Pharmacokinetics, metabolism, and excretion of [14C]axitinib, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, in humanss

Drug Metabolism and Disposition

Volumn 42, Issue 5, 2014, Pages 918-931

  Smith, Bill J ^a   Pithavala, Yazdi ^b   Bu, Hai Zhi ^a   Kang, Ping ^a   Hee, Brian ^b   Deese, Alan J ^c   Pool, William F ^a   Klamerus, Karen J ^b   Wu, Ellen Y ^a   Dalvie, Deepak K ^a  

^a Dermatology/Cosmetic Laser Associates   (United States)

^b PFIZER INC   (United States)

^c American Life Science Pharmaceuticals   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AXITINIB; AXITINIB C 14; AXITINIB N GLUCURONIDE; AXITINIB SULFOXIDE; CARBON 14; CARBOXYLIC ACID; DRUG METABOLITE; EPOXIDE; GLUCURONIDE; KETONE; METHYLHYDROXY GLUCURONIDE; OXIDE; PEROXIDE; SULFONE; SULFOXIDE; UNCLASSIFIED DRUG; CARBON; IMIDAZOLE DERIVATIVE; INDAZOLE DERIVATIVE; PROTEIN KINASE INHIBITOR; PROTEIN TYROSINE KINASE; VASCULOTROPIN RECEPTOR;

ADULT; AREA UNDER THE CURVE; ARTICLE; BAEYER VILLIGER REARRANGEMENT; CARBON CARBON BOND CLEAVAGE; CHEMICAL REACTION; CONTROLLED STUDY; DRUG ABSORPTION; DRUG ACTIVITY; DRUG BLOOD LEVEL; DRUG EXCRETION; DRUG HALF LIFE; DRUG METABOLISM; FECES; HUMAN; HUMAN EXPERIMENT; MALE; NORMAL HUMAN; OXIDATION; PHARMACOKINETICS; PRIORITY JOURNAL; RADIOACTIVITY; SINGLE DRUG DOSE; URINARY EXCRETION; ANTAGONISTS AND INHIBITORS; BLOOD; CHEMICAL STRUCTURE; CHEMISTRY; CLINICAL TRIAL; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; MASS SPECTROMETRY; METABOLISM; MIDDLE AGED; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; URINE;

ADULT; CARBON RADIOISOTOPES; CHROMATOGRAPHY, HIGH PRESSURE LIQUID; FECES; HUMANS; IMIDAZOLES; INDAZOLES; MAGNETIC RESONANCE SPECTROSCOPY; MALE; MASS SPECTROMETRY; MIDDLE AGED; MOLECULAR STRUCTURE; PROTEIN KINASE INHIBITORS; PROTEIN-TYROSINE KINASES; RECEPTORS, VASCULAR ENDOTHELIAL GROWTH FACTOR;

EID: 84898795714     PISSN: 00909556     EISSN: 1521009X     Source Type: Journal    
DOI: 10.1124/dmd.113.056531     Document Type: Article

References (33)

