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Meta-analysis of contribution of genetic polymorphisms in drug-metabolizing enzymes or transporters to axitinib pharmacokinetics

  • Pharmacogenetics
  • Published:
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Abstract

Purpose

Axitinib, an orally administered inhibitor of vascular endothelial growth factor 1, 2 and 3, is primarily metabolized by cytochrome P450 (CYP) 3A4/5 but is also a substrate for CYP1A2, CYP2C19, UDP-glucuronosyltransferase (UGT)1A1 and the drug transporters P-glycoprotein (encoded by the ABCB1 gene) and OATP1B1 (encoded by SLC01B1). The potential contribution of polymorphisms in genes encoding these enzymes and transporters to axitinib pharmacokinetic variability was assessed.

Methods

A fixed effects meta-analysis was performed using data pooled from 11 healthy volunteer clinical pharmacology trials to investigate the potential association between axitinib exposure and major polymorphisms in these genes following a 5-mg dose of axitinib.

Results

Up to 15 variant alleles were evaluated and up to 315 healthy volunteers per polymorphism were assayed. None of the polymorphisms analysed was a statistically significant predictor of axitinib pharmacokinetic variability. Amongst genotypes and inferred phenotypes, CYP2C19 genotype and the ABCB1 (G2677T/A) polymorphism were the closest to statistical significance in influencing axitinib pharmacokinetic variability after multiple-testing adjustment. However, no enzyme or transporter genotype/inferred phenotype contributed >5% to the overall pharmacokinetic variability of axitinib.

Conclusions

No statistically significant associations between the specific polymorphisms analysed and axitinib plasma exposure were observed, suggesting that genotype- or inferred phenotype-based adjustment of axitinib dose in individual subjects is not warranted.

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References

  1. Hu-Lowe DD, Zou HY, Grazzini ML, Hallin ME, Wickman GR, Amundson K, Chen JH, Rewolinski DA, Yamazaki S, 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. doi:10.1158/1078-0432.CCR-08-0652

    Article  PubMed  CAS  Google Scholar 

  2. Kelly RJ, Rixe O (2010) Axitinib (AG-013736). Recent Results Cancer Res 184:33–44. doi:10.1007/978-3-642-01222-8_3

    Article  PubMed  CAS  Google Scholar 

  3. Rixe O, Bukowski RM, Michaelson MD, Wilding G, Hudes GR, Bolte O, Motzer RJ, Bycott P, Liau KF, Freddo J et al (2007) Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer: a phase II study. Lancet Oncol 8:975–984. doi:10.1016/S1470-2045(07)70285-1

    Article  PubMed  Google Scholar 

  4. Rini BI, Wilding G, Hudes G, Stadler WM, Kim S, Tarazi J, Rosbrook B, Trask PC, Wood L, Dutcher JP (2009) Phase II study of axitinib in sorafenib-refractory metastatic renal cell carcinoma. J Clin Oncol 27:4462–4468. doi:10.1200/JCO.2008.21.7034

    Article  PubMed  CAS  Google Scholar 

  5. Schiller JH, Larson T, Ou SH, Limentani S, Sandler A, Vokes E, Kim S, Liau K, Bycott P, Olszanski AJ et al (2009) Efficacy and safety of axitinib in patients with advanced non-small-cell lung cancer: results from a phase II study. J Clin Oncol 27:3836–3841. doi:10.1200/JCO.2008.20.8355

    Article  PubMed  Google Scholar 

  6. Fruehauf J, Lutzky J, McDermott D, Brown CK, Meric J-B, Rosbrook B (2011) Multicenter, phase II study of axitinib (AG-013736), an oral and selective inhibitor of VEGFR 1, 2, 3, in patients with metastatic melanoma. Clin Cancer Res. doi: 10.1158/1078-0432.CCR-11-0534

  7. Rugo HS, Stopeck A, Joy AA, Chan S, Verma S, Lluch S, et al (2007) A randomized, double-blind phase II study of the oral tyrosine kinase inhibitor (TKI) axitinib (AG-013376) in combination with docetaxel (DOC) compared to DOC plus placebo (PL) in metastatic breast cancer. Presented at: 43rd Ann Meet American Society of Clinical Oncology. Chicago

  8. Cohen EE, Rosen LS, Vokes EE, Kies MS, Forastiere AA, Worden FP, Kane MA, Sherman E, Kim S, Bycott P et al (2008) Axitinib is an active treatment for all histologic subtypes of advanced thyroid cancer: results from a phase II study. J Clin Oncol 26:4708–4713. doi:10.1200/JCO.2007.15.9566

    Article  PubMed  CAS  Google Scholar 

  9. Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, Michaelson MD, Gorbunova VA, Gore ME, Rusakov IG, Negrier S, Ou Y, Castellano D, Lim HY, Uemura H, Tarazi J, Cella D, Chen C, Rosbrook B, Kim S, Motzer RJ (2011) Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet doi:10.1016/S0140-6736(11):61613–9

