J. Med. Chem. 55, 1318-1333 (2012).
Koro, C.E., Lee, B.H. & Bowlin, S.J. Antidiabetic medication use and prevalence of chronic kidney disease among patients with type 2 diabetes mellitus in the United States. Clin. Ther. 31, 2608-2617 (2009).
Bailey, R.A., Wang, Y., Zhu, V. & Rupnow, M.F. Chronic kidney disease in US adults with type 2 diabetes: an updated national estimate of prevalence based on kidney disease: Improving Global Outcomes (KDIGO) staging. BMC Res. Notes 7, 415 (2014).
Mathialagan, S., Piotrowski, M.A., Tess, D.A., Feng, B., Litchfield, J. & Varma, M.V. Quantitative prediction of human renal clearance and drug-drug interactions of organic anion transporter substrates using in vitro transport data: a relative activity factor approach. Drug Metab. Dispos. 45, 409-417 (2017).
Varma, M.V., Lai, Y., Feng, B., Litchfield, J., Goosen, T.C. & Bergman, A. Physiologically based modeling of pravastatin transporter-mediated hepatobiliary disposition and drug-drug interactions. Pharm. Res. 29, 2860-2873 (2012).
El-Kattan, A.F. & Varma, M.V.S. Navigating transporter sciences in pharmacokinetics characterization using the extended clearance classification system. Drug Metab. Dispos. 46, 729-739 (2018).
Varma, M.V., Steyn, S.J., Allerton, C. & El-Kattan, A.F. Predicting clearance mechanism in drug discovery: Extended Clearance Classification System (ECCS). Pharm. Res. 32, 3785-3802 (2015).
Xia, C., Liu, N., Miwa, G. & Gan, L. Interactions of cyclosporin a with breast cancer resistance protein. Drug Metab. Dispos. 35, 576-582 (2007).
Wason, S., DiGiacinto, J.L. & Davis, M.W. Effect of cyclosporine on the pharmacokinetics of colchicine in healthy subjects. Postgrad. Med. 124, 189-196 (2012).
Sharma, R. et al. Comparison of the circulating metabolite profile of PF-04991532, a hepatoselective glucokinase activator, across preclinical species and humans: potential implications in metabolites in safety testing assessment. Drug Metab. Dispos. 43, 190-198 (2015).
Gertz, M. et al. Cyclosporine inhibition of hepatic and intestinal CYP3A4, uptake and efflux transporters: application of PBPK modeling in the assessment of drug-drug interaction potential. Pharm. Res. 30, 761-780 (2013).
Watanabe, T., Kusuhara, H., Maeda, K., Shitara, Y. & Sugiyama, Y. Physiologically based pharmacokinetic modeling to predict transporter-mediated clearance and distribution of pravastatin in humans. J. Pharmacol. Exp. Ther. 328, 652-662 (2009).
Maeda, K. et al. Identification of the rate-determining process in the hepatic clearance of atorvastatin in a clinical cassette microdosing study. Clin. Pharmacol. Ther. 90, 575-581 (2011).
Nakagomi-Hagihara, R., Nakai, D. & Tokui, T. Inhibition of human organic anion transporter 3 mediated pravastatin transport by gemfibrozil and the metabolites in humans. Xenobiotica 37, 416-426 (2007).
Nolin, T., Naud, J., Leblond, F. & Pichette, V. Emerging evidence of the impact of kidney disease on drug metabolism and transport. Clin. Pharmacol. Ther. 83, 898-903 (2008).
Yeung, C.K., Shen, D.D., Thummel, K.E. & Himmelfarb, J. Effects of chronic kidney disease and uremia on hepatic drug metabolism and transport. Kidney Int. 85, 522-528 (2014).
Yoshida, K. et al. Systematic and quantitative assessment of the effect of chronic kidney disease on CYP2D6 and CYP3A4/5. Clin. Pharmacol. Ther. 100, 75-87 (2016).
Tan, M.L. et al. Effect of chronic kidney disease on nonrenal elimination pathways: a systematic assessment of CYP1A2, CYP2C8, CYP2C9, CYP2C19, and OATP. Clin. Pharmacol. Ther. 103, 854-867 (2018).
Hirako, M. et al. Impaired gastric motility and its relationship to gastrointestinal symptoms in patients with chronic renal failure. J. Gastroenterol. 40, 1116 (2005).
Tan, M.L. et al. Use of physiologically based pharmacokinetic modeling to evaluate the effect of chronic kidney disease on the disposition of hepatic CYP2C8 and OATP1B drug substrates. Clin. Pharmacol. Ther. 105, 719-729 (2019).
