Can Bile Salt Export Pump Inhibition Testing in Drug Discovery and Development Reduce Liver Injury Risk? An International Transporter Consortium Perspective.

Autor: Kenna JG; Safer Medicines Trust, Kingsbridge, UK., Taskar KS; Mechanistic Safety and Disposition, IVIVT, GlaxoSmithKline, Ware, Hertfordshire, UK., Battista C; DILIsym Services Inc., a Simulations Plus Company, Research Triangle Park, North Carolina, USA., Bourdet DL; Drug Metabolism and Pharmacokinetics, Theravance Biopharma, South San Francisco, California, USA., Brouwer KLR; Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA., Brouwer KR; ADME-TOX, BioIVT, Durham, North Carolina, USA., Dai D; Clinical Pharmacology, Research and Development Sciences, Agios Pharmaceuticals, Cambridge, Massachusetts, USA., Funk C; Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Basel, Switzerland., Hafey MJ; Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Inc, Kenilworth, New Jersey, USA., Lai Y; Drug Metabolism, Gilead Sciences Inc., Foster City, California, USA., Maher J; Safety Assessment, Genentech, South San Francisco, California, USA., Pak YA; Lilly Research Laboratory, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, Indiana, USA., Pedersen JM; Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Novum, Huddinge, Sweden., Polli JW; Mechanistic Safety and Drug Disposition, GlaxoSmithKline, King of Prussia, Pennsylvania, USA., Rodrigues AD; PDM, Medicine Design, Pfizer Inc., Groton, Connecticut, USA., Watkins PB; Institute for Drug Safety Sciences, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA., Yang K; DILIsym Services Inc., a Simulations Plus Company, Research Triangle Park, North Carolina, USA., Yucha RW; Takeda Pharmaceuticals, Global Drug Metabolism and Pharmacokinetics, Cambridge, Massachusetts, USA.
Jazyk: angličtina
Zdroj: Clinical pharmacology and therapeutics [Clin Pharmacol Ther] 2018 Nov; Vol. 104 (5), pp. 916-932.
DOI: 10.1002/cpt.1222
Abstrakt: Bile salt export pump (BSEP) inhibition has emerged as an important mechanism that may contribute to the initiation of human drug-induced liver injury (DILI). Proactive evaluation and understanding of BSEP inhibition is recommended in drug discovery and development to aid internal decision making on DILI risk. BSEP inhibition can be quantified using in vitro assays. When interpreting assay data, it is important to consider in vivo drug exposure. Currently, this can be undertaken most effectively by consideration of total plasma steady state drug concentrations (C ss,plasma ). However, because total drug concentrations are not predictive of pharmacological effect, the relationship between total exposure and BSEP inhibition is not causal. Various follow-up studies can aid interpretation of in vitro BSEP inhibition data and may be undertaken on a case-by-case basis. BSEP inhibition is one of several mechanisms by which drugs may cause DILI, therefore, it should be considered alongside other mechanisms when evaluating possible DILI risk.
(© 2018 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)
Databáze: MEDLINE
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