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Docetaxel metabolism is not altered by imatinib: findings from an early phase study in metastatic breast cancer

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Abstract

Docetaxel is primarily metabolized by CYP3A4 and susceptible to alterations in clearance by CYP3A4 inhibition and induction. Imatinib is a CYP3A4 inhibitor. A phase I study of docetaxel and imatinib in metastatic breast cancer (MBC) was conducted to test the hypothesis that imatinib decreased docetaxel clearance. Docetaxel was administered weekly × 3 with daily imatinib, repeated every 28 days; during cycle 1, imatinib was started on day 8. Docetaxel and imatinib pharmacokinetics, and hepatic CYP3A4 activity (erythromycin breath test) were evaluated during cycles 1 and 2. Toxicity and efficacy were assessed. Twelve patients were enrolled to three docetaxel/imatinib dose levels: 20 mg/m2/600 mg (DL1), 25 mg/m2/600 mg (DL2), and 25 mg/m2/400 mg (DL2a). Median number of prior chemotherapy regimens was 2 (range, 0–8). Toxicities were primarily observed at DL2; dose-limiting toxicities were Grade 3 transaminase elevations and diarrhea, and 5 patients had grade 2 nausea. Two patients had partial responses (7 months); two stable disease (2 and 4 months); five had progressive disease. Despite a 42% decrease in CYP3A4 activity after 3 weeks of imatinib co-administration, docetaxel clearance was unchanged. Mean ± standard deviation steady-state imatinib trough concentration (2.6 ± 1.2 μg/ml) was approximately 2.6-fold higher than previously observed in other cancer populations, and likely contributed to the poor tolerability of the combination in MBC. In conclusion, imatinib inhibited CYP3A4 but did not affect docetaxel clearance. Clinically, further investigation of this combination in MBC is not warranted due to excessive toxicities. However, these unexpected pharmacokinetic findings support further investigation of mechanisms underlying docetaxel elimination pathways.

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References

  1. Lavelle F, Bissery MC, Combeau C, Riou JF, Vrignaud P, Andre S (1995) Preclinical evaluation of docetaxel (Taxotere). Semin Oncol 22:3–16

    CAS  Google Scholar 

  2. Martin M, Pienkowski T, Mackey J, Pawlicki M, Guastalla JP, Weaver C, Tomiak E, Al-Tweigeri T, Chap L, Juhos E, Guevin R, Howell A, Fornander T, Hainsworth J, Coleman R, Vinholes J, Modiano M, Pinter T, Tang SC, Colwell B, Prady C, Provencher L, Walde D, Rodriguez-Lescure A, Hugh J, Loret C, Rupin M, Blitz S, Jacobs P, Murawsky M, Riva A, Vogel C (2005) Adjuvant docetaxel for node-positive breast cancer. N Engl J Med 352:2302–2313. doi:10.1056/NEJMoa043681

    Article  PubMed  CAS  Google Scholar 

  3. Jones S, Holmes FA, O’Shaughnessy J, Blum JL, Vukelja SJ, McIntyre KJ, Pippen JE, Bordelon JH, Kirby RL, Sandbach J, Hyman WJ, Richards DA, Mennel RG, Boehm KA, Meyer WG, Asmar L, Mackey D, Riedel S, Muss H, Savin MA (2009) Docetaxel with cyclophosphamide is associated with an overall survival benefit compared with doxorubicin and cyclophosphamide: 7-year follow-up of US Oncology Research Trial 9735. J Clin Oncol 27:1177–1183. doi:10.1200/JCO.2008.18.4028

    Article  PubMed  CAS  Google Scholar 

  4. Nabholtz JM, Senn HJ, Bezwoda WR, Melnychuk D, Deschenes L, Douma J, Vandenberg TA, Rapoport B, Rosso R, Trillet-Lenoir V, Drbal J, Molino A, Nortier JW, Richel DJ, Nagykalnai T, Siedlecki P, Wilking N, Genot JY, Hupperets PS, Pannuti F, Skarlos D, Tomiak EM, Murawsky M, Alakl M, Aapro M et al (1999) Prospective randomized trial of docetaxel versus mitomycin plus vinblastine in patients with metastatic breast cancer progressing despite previous anthracycline-containing chemotherapy. 304 Study Group. J Clin Oncol 17:1413–1424

