Abstract
Time-dependent inhibition (TDI) is an important consideration in the drug development process. To date, methods to accurately predict the magnitude of a clinical interaction from pre-clinical TDI data have been lacking. Although more complex prediction algorithms have been developed, the accuracy has still improved little. This suggests alternate methods to collect input data may improve prediction robustness. Historically, human liver microsomes have been used to generate inhibition kinetic data used as inputs in the in vivo DDI predictions. Recently, it has been suggested that human hepatocytes and the kinetic data derived from this matrix may provide a better prediction for assessing clinical interactions related to TDI. This chapter reviews a detailed method to assess TDI related to CYP3A in human hepatocytes.
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References
Juurlink DN, Mamdani M, Kopp A, Laupacis A, Redelmeier DA (2003) Drug-drug interactions among elderly patients hospitalized for drug toxicity. JAMA 289(13):1652–1658
Monahan BP, Ferguson CL, Killeavy ES, Lloyd BK, Troy J, Cantilena LR Jr (1990) Torsades de pointes occurring in association with terfenadine use. JAMA 264(21):2788–2790
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm292362.pdf
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/07/WC500129606.pdf
Lin JH, Lu AY (1998) Inhibition and induction of cytochrome P450 and the clinical implications. Clin Pharmacokinet 35(5):361–390
Lin JH (2007) Transporter-mediated drug interactions: clinical implications and in vitro assessment. Expert Opin Drug Metab Toxicol 3(1):81–92
Lynch T, Price A (2007) The effect of cytochrome P450 metabolism on drug response, interactions, and adverse events. Am Fam Physician 76:391–396
Riley RJ, Grime K, Weaver R (2007) Time-dependent CYP inhibition. Expert Opin Drug Metab Toxicol 3(1):51–66
Grimm SW, Einolf HJ, Hall SD, He K, Lim HK, Ling KH, Lu C, Nomeir AA, Seibert E, Skordos KW, Tonn GR, Van Horn R, Wang RW, Wong YN, Yang TJ, Obach RS (2009) The conduct of in vitro studies to address time-dependent inhibition of drug-metabolizing enzymes: a perspective of the pharmaceutical research and manufacturers of America. Drug Metab Dispos 37:1355–1370
Fahmi OA, Hurst S, Plowchalk D, Cook J, Guo F, Youdim K, Dickins M, Phipps A, Darekar A, Hyland R, Obach RS (2009) Comparison of different algorithms for predicting clinical drug-drug interactions, based on the use of CYP3A4 in vitro data: predictions of compounds as precipitants of interaction. Drug Metab Dispos 37(8):1658–1666
Jamei M, Marciniak S, Feng K, Barnett A, Tucker G, Rostami-Hodjegan A (2009) The Simcyp population-based ADME simulator. Expert Opin Drug Metab Toxicol 5(2):211–223
Wang YH (2010) Confidence assessment of the Simcyp time-based approach and static mathematical model in predicting clinical drug-drug interactions for mechanism-based CYP3A inhibitors. Drug Metab Dispos 38: 1094–1104
Zhao P, Kunze KL, Lee CA (2005) Evaluation of time-dependent inactivation of CYP3A in cryopreserved human hepatocytes. Drug Metab Dispos 33:853–861
McGinnity DF, Berry AJ, Kenny JR, Grime K, Riley RJ (2006) Evaluation of time-dependent cytochrome P450 inhibition using cultured human hepatocytes. Drug Metab Dispos 34: 1291–1300
Xu L, Chen Y, Pan Y, Skiles GL, Shou M (2009) Prediction of human drug-drug interactions from time-dependent inactivation of CYP3A4 in primary hepatocytes using a population-based simulator. Drug Metab Dispos 37:2330–2339
Chen Y, Liu L, Monshouwer M, Fretland AJ (2011) Determination of time-dependent inactivation of CYP3A4 in cryopreserved human hepatocytes and assessment of human drug-drug interactions. Drug Metab Dispos 39: 2085–2092
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Chen, Y., Fretland, A.J. (2014). Evaluation of Time-Dependent CYP3A4 Inhibition Using Human Hepatocytes. In: Caldwell, G., Yan, Z. (eds) Optimization in Drug Discovery. Methods in Pharmacology and Toxicology. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-742-6_16
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DOI: https://doi.org/10.1007/978-1-62703-742-6_16
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