The pharmacokinetics, metabolism and clearance mechanisms of tofacitinib, a janus kinase inhibitor, in humans

Drug Metabolism and Disposition

Volumn 42, Issue 4, 2014, Pages 759-773

  Dowty, Martin E ^a   Lin, Jinyan ^a   Ryder, Tim F ^a   Wang, Weiwei ^a   Walker, Gregory S ^a   Vaz, Alfin ^a   Chan, Gary L ^a   Krishnaswami, Sriram ^a   Prakash, Chandra ^a  

^a PFIZER INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CARBON 14; CYTOCHROME P450 2C19; CYTOCHROME P450 3A4; JANUS KINASE INHIBITOR; PIPERIDINE; PYRROLOPYRIMIDINE DERIVATIVE; TOFACITINIB;

ADULT; AREA UNDER THE CURVE; ARTICLE; DEMETHYLATION; DRUG ABSORPTION; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG FECES LEVEL; DRUG GLUCURONIDATION; DRUG HALF LIFE; DRUG METABOLISM; DRUG OXIDATION; DRUG STRUCTURE; DRUG URINE LEVEL; HUMAN; HUMAN EXPERIMENT; ISOTOPE LABELING; MALE; MAXIMUM PLASMA CONCENTRATION; MIDDLE AGED; NORMAL HUMAN; PRIORITY JOURNAL; RADIOACTIVITY; SINGLE DRUG DOSE; TIME TO MAXIMUM PLASMA CONCENTRATION; VOLUNTEER; YOUNG ADULT;

ARYL HYDROCARBON HYDROXYLASES; BIOTRANSFORMATION; CHROMATOGRAPHY, HIGH PRESSURE LIQUID; CYTOCHROME P-450 CYP3A; FECES; FEMALE; HUMANS; JANUS KINASES; LIVER; MAGNETIC RESONANCE SPECTROSCOPY; MALE; METABOLIC CLEARANCE RATE; MICROSOMES, LIVER; PIPERIDINES; PROTEIN KINASE INHIBITORS; PYRIMIDINES; PYRROLES; TANDEM MASS SPECTROMETRY;

EID: 84896110513     PISSN: 00909556     EISSN: 1521009X     Source Type: Journal    
DOI: 10.1124/dmd.113.054940     Document Type: Article

References (27)