    PubMed  CAS  Google Scholar 

  5. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory. Accessed online 15 Jan 2011

  6. Martin M, Segui MA, Anton A, Ruiz A, Ramos M, Adrover E, Aranda I, Rodriguez-Lescure A, Grosse R, Calvo L, Barnadas A, Isla D, Martinez del Prado P, Ruiz Borrego M, Zaluski J, Arcusa A, Munoz M, Lopez Vega JM, Mel JR, Munarriz B, Llorca C, Jara C, Alba E, Florian J, Li J, Lopez Garcia-Asenjo JA, Saez A, Rios MJ, Almenar S, Peiro G, Lluch A (2010) Adjuvant docetaxel for high-risk, node-negative breast cancer. N Engl J Med 363:2200–2210. doi:10.1056/NEJMoa0910320

    Article  PubMed  CAS  Google Scholar 

  7. Roussidis AE, Mitropoulou TN, Theocharis AD, Kiamouris C, Papadopoulos S, Kletsas D, Karamanos NK (2004) STI571 as a potent inhibitor of growth and invasiveness of human epithelial breast cancer cells. Anticancer Res 24:1445–1447

    PubMed  CAS  Google Scholar 

  8. Sims JT, Ganguly S, Fiore LS, Holler CJ, Park ES, Plattner R (2009) STI571 sensitizes breast cancer cells to 5-fluorouracil, cisplatin and camptothecin in a cell type-specific manner. Biochem Pharmacol 78:249–260. doi:S0006-2952(09)00292-510.1016/j.bcp.2009.04.007

    Article  PubMed  CAS  Google Scholar 

  9. Mathew P, Thall PF, Jones D, Perez C, Bucana C, Troncoso P, Kim SJ, Fidler IJ, Logothetis C (2004) Platelet-derived growth factor receptor inhibitor imatinib mesylate and docetaxel: a modular phase I trial in androgen-independent prostate cancer. J Clin Oncol 22:3323–3329. doi:10.1200/JCO.2004.10.11622/16/3323

    Article  PubMed  CAS  Google Scholar 

  10. Krause DS, Van Etten RA (2005) Tyrosine kinases as targets for cancer therapy. N Engl J Med 353:172–187. doi:353/2/17210.1056/NEJMra044389

    Article  PubMed  CAS  Google Scholar 

  11. Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, Chan KW, Ciceri P, Davis MI, Edeen PT, Faraoni R, Floyd M, Hunt JP, Lockhart DJ, Milanov ZV, Morrison MJ, Pallares G, Patel HK, Pritchard S, Wodicka LM, Zarrinkar PP (2008) A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol 26:127–132. doi:10.1038/nbt1358

    Article  PubMed  CAS  Google Scholar 

  12. Bhardwaj B, Klassen J, Cossette N, Sterns E, Tuck A, Deeley R, Sengupta S, Elliott B (1996) Localization of platelet-derived growth factor beta receptor expression in the periepithelial stroma of human breast carcinoma. Clin Cancer Res 2:773–782

    PubMed  CAS  Google Scholar 

  13. Pietras K, Rubin K, Sjoblom T, Buchdunger E, Sjoquist M, Heldin CH, Ostman A (2002) Inhibition of PDGF receptor signaling in tumor stroma enhances antitumor effect of chemotherapy. Cancer Res 62:5476–5484

    PubMed  CAS  Google Scholar 

  14. Pietras K, Ostman A, Sjoquist M, Buchdunger E, Reed RK, Heldin CH, Rubin K (2001) Inhibition of platelet-derived growth factor receptors reduces interstitial hypertension and increases transcapillary transport in tumors. Cancer Res 61:2929–2934

    PubMed  CAS  Google Scholar 

  15. Sotiriou C, Neo SY, McShane LM, Korn EL, Long PM, Jazaeri A, Martiat P, Fox SB, Harris AL, Liu ET (2003) Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc Natl Acad Sci USA 100:10393–10398. doi:10.1073/pnas.1732912100

    Article  PubMed  CAS  Google Scholar 

  16. Engels FK, Ten Tije AJ, Baker SD, Lee CK, Loos WJ, Vulto AG, Verweij J, Sparreboom A (2004) Effect of cytochrome P450 3A4 inhibition on the pharmacokinetics of docetaxel. Clin Pharmacol Ther 75:448–454. doi:10.1016/j.clpt.2004.01.001

