title: Evaluation of cytochrome P450-mediated drug-drug interactions based on the strategies recommended by regulatory authorities.
abstract: Herein, we aimed to evaluate the recently proposed risk assessment strategies of a cytochrome P450 (CYP) mediated drug-drug interaction (DDI) according to the European Medicines Evaluation Agency (EMEA) draft guideline, and discuss the differences between this guideline and the Food and Drug Administration (FDA) draft guidance.        A retrospective study on reported 35 clinical DDI cases revealed that the EMEA assessment successfully predicts moderate-to-strong DDIs, i.e. drugs that cause more than 2-fold increase in the area under the curve in the presence and absence of CYP inhibitor (AUC(i)/AUC); however, EMEA tends to overlook weak DDIs with AUC(i)/AUC ≤ 2 to > 1.25. For CYP3A4 inhibitors, even clinically insignificant DDIs were overemphasized if the intestinal DDI is considered.        The differences between unbound fraction in plasma and microsomes account for the discrepancies in DDI risk assessment results between EMEA and FDA assessments. Comparing two assessment results for CYP2D6 and CYP2C9 inhibitors, the FDA assessment suggested potential DDI risks for sulphinpyrazone and amitriptyline, while the EMEA assessment indicated no potential risk for these drugs.        Through a retrospective study, we showed practical differences in the DDI assessment strategies of EMEA and FDA and suggested improvements in their current strategies.
authors: Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Yodogawa-ku, Osaka, Japan. Kosugi_Youhei@takeda.co.jp
authors: Yohei
authors: Y
authors: Kosugi
authors: Hideki
authors: H
authors: Hirabayashi
authors: Tomoko
authors: T
authors: Igari
authors: Yasushi
authors: Y
authors: Fujioka
authors: Yoko
authors: Y
authors: Hara
authors: Teruaki
authors: T
authors: Okuda
authors: Toshiya
authors: T
authors: Moriwaki
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000737:chemistry; D065729:Cytochrome P-450 CYP2C9; D019389:Cytochrome P-450 CYP2D6 / Q000737:chemistry; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005060:Europe; D017408:Guidelines as Topic; D006801:Humans; D008861:Microsomes; D012189:Retrospective Studies; D018570:Risk Assessment / Q000379:methods; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human