Hsu, V. et al. Towards quantitation of the effects of renal impairment and probenecid inhibition on kidney uptake and efflux transporters, using physiologically based pharmacokinetic modelling and simulations. Clin. Pharmacokinet. 53, 283-293 (2014).
Li, R., Barton, H.A. & Varma, M.V. Prediction of pharmacokinetics and drug-drug interactions when hepatic transporters are involved. Clin. Pharmacokinet. 53, 659-678 (2014).
Shitara, Y., Maeda, K., Ikejiri, K., Yoshida, K., Horie, T. & Sugiyama, Y. Clinical significance of organic anion transporting polypeptides (OATPs) in drug disposition: their roles in hepatic clearance and intestinal absorption. Biopharm. Drug Dispos. 34, 45-78 (2013).
Patilea-Vrana, G. & Unadkat, J.D. Transport vs. metabolism: what determines the pharmacokinetics and pharmacodynamics of drugs? Insights from the extended clearance model. Clin. Pharmacol. Ther. 100, 413-418 (2016).
Kusuhara, H. Imaging in the study of membrane transporters. Clin. Pharmacol. Ther. 94, 33-36 (2013).
Chu, X. et al. Intracellular drug concentrations and transporters: measurement, modeling, and implications for the liver. Clin. Pharmacol. Ther. 94, 126-141 (2013).
Bi, Y. et al. Role of hepatic organic anion transporter 2 in the pharmacokinetics of R- and S-warfarin: in vitro studies and mechanistic evaluation. Mol. Pharm. 15, 1284-1295 (2018).
Bi, Y. et al. Organic anion transporter 2 mediates hepatic uptake of tolbutamide, a CYP2C9 probe drug. J. Pharmacol. Exp. Ther. 364, 390-398 (2018).
Varma, M.V., Bi, Y.A., Kimoto, E. & Lin, J. Quantitative prediction of transporter- and enzyme-mediated clinical drug-drug interactions of organic anion-transporting polypeptide 1B1 substrates using a mechanistic net-effect model. J. Pharmacol. Exp. Ther. 351, 214-223 (2014).
Kimoto, E., Bi, Y.-A., Kosa, R.E., Tremaine, L.M. & Varma, M.V. Hepatobiliary clearance prediction: species scaling from monkey, dog and rat, and in vitro-in vivo extrapolation of sandwich cultured human hepatocytes using 17 drugs. J. Pharm. Sci. 106, 2795-2804 (2017).
Varma, M.V. et al. Mechanism-based pharmacokinetic modeling to evaluate transporter-enzyme interplay in drug interactions and pharmacogenetics of glyburide. AAPS J. 16, 736-748 (2014).
Varma, M.V., Lin, J., Bi, Y.A., Kimoto, E. & Rodrigues, A.D. Quantitative rationalization of gemfibrozil drug interactions: consideration of transporters-enzyme interplay and the role of circulating metabolite gemfibrozil 1-O-beta-glucuronide. Drug Metab. Dispos. 43, 1108-1118 (2015).
Varma, M. et al. Transporter-mediated hepatic uptake plays an important role in the pharmacokinetics and drug-drug interactions of montelukast. Clin. Pharmacol. Ther. 101, 406-415 (2017).
Jamei, M. et al. A mechanistic framework for in vitro-in vivo extrapolation of liver membrane transporters: prediction of drug-drug interaction between rosuvastatin and cyclosporine. Clin. Pharmacokinet. 53, 73-87 (2014).
Rodgers, T. & Rowland, M. Physiologically based pharmacokinetic modelling 2: predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions. J. Pharm. Sci. 95, 1238-1257 (2006).
Varma, M.V., Lai, Y., Kimoto, E., Goosen, T.C., El-Kattan, A.F. & Kumar, V. Mechanistic modeling to predict the transporter- and enzyme-mediated drug-drug interactions of repaglinide. Pharm. Res. 30, 1188-1199 (2013).
Amundsen, R., Christensen, H., Zabihyan, B. & Åsberg, A. Cyclosporine A, but not tacrolimus, shows relevant inhibition of organic anion-transporting protein 1B1-mediated transport of atorvastatin. Drug Metab. Dispos. 38, 1499-1504 (2010).
Wagner, C. et al. Predicting the effect of cytochrome P450 inhibitors on substrate drugs: analysis of physiologically based pharmacokinetic modeling submissions to the US Food and Drug Administration. Clin. Pharmacokinet. 54, 117-127 (2015).