    Article  PubMed  CAS  Google Scholar 

  17. Bruno R, Hille D, Riva A, Vivier N, ten Bokkel Huinnink WW, van Oosterom AT, Kaye SB, Verweij J, Fossella FV, Valero V, Rigas JR, Seidman AD, Chevallier B, Fumoleau P, Burris HA, Ravdin PM, Sheiner LB (1998) Population pharmacokinetics/pharmacodynamics of docetaxel in phase II studies in patients with cancer. J Clin Oncol 16:187–196

    PubMed  CAS  Google Scholar 

  18. Gurney H, Wong M, Balleine RL, Rivory LP, McLachlan AJ, Hoskins JM, Wilcken N, Clarke CL, Mann GJ, Collins M, Delforce SE, Lynch K, Schran H (2007) Imatinib disposition and ABCB1 (MDR1, P-glycoprotein) genotype. Clin Pharmacol Ther 82:33–40. doi:10.1038/sj.clpt.6100201

    Article  PubMed  CAS  Google Scholar 

  19. http://products.sanofi-aventis.us/Taxotere/taxotere.html#S15. Accessed online 15 Jan 2011

  20. Baker SD, Zhao M, Lee CK, Verweij J, Zabelina Y, Brahmer JR, Wolff AC, Sparreboom A, Carducci MA (2004) Comparative pharmacokinetics of weekly and every-three-weeks docetaxel. Clin Cancer Res 10:1976–1983

    Article  PubMed  CAS  Google Scholar 

  21. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216

    Article  PubMed  CAS  Google Scholar 

  22. Baker SD, van Schaik RH, Rivory LP, Ten Tije AJ, Dinh K, Graveland WJ, Schenk PW, Charles KA, Clarke SJ, Carducci MA, McGuire WP, Dawkins F, Gelderblom H, Verweij J, Sparreboom A (2004) Factors affecting cytochrome P-450 3A activity in cancer patients. Clin Cancer Res 10:8341–8350. doi:10/24/834110.1158/1078-0432.CCR-04-1371

    Article  PubMed  CAS  Google Scholar 

  23. Baker SD, Zhao M, He P, Carducci MA, Verweij J, Sparreboom A (2004) Simultaneous analysis of docetaxel and the formulation vehicle polysorbate 80 in human plasma by liquid chromatography/tandem mass spectrometry. Anal Biochem 324:276–284

    Article  PubMed  CAS  Google Scholar 

  24. van Erp NP, Gelderblom H, Karlsson MO, Li J, Zhao M, Ouwerkerk J, Nortier JW, Guchelaar HJ, Baker SD, Sparreboom A (2007) Influence of CYP3A4 inhibition on the steady-state pharmacokinetics of imatinib. Clin Cancer Res 13:7394–7400. doi:10.1158/1078-0432.CCR-07-0346

    Article  PubMed  Google Scholar 

  25. Gibaldi M, Perrier D (1982) Noncompartmental analysis based on statistical moment theory. In: Gibaldi M, Perrier D (eds) Pharmacokinetics. Marcel Dekker, New York, NY, pp 409–417

  26. Peng B, Lloyd P, Schran H (2005) Clinical pharmacokinetics of imatinib. Clin Pharmacokinet 44:879–894

    Article  PubMed  CAS  Google Scholar 

  27. Larson RA, Druker BJ, Guilhot F, O’Brien SG, Riviere GJ, Krahnke T, Gathmann I, Wang Y (2008) Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study. Blood 111:4022–4028. doi:10.1182/blood-2007-10-116475

    Article  PubMed  CAS  Google Scholar 

  28. Demetri GD, Wang Y, Wehrle E, Racine A, Nikolova Z, Blanke CD, Joensuu H, von Mehren M (2009) Imatinib plasma levels are correlated with clinical benefit in patients with unresectable/metastatic gastrointestinal stromal tumors. J Clin Oncol 27:3141–3147. doi:JCO.2008.20.481810.1200/JCO.2008.20.4818