  10. Fujiwara Y, Kiyota N, Chayahara N, Suzuki A, Umeyama Y, Mukohara T, Minami H (2011) Management of axitinib (AG-013736)-induced fatigue and thyroid dysfunction, and predictive biomarkers of axitinib exposure: results from phase 1 studies in Japanese patients. Invest New Drugs. doi:10.1007/s10637-011-9637-1

  11. Rugo HS, Herbst RS, Liu G, Park JW, Kies MS, Steinfeldt HM, Pithavala YK, Reich SD, Freddo JL, 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. doi:10.1200/JCO.2005.04.192

    Article  PubMed  CAS  Google Scholar 

  12. Pithavala YK, Tortorici M, Toh M, Garrett M, Hee B, Kuruganti U, Ni G, 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. doi:10.1007/s00280-009-1065-y

    Article  PubMed  CAS  Google Scholar 

  13. Pithavala YK, Chen Y, Toh M, Selaru P, La Badie RR, Garrett M, Hee B, Mount J, Ni G, Klamerus KJ, et al. (2011) Evaluation of the effect of food on the pharmacokinetics of axitinib in healthy volunteers. Cancer Chemother Pharmacol (submitted)

  14. Strumberg D, Clark JW, Awada A, Moore MJ, Richly H, Hendlisz A, Hirte HW, Eder JP, Lenz HJ, Schwartz B (2007) Safety, pharmacokinetics, and preliminary antitumor activity of sorafenib: a review of four phase I trials in patients with advanced refractory solid tumors. Oncologist 12:426–437. doi:10.1634/theoncologist.12-4-426

    Article  PubMed  CAS  Google Scholar 

  15. Bello CL, Sherman L, Zhou J, Verkh L, Smeraglia J, Mount J, Klamerus KJ (2006) Effect of food on the pharmacokinetics of sunitinib malate (SU11248), a multi-targeted receptor tyrosine kinase inhibitor: results from a phase I study in healthy subjects. Anticancer Drugs 17:353–358. doi:10.1097/00001813-200603000-00015

    Article  PubMed  CAS  Google Scholar 

  16. Pithavala YK, Tong W, Mount J, Rahavendran SV, Garrett M, Hee B, Selaru P, Sarapa N, Klamerus KJ (2010) Effect of ketoconazole on the pharmacokinetics of axitinib in healthy volunteers. Invest New Drugs. doi:10.1007/s10637-010-9511-6

  17. Roh HK, Dahl ML, Johansson I, Ingelman-Sundberg M, Cha YN, Bertilsson L (1996) Debrisoquine and S-mephenytoin hydroxylation phenotypes and genotypes in a Korean population. Pharmacogenetics 6:441–447. doi: (Asian Pharmacogenetics Library tag) nnn korea cyp2d6 cyp2c19

    Article  PubMed  CAS  Google Scholar 

  18. Hunfeld NG, Mathot RA, Touw DJ, van Schaik RH, Mulder PG, Franck PF, Kuipers EJ, Geus WP (2008) Effect of CYP2C19*2 and *17 mutations on pharmacodynamics and kinetics of proton pump inhibitors in Caucasians. Br J Clin Pharmacol 65:752–760. doi:10.1111/j.1365-2125.2007.03094.x

    Article  PubMed  CAS  Google Scholar 

  19. Sai K, Saeki M, Saito Y, Ozawa S, Katori N, Jinno H, Hasegawa R, Kaniwa N, Sawada J, Komamura K et al (2004) UGT1A1 haplotypes associated with reduced glucuronidation and increased serum bilirubin in irinotecan-administered Japanese patients with cancer. Clin Pharmacol Ther 75:501–515. doi:10.1016/j.clpt.2004.01.010

    Article  PubMed  CAS  Google Scholar 

  20. Sata F, Sapone A, Elizondo G, Stocker P, Miller VP, Zheng W, Raunio H, Crespi CL, Gonzalez FJ (2000) CYP3A4 allelic variants with amino acid substitutions in exons 7 and 12: evidence for an allelic variant with altered catalytic activity. Clin Pharmacol Ther 67:48–56. doi:10.1067/mcp. 2000.104391

    Article  PubMed  CAS  Google Scholar 

  21. Kuehl P, Zhang J, Lin Y, Lamba J, Assem M, Schuetz J, Watkins PB, Daly A, Wrighton SA, Hall SD et al (2001) Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Gen 27:383–391. doi:10.1038/86882

    Article  CAS  Google Scholar 

  22. Williams JA, Andersson T, Andersson TB, Blanchard R, Behm MO, Cohen N, Edeki T, Franc M, Hillgren KM, Johnson KJ et al (2008) PhRMA white paper on ADME pharmacogenomics. J Clin Pharmacol 48:849–889. doi:10.1177/0091270008319329

