title: In vitro assessment of metabolic drug-drug interaction potential of apixaban through cytochrome P450 phenotyping, inhibition, and induction studies.
abstract: Apixaban is an oral, direct, and highly selective factor Xa inhibitor in late-stage clinical development for the prevention and treatment of thromboembolic diseases. The metabolic drug-drug interaction potential of apixaban was evaluated in vitro. The compound did not show cytochrome P450 inhibition (IC(50) values >20 microM) in incubations of human liver microsomes with the probe substrates of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5. Apixaban did not show any effect at concentrations up to 20 muM on enzyme activities or mRNA levels of selected P450 enzymes (CYP1A2, 2B6, and 3A4/5) that are sensitive to induction in incubations with primary human hepatocytes. Apixaban showed a slow metabolic turnover in incubations of human liver microsomes with formation of O-demethylation (M2) and hydroxylation products (M4 and M7) as prominent in vitro metabolites. Experiments with human cDNA-expressed P450 enzymes and P450 chemical inhibitors and correlation with P450 activities in individual human liver microsomes demonstrated that the oxidative metabolism of apixaban for formation of all metabolites was predominantly catalyzed by CYP3A4/5 with a minor contribution of CYP1A2 and CYP2J2 for formation of M2. The contribution of CYP2C8, 2C9, and 2C19 to metabolism of apixaban was less significant. In addition, a human absorption, distribution, metabolism, and excretion study showed that more than half of the dose was excreted as unchanged parent (f(m CYP) <0.5), thus significantly reducing the overall metabolic drug-drug interaction potential of apixaban. Together with a low clinical efficacious concentration and multiple clearance pathways, these results demonstrate that the metabolic drug-drug interaction potential between apixaban and coadministered drugs is low.
authors: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, Princeton, New Jersey 08543, USA.
authors: Lifei
authors: L
authors: Wang
authors: Donglu
authors: D
authors: Zhang
authors: Nirmala
authors: N
authors: Raghavan
authors: Ming
authors: M
authors: Yao
authors: Li
authors: L
authors: Ma
authors: Charles E
authors: CE
authors: Frost
authors: Charles A
authors: CA
authors: Frost
authors: Brad D
authors: BD
authors: Maxwell
authors: Shiang-yuan
authors: SY
authors: Chen
authors: Kan
authors: K
authors: He
authors: Theunis C
authors: TC
authors: Goosen
authors: W Griffith
authors: WG
authors: Humphreys
authors: Scott J
authors: SJ
authors: Grossman
mesh_terms: D000375:Aging; D000925:Anticoagulants / Q000493:pharmacokinetics*; D002478:Cells, Cultured; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D065427:Factor Xa Inhibitors; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D007527:Isoenzymes / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000235:genetics; D007700:Kinetics; D050216:Metabolic Detoxication, Phase I; D008861:Microsomes / Q000201:enzymology / Q000378:metabolism; D009928:Organ Specificity; D011720:Pyrazoles / Q000493:pharmacokinetics*; D011728:Pyridones / Q000493:pharmacokinetics*; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism
chemical_list: D000925:Anticoagulants; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D065427:Factor Xa Inhibitors; D007527:Isoenzymes; D011720:Pyrazoles; D011728:Pyridones; D012333:RNA, Messenger; D011994:Recombinant Proteins; C522181:apixaban; D003577:Cytochrome P-450 Enzyme System; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human