    Article  PubMed  CAS  Google Scholar 

  29. O’Brien SG, Meinhardt P, Bond E, Beck J, Peng B, Dutreix C, Mehring G, Milosavljev S, Huber C, Capdeville R, Fischer T (2003) Effects of imatinib mesylate (STI571, Glivec) on the pharmacokinetics of simvastatin, a cytochrome p450 3A4 substrate, in patients with chronic myeloid leukaemia. Br J Cancer 89:1855–1859. doi:10.1038/sj.bjc.6601152

    Article  PubMed  Google Scholar 

  30. Hooker AC, Ten Tije AJ, Carducci MA, Weber J, Garrett-Mayer E, Gelderblom H, McGuire WP, Verweij J, Karlsson MO, Baker SD (2008) Population pharmacokinetic model for docetaxel in patients with varying degrees of liver function: incorporating cytochrome P4503A activity measurements. Clin Pharmacol Ther 84:111–118. doi:10.1038/sj.clpt.6100476

    Article  PubMed  CAS  Google Scholar 

  31. Hirth J, Watkins PB, Strawderman M, Schott A, Bruno R, Baker LH (2000) The effect of an individual’s cytochrome CYP3A4 activity on docetaxel clearance. Clin Cancer Res 6:1255–1258

    PubMed  CAS  Google Scholar 

  32. Slaviero KA, Clarke SJ, McLachlan AJ, Blair EY, Rivory LP (2004) Population pharmacokinetics of weekly docetaxel in patients with advanced cancer. Br J Clin Pharmacol 57:44–53. doi:1956

    Article  PubMed  CAS  Google Scholar 

  33. Baker SD, Verweij J, Cusatis GA, van Schaik RH, Marsh S, Orwick SJ, Franke RM, Hu S, Schuetz EG, Lamba V, Messersmith WA, Wolff AC, Carducci MA, Sparreboom A (2009) Pharmacogenetic pathway analysis of docetaxel elimination. Clin Pharmacol Ther 85:155–163. doi:10.1038/clpt.2008.95

    Article  PubMed  CAS  Google Scholar 

  34. Franke RM, Baker SD, Mathijssen RH, Schuetz EG, Sparreboom A (2008) Influence of solute carriers on the pharmacokinetics of CYP3A4 probes. Clin Pharmacol Ther 84:704–709. doi:10.1038/clpt.2008.94

    Article  PubMed  CAS  Google Scholar 

  35. Hu S, Franke RM, Filipski KK, Hu C, Orwick SJ, de Bruijn EA, Burger H, Baker SD, Sparreboom A (2008) Interaction of imatinib with human organic ion carriers. Clin Cancer Res 14:3141–3148. doi:10.1158/1078-0432.CCR-07-4913

    Article  PubMed  CAS  Google Scholar 

  36. Franke RM, Sparreboom A (2008) Inhibition of imatinib transport by uremic toxins during renal failure. J Clin Oncol 26:4226–4227. doi:10.1200/JCO.2008.18.4390 author reply 4227–4228

    Article  PubMed  Google Scholar 

  37. Frassetto LA, Poon S, Tsourounis C, Valera C, Benet LZ (2007) Effects of uptake and efflux transporter inhibition on erythromycin breath test results. Clin Pharmacol Ther 81:828–832. doi:10.1038/sj.clpt.6100148

    Article  PubMed  CAS  Google Scholar 

  38. Schmith VD, Foss JF (2008) Effects of inflammation on pharmacokinetics/pharmacodynamics: increasing recognition of its contribution to variability in response. Clin Pharmacol Ther 83:809–811. doi:10.1038/clpt.2008.62

    Article  PubMed  CAS  Google Scholar 

  39. Seidman AD, Berry D, Cirrincione C, Harris L, Muss H, Marcom PK, Gipson G, Burstein H, Lake D, Shapiro CL, Ungaro P, Norton L, Winer E, Hudis C (2008) Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol 26:1642–1649. doi:10.1200/JCO.2007.11.6699

    Article  PubMed  CAS  Google Scholar 

  40. Sparano JA, Wang M, Martino S, Jones V, Perez EA, Saphner T, Wolff AC, Sledge GW Jr, Wood WC, Davidson NE (2008) Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med 358:1663–1671. doi:10.1056/NEJMoa0707056