1. Bender SL, Kania RS, McTigue MA, Palmer CL, Pinko C, and Wickersham J (2004) inventors, Pfizer Inc., assignee. Crystal structure of human VEGFR2 kinase domain-ligand complexes and use of the atomic coordinates in drug discovery. International patent WO2004092217A1. Oct 28.
2. Beumer JH, Beijnen JH, and Schellens JH (2006) Mass balance studies, with a focus on anticancer drugs. Clin Pharmacokinet 45:33-58.
3. Borchardt AJ, Kania RS, and Palmer CL (2006) inventors, Agouron Pharmaceuticals, Inc., assignee. Indazole compounds and pharmaceutical compositions for inhibiting protein kinases, and methods for their use. U.S. patent 7,053,107 B2. 2006 May 30.
4. Brennan M, Williams JA, Chen Y, Tortorici M, Pithavala Y, and Liu YC (2012) Meta-analysis of contribution of genetic polymorphisms in drug-metabolizing enzymes or transporters to axitinib pharmacokinetics. Eur J Clin Pharmacol 68:645-655.
5. Bu HZ, Zhao P, Kang P, Pool WF, Wu EY, and Shetty BV (2007) Evaluation of capravirine as a CYP3A probe substrate: in vitro and in vivo metabolism of capravirine in rats and dogs. Drug Metab Dispos 35:1593-1602.
6. Campeta AM, Chekal BP, Abramov YA, Meenan PA, Henson MJ, Shi B, Singer RA, and Horspool KR (2010) Development of a targeted polymorph screening approach for a complex polymorphic and highly solvating API. J Pharm Sci 99:3874-3886.
7. Chen GP, Poulsen LL, and Ziegler DM (1995) Oxidation of aldehydes catalyzed by pig liver flavin-containing monooxygenase. Drug Metab Dispos 23:1390-1393.
8. Dalvie D, Zhang C, Chen W, Smolarek T, Obach RS, and Loi CM (2010) Cross-species comparison of the metabolism and excretion of zoniporide: contribution of aldehyde oxidase to interspecies differences. Drug Metab Dispos 38:641-654.
9. Dalvie DK, Khosla NB, Navetta KA, and Brighty KE (1996) Metabolism and excretion of trovafloxacin, a new quinolone antibiotic, in Sprague-Dawley rats and beagle dogs. Effect of bile duct cannulation on excretion pathways. Drug Metab Dispos 24:1231-1240.
10. Davis-Bruno KL and Atrakchi A (2006) A regulatory perspective on issues and approaches in characterizing human metabolites. Chem Res Toxicol 19:1561-1563.
11. Deacon M, Singleton D, Szalkai N, Pasieczny R, Peacock C, Price D, Boyd J, Boyd H, Steidl-Nichols JV, and Williams C (2007) Early evaluation of compound QT prolongation effects: a predictive 384-well fluorescence polarization binding assay for measuring hERG blockade. J Pharmacol Toxicol Methods 55:238-247.
12. European Medicines Agency (2009) ICH guideline M3(R2) on non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for pharmaceuticals. EMA/CPMP/ICH/286/1995. European Medicines Agency, London, UK. http://www.ema.europa.eu/docs/en-GB/document-library/ Scientific-guideline/2009/09/WC500002720.pdf.
13. Folkman J, Merler E, Abernathy C, and Williams G (1971) Isolation of a tumor factor responsible for angiogenesis. J Exp Med 133:275-288.
14. Hamilton RA, Garnett WR, and Kline BJ (1981) Determination of mean valproic acid serum level by assay of a single pooled sample. Clin Pharmacol Ther 29:408-413.
15. Hanahan D and Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86:353-364.
16. Hu-Lowe DD, Zou HY, Grazzini ML, Hallin ME, Wickman GR, Amundson K, Chen JH, Rewolinski DA, Yamazaki S, and Wu EY, et al. (2008) Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clin Cancer Res 14:7272-7283.
17. Inlyta (2012) Prescribing information. Pfizer Labs, Division of Pfizer Inc., New York, NY.
18. Lai WG, Farah N, Moniz GA, and Wong YN (2011) A Baeyer-Villiger oxidation specifically catalyzed by human flavin-containing monooxygenase 5. Drug Metab Dispos 39:61-70.
19. Ling J, Johnson KA, Miao Z, Rakhit A, Pantze MP, Hamilton M, Lum BL, and Prakash C (2006) Metabolism and excretion of erlotinib, a small molecule inhibitor of epidermal growth factor receptor tyrosine kinase, in healthy male volunteers. Drug Metab Dispos 34:420-426.
20. Loi CM, Smith DA, and Dalvie D (2013) Which metabolites circulate? Drug Metab Dispos 41: 933-951.
21. Lutz JD, Fujioka Y, and Isoherranen N (2010) Rationalization and prediction of in vivo metabolite exposures: the role of metabolite kinetics, clearance predictions and in vitro parameters. Expert Opin Drug Metab Toxicol 6:1095-1109.
22. Mayol RF, Cole CA, Luke GM, Colson KL, and Kerns EH (1994) Characterization of the metabolites of the antidepressant drug nefazodone in human urine and plasma. Drug Metab Dispos 22:304-311.
23. McTigue M, Murray BW, Chen JH, Deng YL, Solowiej J, and Kania RS (2012) Molecular conformations, interactions, and properties associated with drug efficiency and clinical performance among VEGFR TK inhibitors. Proc Natl Acad Sci USA 109:18281-18289.
24. Nedderman AN, Dear GJ, North S, Obach RS, and Higton D (2011) From definition to implementation: a cross-industry perspective of past, current and future MIST strategies. Xenobiotica 41:605-622.
25. Ortiz de Montellano PR and DeVoss JJ (2005) Substrate oxidation by cytochrome P450 enzymes, in Cytochrome P450: Structure, Mechanism and Biochemistry, 3rd ed (Ortiz de Montellano PR ed) pp 183-192, Kluwer Academic/Plenum Publishers, New York.
26. Pithavala YK, Chen Y, Toh M, Selaru P, LaBadie RR, Garrett M, Hee B, Mount J, Ni G, and Klamerus KJ, et al. (2012a) Evaluation of the effect of food on the pharmacokinetics of axitinib in healthy volunteers. Cancer Chemother Pharmacol 70:103-112.
27. Pithavala YK, Tong W, Mount J, Rahavendran SV, Garrett M, Hee B, Selaru P, Sarapa N, and Klamerus KJ (2012b) Effect of ketoconazole on the pharmacokinetics of axitinib in healthy volunteers. Invest New Drugs 30:273-281.
28. Pithavala YK, Tortorici M, Toh M, Garrett M, Hee B, Kuruganti U, Ni G, and Klamerus KJ (2010) Effect of rifampin on the pharmacokinetics of axitinib (AG-013736) in Japanese and Caucasian healthy volunteers. Cancer Chemother Pharmacol 65:563-570.
29. Roffey SJ, Obach RS, Gedge JI, and Smith DA (2007) What is the objective of the mass balance study? A retrospective analysis of data in animal and human excretion studies employing radiolabeled drugs. Drug Metab Rev 39:17-43.
30. Rugo HS, Herbst RS, Liu G, Park JW, Kies MS, Steinfeldt HM, Pithavala YK, Reich SD, Freddo JL, and Wilding G (2005) Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: pharmacokinetic and clinical results. J Clin Oncol 23: 5474-5483.
31. Shimizu S, Atsumi R, Nakazawa T, Fujimaki Y, Sudo K, and Okazaki O (2009) Metabolism of ticlopidine in rats: identification of the main biliary metabolite as a glutathione conjugate of ticlopidine S-oxide. Drug Metab Dispos 37:1904-1915.
32. Wang Z, Hop CE, Kim MS, Huskey SE, Baillie TA, and Guan Z (2003) The unanticipated loss of SO2 from sulfonamides in collision-induced dissociation. Rapid Commun Mass Spectrom 17: 81-86.
33. Zientek M, Jiang Y, Kang P, and Smith BJ (2010) In vitro kinetic characterization of axitinib metabolism to estimate the clinical implications of genetic polymorphisms. International Society for the Study of Xenobiotics Workshop on Genetic Polymorphisms in Drug Disposition; 2010 Apr 11-13; Indianapolis, IN. International Society for the Study of Xenobiotics, Washington. http://issx.confex.com/issx/gpddw/webprogram/Paper19628.html.