    Article  PubMed  CAS  Google Scholar 

  23. Pasanen MK, Neuvonen PJ, Niemi M (2008) Global analysis of genetic variation in SLCO1B1. Pharmacogenomics 9:19–33. doi:10.2217/14622416.9.1.19

    Article  PubMed  CAS  Google Scholar 

  24. Myrand SP, Sekiguchi K, Man MZ, Lin X, Tzeng RY, Teng CH, Hee B, Garrett M, Kikkawa H, Lin CY et al (2008) Pharmacokinetics/genotype associations for major cytochrome P450 enzymes in native and first- and third-generation Japanese populations: comparison with Korean, Chinese, and Caucasian populations. Clin Pharmacol Ther 84:347–361. doi:10.1038/sj.clpt.6100482

    Article  PubMed  CAS  Google Scholar 

  25. Fu JF, Shi JY, Zhao WL, Li G, Pan Q, Li JM, Hu J, Shen ZX, Jin J, Chen FY et al (2008) MassARRAY assay: a more accurate method for JAK2V617F mutation detection in Chinese patients with myeloproliferative disorders. Leukemia 22:660–663. doi:10.1038/sj.leu.2404931

    Article  PubMed  CAS  Google Scholar 

  26. Lamba JK, Lin YS, Schuetz EG, Thummel KE (2002) Genetic contribution to variable human CYP3A-mediated metabolism. Adv Drug Deliv Rev 54:1271–1294. doi:10.1016/S0169-409X(02)00066-2

    Article  PubMed  CAS  Google Scholar 

  27. Wang J (2009) CYP3A polymorphisms and immunosuppressive drugs in solid-organ transplantation. Expert Rev Mol Diagn 9:330–390. doi:10.1517/17425250903379546

    Article  CAS  Google Scholar 

  28. Perera MA (2010) The missing linkage: what pharmacogenetic associations are left to find in CYP3A? Expert Opin Drug Metab Toxicol 6:17–28. doi:10.1517/17425250903379546

    Article  PubMed  CAS  Google Scholar 

  29. Deenen MJ, Cats A, Beijnen JH, Schellens JH (2011) Part 2: pharmacogenetic variability in drug transport and phase I anticancer drug metabolism. Oncologist 16:820–834. doi:10.1634/theoncologist.2010-0259

    Article  PubMed  CAS  Google Scholar 

  30. Zientek M, Kang P, Jiang Y, Neul D, Freiwald S, Smith BJ (2010) In vitro kinetic characterization of axitinib metabolism to estimate the clinical implications of genetic polymorphisms. Presented at: Int Soc Study of Xenobiotics Workshop on Genetic Polymorphisms in Drug Disposition. Indianapolis

  31. Williams JA, Cook J, Hurst SI (2003) A significant drug-metabolizing role for CYP3A5? Drug Metab Dispos 31:1526–1530

    Article  PubMed  CAS  Google Scholar 

  32. Williams JA, Johnson K, Paulauskis J, Cook J (2006) So many studies, too few subjects: establishing functional relevance of genetic polymorphisms on pharmacokinetics. J Clin Pharmacol 46(3):258–264

    Article  CAS  Google Scholar 

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Acknowledgements

This study was sponsored by Pfizer Inc. Editorial assistance was provided by Larry Rosenberg and Joseph Ramcharan of UBC Scientific Solutions and was funded by Pfizer Inc.

Conflict of interest/disclosure

The authors are currently employed by Pfizer Inc or were employed by Pfizer Inc at the time of the study.

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Authors and Affiliations

  1. Pfizer Research Center of Emphasis for DNA and Biofluids—Biobank, Groton, CT, USA

    Meghan Brennan

  2. Translational Oncology, Pfizer Inc, 10777 Science Center Drive, La Jolla, CA, 92121, USA

    J. Andrew Williams

  3. Clinical Pharmacology, Pfizer Inc, 10777 Science Center Drive, La Jolla, CA, 92121, USA

    Ying Chen, Michael Tortorici & Yazdi Pithavala

  4. Pfizer China, Clinical Statistics, 88 Keyuan Rd, Pudong Zhangjiang Hi-Tech Park, Shanghai, 201203, China

    Yingxue Cathy Liu

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  1. Meghan Brennan
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  2. J. Andrew Williams
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  4. Michael Tortorici
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  5. Yazdi Pithavala
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Corresponding author

Correspondence to J. Andrew Williams.

Additional information

Meghan Brennan and Yingxue Cathy Liu were employed by Pfizer Inc at the time of the study

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Brennan, M., Williams, J.A., Chen, Y. et al. Meta-analysis of contribution of genetic polymorphisms in drug-metabolizing enzymes or transporters to axitinib pharmacokinetics. Eur J Clin Pharmacol 68, 645–655 (2012). https://doi.org/10.1007/s00228-011-1171-8

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  • DOI: https://doi.org/10.1007/s00228-011-1171-8

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