Effects of nilotinib on single-dose warfarin pharmacokinetics and pharmacodynamics: A Randomized, single-blind, two-period crossover study in healthy subjects

Clinical Drug Investigation

Volumn 31, Issue 3, 2011, Pages 169-179

  Yin, Ophelia Q P ^a   Gallagher, Neil ^a   Fischer, Deirdre ^a   Zhao, Lily ^a   Zhou, Wei ^b   Leroy, Elisabeth ^b   Golor, Georg ^c   Schran, Horst ^a  

^a NOVARTIS PHARMA AG   (Switzerland)

^b NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH   (United States)

^c PAREXEL INTERNATIONAL   (United States)

Author keywords

Cytochrome P450; Nilotinib, pharmacodynamics; Nilotinib, pharmacokinetics; Protein tyrosine kinase inhibitors, pharmacokinetics; Warfarin, pharmacodynamics; Warfarin, pharmacokinetics

Indexed keywords

CYTOCHROME P450 2C9; NILOTINIB; PLACEBO; WARFARIN;

ADULT; AGED; ALANINE AMINOTRANSFERASE BLOOD LEVEL; AREA UNDER THE CURVE; ARTICLE; ASPARTATE AMINOTRANSFERASE BLOOD LEVEL; BLOOD SAMPLING; CANCER PATIENT; CROSSOVER PROCEDURE; DRUG ACTIVITY; DRUG BLOOD LEVEL; DRUG EFFECT; DRUG INDUCED HEADACHE; DRUG MEGADOSE; DRUG SAFETY; DRUG TOLERABILITY; DRUG WITHDRAWAL; FATIGUE; FEMALE; GASTROINTESTINAL STROMAL TUMOR; GENOTYPE; GEOMETRY; HOT FLUSH; HUMAN; INTERNATIONAL NORMALIZED RATIO; LIPID DIET; MALE; MAXIMUM PLASMA CONCENTRATION; MUSCLE SPASM; NAUSEA; NORMAL HUMAN; PAIN; PRIORITY JOURNAL; PROTHROMBIN TIME; RANDOMIZED CONTROLLED TRIAL; SIDE EFFECT; SINGLE BLIND PROCEDURE; SINGLE DRUG DOSE; SOMNOLENCE; STEADY STATE; VOMITING;

ADMINISTRATION, ORAL; ADULT; AGED; ANTICOAGULANTS; AREA UNDER CURVE; ARYL HYDROCARBON HYDROXYLASES; CROSS-OVER STUDIES; DRUG INTERACTIONS; FEMALE; FUSION PROTEINS, BCR-ABL; GENOTYPE; HUMANS; INTERNATIONAL NORMALIZED RATIO; MALE; MIDDLE AGED; PROTEIN KINASE INHIBITORS; PROTEIN-TYROSINE KINASES; PROTHROMBIN TIME; PYRIMIDINES; SINGLE-BLIND METHOD; WARFARIN; YOUNG ADULT;

EID: 79751474810     PISSN: 11732563     EISSN: 11791918     Source Type: Journal    
DOI: 10.2165/11538700-000000000-00000     Document Type: Article

References (26)