1. Chow V, Wilkinson B, LaBadie R, Ni G, and Zwillich S (2008a) Open label study of the pharmacokinetics of a JAK3 antagonist (CP-690,550) and single doses of oral methotrexate in rheumatoid arthritis subjects (Abstract). Clin Pharmacol Ther 83 (Suppl 1):PI-82.
2. Chow V, Ni G, LaBadie R, and Chan G (2008b) An open label study to estimate the effect of fluconazole on the pharmacokinetics of CP-690,550 in healthy adult subjects (Abstract). Clin Pharmacol Ther 83 (Suppl 36):PI-93.
3. Ghoreschi K, Laurence A, and O'Shea JJ (2009) Janus kinases in immune cell signaling. Immunol Rev 228:273-287.
4. Gupta P, Harness J, Buonanno M, Krishnaswami S, and Chapel S (2011a) Population pharmacokinetics of tasocitinib (CP-690,550) in patients with moderate to severe plaque psoriasis (Abstract). J Am Academy Dermatology 64 (Suppl 1): AB163.
5. Gupta P, Stock TC, Wang R, Alvey C, Choo HW, and Krishnaswami S (2001b) A phase 1 study to estimate the absolute oral bioavailability of tofacitinib (CP-690,550) in healthy subjects (Abstract 1122902). J Clin Pharmacol 51:1348
6. Gupta P, Wang R, Kaplan I, Alvey CW, Ndongo M, and Krishnaswami S (2012) A phase 1 study to estimate the effect of ketoconazole on the pharmacokinetics of tofacitinib (CP-690,550) in healthy volunteers (Abstract PI-64). Clin Pharmacol Ther 91 (Suppl 1):S31.
7. 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. (Pubitemid 11134120)
8. Krishnaswami S, Busque S, Leventhal J, Steinberg S, Klintmalm G, Brennan D, Chow V, Gupta P, Menon S, Lawendy N et al. (2008a) Pharmacokinetic (PK) profile of CP-690,550 in de novo renal allograft recipients (Abstract). Annual Meeting of the American Association of Pharmaceutical Scientists; 2008 November 16-20, Atlanta, Georgia. Poster T3328.
9. Krishnaswami S, Gupta P, French J, Cook J, Gruben D, and Chan G (2008b) The effect of CP- 690,550, a Janus kinase inhibitor, on QTc interval and blood pressure (BP): a concentration-response analysis of phase 1 data (Abstract). 2008 Annual Meeting of the American Association of Pharmaceutical Scientists; November 16-20; Atlanta, Georgia. Poster T3006.
10. Krishnaswami S, Kudlacz E, Yocum S, Dowty M, Alvey C, Wang R, and Chan G (2009) Effect of CYP2C19 polymorphism on the pharmacokinetics of CP-690,550, a Janus kinase inhibitor (Abstract). 2009 Annual Meeting of the American Association of Pharmaceutical Scientists; 2009 November 8-12, Seattle, Washington. Poster T3134.
11. Lamba M, Wang R, Kaplan I, Salageanu J, Tarabar S, and Krishnaswami S (2012) The effect of rifampin on the pharmacokinetics of tofacitinib (CP-690,550) in healthy volunteers (Abstract PI-73). Clin Pharmacol Ther 91 (Suppl 1):S35.
12. Lawendy N, Krishnaswami S, Wang R, Gruben D, Cannon C, Swan S, and Chan G (2009) Effect of CP-690,550, an orally active janus kinase inhibitor, on renal function in healthy adult volunteers. J Clin Pharmacol 49:423-429.
13. McInnes IB and Schett G (2011) The pathogenesis of rheumatoid arthritis. N Engl J Med 365: 2205-2219.
14. McInnes IB and Schett G (2007) Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol 7:429-442. (Pubitemid 46834849)
15. Meyer D, Head R, Thompson J, Ghosh S, LaBranche T, Storer C, Minnerly J, Jesson M, and Kishore N (2010a) Mechanism of action of the JAK inhibitor, CP-690550, in rheumatoid arthritis (Abstract). Eighth Cytokines and Inflammation Conference; 2010 January 28, San Diego, California.
16. Meyer DM, Jesson MI, Li X, Elrick MM, Funckes-Shippy CL, Warner JD, Gross CJ, Dowty ME, Ramaiah SK, and Hirsch JL, et al. (2010b) Anti-inflammatory activity and neutrophil reductions mediated by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis. J Inflamm (Lond) 7:41.
17. Murray PJ (2007) The JAK-STAT signaling pathway: input and output integration. J Immunol 178:2623-2629.
18. Nograles KE, Davidovici B, and Krueger JG (2010) New insights in the immunologic basis of psoriasis. Semin Cutan Med Surg 29:3-9.
19. O'Shea JJ (1997) Jaks, STATs, cytokine signal transduction, and immunoregulation: are we there yet? Immunity 7:1-11.
20. O'Shea JJ (2004) Targeting the Jak/STAT pathway for immunosuppression. Ann Rheum Dis 63 (Suppl 2):ii67-ii71.
21. O'Shea JJ, Gadina M, and Schreiber RD (2002) Cytokine signaling in 2002: new surprises in the Jak/Stat pathway. Cell 109 (Suppl):S121-S131. (Pubitemid 34457857)
22. Robison TW and Jacobs A (2009) Metabolites in safety testing. Bioanalysis 1:1193-1200.
23. Sandborn WJ, Ghosh S, Panes J, Vranic I, Spanton J, Niezychowski W (2011) Phase 2 randomized study of CP-690,550, an oral janus kinase inhibitor, in active Crohn's disease (Abstract). Gastroenterology 140 (Suppl 1) S-124.
24. Sandborn WJ, Ghosh S, Panes J, Vranic I, Su C, Rousell S, and Niezychowski W; Study A3921063 Investigators (2012) Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. N Engl J Med 367:616-624.
25. Schindler C, Levy DE, and Decker T (2007) JAK-STAT signaling: from interferons to cytokines. J Biol Chem 282:20059-20063. (Pubitemid 47099977)
26. Shuai K and Liu B (2003) Regulation of JAK-STAT signalling in the immune system. Nat Rev Immunol 3:900-911. (Pubitemid 37411719)
27. Walsky RL and Obach RS (2004) Validated assays for human cytochrome P450 activities. Drug Metab Dispos 32:647-660. (Pubitemid 38668158)