1. Weisberg E, Manley P, Mestan J, et al. AMN107 (nilotinib) a novel and selective inhibitor of BCR-ABL. Br J Cancer 2006; 94: 1765-9 (Pubitemid 43882564)
2. Verstovsek S, Golemovic M, Kantarjian H, et al. AMN107, a novel aminopyrimidine inhibitor of p190 BCR-ABL activation and of in vitro proliferation of Philadelphia-positive acute lymphoblastic leukemia cells. Cancer 2005; 104: 1230-6 (Pubitemid 41278958)
3. Golemovic M, Verstovsek S, Giles F, et al. AMN107, a novel aminopyrimidine inhibitor of Bcr-Abl, had in vitro activity against imatinib-resistant chronic myeloid leukemia. Clin Cancer Res 2005; 11: 4941-7 (Pubitemid 41557215)
4. Weisberg E, Manley PW, Breitenstein W, et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 2005; 7: 129-41 (Pubitemid 40248339)
5. Nilotinib (Tasigna-) [package insert]. East Hanover (NJ): Novartis Pharmaceuticals Corporation, 2007 Oct
6. Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosomepositive ALL. N Engl J Med 2006; 354: 2542-51 (Pubitemid 43882350)
7. Bjornsson TD, Callaghan JT, Einolf HJ, et al. The conduct of in vitro and in vivo drug-drug interaction studies: a PhRMA perspective. J Clin Pharmacol 2003; 43: 443-69 (Pubitemid 36506147)
8. U.S. Food and Drug Administration (FDA). Guidance for industry: drug interaction studies - study design, data analysis, and implications for dosing and labeling. Rockville (MD): FDA 2006
9. Breckenridge A, Orme M, Wesseling H, et al. Pharmacokinetics and pharmacodynamics of the enantiomers of warfarin in men. Clin Pharmacol Ther 1974; 15: 424-30
10. Kaminsky LS, Zhang ZY. Human P450 metabolism of warfarin. Pharmacol Ther 1997; 73: 67-74 (Pubitemid 26425815)
11. Tamazaki H, Shimada T. Human liver cytochrome P450 enzymes involved in the 7-hydroxylation of R- and Swarfarin enantiomers. Biochem Pharmacol 1997; 54: 1195-203 (Pubitemid 27497246)
12. Takahashi H, Echizen H. Pharmacogenetics of CYP2C9 and interindividual variability in anticoagulant response to warfarin. Pharmacogenomics 2003; 3: 202-14 (Pubitemid 37167925)
13. Aithal GP, Day CP, Kesteven PJ, et al. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 1999; 353: 717-9 (Pubitemid 29103806)
14. Kumar V, Brundage RC, Oetting WS, et al. Differential genotype dependent inhibition of CYP2C9 in humans. Drug Metab Dispos 2008; 36: 1242-8 (Pubitemid 351929306)
15. U.S. Food and Drug Administration (FDA). Guidance for industry: food-effect bioavailability and fed bioequivalence studies. Rockville (MD): FDA 2002
16. Benet L. Relevance of pharmacokinetics in narrow therapeutic index drugs. Transplant Proc 1999; 31: 1642-4 (Pubitemid 29234961)
17. He YL, Sabo R, Riviere GJ, et al. Effect of the novel oral dipeptidyl peptidase IV inhibitor vildagliptin on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. Curr Med Res Opin 2007; 5: 1131-8 (Pubitemid 46799597)
18. Common Toxicity Criteria forAdverse Events v 3.0 (CTCAE) [online]. Available from URL: http://ctep.cancer.gov/ protocolDevelopment/electronic- applications/docs/ctcaev3. pdf. [Accessed 2010 Nov 19]
19. Obach RS, Walsky RL, Venkatakrishnan K, et al. The utility of in vitro cytochrome P450 inhibition data in the prediction of drug-drug interactions. J Pharmacol Exp Ther 2006; 316: 336-48 (Pubitemid 41832613)
20. Yacobi A, Levy G. Protein binding of warfarin enantiomers in serum of humans and rats. J Pharmacokinet Biopharm 1977; 5: 123-31 (Pubitemid 8128156)
21. Bjornsson TD, Meffin PJ, Swezey S, et al. Clofibrate displaces warfarin from plasma proteins in man: an example of a pure displacement interaction. J Pharmacol Exp Ther 1979; 210: 316-21 (Pubitemid 10227351)
22. Diana FJ, Veronich K, Kapoor AL. Binding of nonsteroidal anti-inflammatory agents and their effect on binding of racemic warfarin and its enantiomers to human serum albumin. J Pharm Sci 1989; 78: 195-9 (Pubitemid 19079841)
23. Serlin MJ, Mossman S, Sibeon RG, et al. Interaction between diflunisal and warfarin. Clin Pharmacol Ther 1980; 28: 493-8 (Pubitemid 11253935)
24. Sands CD, Chan ES, Welty TE. Revisiting the significance of warfarin protein-binding displacement interactions. Ann Pharmacother 2002 Oct; 36: 1642-4
25. Benet LZ, Hoener B. Changes in plasma protein binding have little clinical relevance. Clin Pharmacol Ther 2002; 71: 115-21 (Pubitemid 34271114)
26. Rowland M, Tozer TN. Clinical pharmacokinetics: concepts and applications. 3rd ed. New York: Lippincott Williams & Wilkins, 1995