    Article  PubMed  CAS  Google Scholar 

  41. Uehara H, Kim SJ, Karashima T, Shepherd DL, Fan D, Tsan R, Killion JJ, Logothetis C, Mathew P, Fidler IJ (2003) Effects of blocking platelet-derived growth factor-receptor signaling in a mouse model of experimental prostate cancer bone metastases. J Natl Cancer Inst 95:458–470

    Article  PubMed  CAS  Google Scholar 

  42. Mathew P, Thall PF, Bucana CD, Oh WK, Morris MJ, Jones DM, Johnson MM, Wen S, Pagliaro LC, Tannir NM, Tu SM, Meluch AA, Smith L, Cohen L, Kim SJ, Troncoso P, Fidler IJ, Logothetis CJ (2007) Platelet-derived growth factor receptor inhibition and chemotherapy for castration-resistant prostate cancer with bone metastases. Clin Cancer Res 13:5816–5824. doi:10.1158/1078-0432.CCR-07-1269

    Article  PubMed  CAS  Google Scholar 

  43. Mathew P, Pisters LL, Wood CG, Papadopoulos JN, Williams DL, Thall PF, Wen S, Horne E, Oborn CJ, Langley R, Fidler IJ, Pettaway CA (2009) Neoadjuvant platelet derived growth factor receptor inhibitor therapy combined with docetaxel and androgen ablation for high risk localized prostate cancer. J Urol 181:81–87. doi:10.1016/j.juro.2008.09.006 discussion 87

    Article  PubMed  CAS  Google Scholar 

  44. Cristofanilli M, Morandi P, Krishnamurthy S, Reuben JM, Lee BN, Francis D, Booser DJ, Green MC, Arun BK, Pusztai L, Lopez A, Islam R, Valero V, Hortobagyi GN (2008) Imatinib mesylate (Gleevec) in advanced breast cancer-expressing C-Kit or PDGFR-beta: clinical activity and biological correlations. Ann Oncol 19:1713–1719. doi:10.1093/annonc/mdn352

    Article  PubMed  CAS  Google Scholar 

  45. Modi S, Seidman AD, Dickler M, Moasser M, D’Andrea G, Moynahan ME, Menell J, Panageas KS, Tan LK, Norton L, Hudis CA (2005) A phase II trial of imatinib mesylate monotherapy in patients with metastatic breast cancer. Breast Cancer Res Treat 90:157–163. doi:10.1007/s10549-004-3974-0

    Article  PubMed  CAS  Google Scholar 

  46. Chew HK, Barlow WE, Albain K, Lew D, Gown A, Hayes DF, Gralow J, Hortobagyi GN, Livingston R (2008) A phase II study of imatinib mesylate and capecitabine in metastatic breast cancer: Southwest Oncology Group Study 0338. Clin Breast Cancer 8:511–515. doi:62183P0858797V3N10.3816/CBC.2008.n.062

    Article  PubMed  CAS  Google Scholar 

  47. Yardley DA, Burris HA III, Markus T, Spigel DR, Greco FA, Mainwaring M, Waterhouse DM, Webb CD, Hainsworth JD (2009) Phase II trial of docetaxal plus imatinib mesylate in the treatment of patients with metastatic breast cancer. Clin Breast Cancer 9:237–242. doi:10.3816/CBC.2009.n.040

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This research was supported by funding from an Avon/NCI Progress for Patients Awards Program (3P40 CA006973-41S) and by the Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (NIH P30 CA069773). We are grateful to Novartis for providing the investigational supply of imatinib mesylate used in this trial. We also would like to thank Ping He for her technical support and Susan Davidson for her quality assurance of the data.

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No authors have any conflict of interest to declare.

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Author notes

  1. Nancy E. Davidson

    Present address: University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

  2. Sharyn D. Baker

    Present address: St. Jude Children’s Research Hospital, Memphis, TN, USA

  3. Elizabeth Garrett-Mayer

    Present address: Medical University of South Carolina, Charleston, SC, USA

Authors and Affiliations

  1. The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans Street, CRB1-189, Baltimore, MD, 21231-1000, USA

    Roisin M. Connolly, Michelle A. Rudek, Elizabeth Garrett-Mayer, Stacie C. Jeter, Michele G. Donehower, Laurie A. Wright, Ming Zhao, John H. Fetting, Leisha A. Emens, Vered Stearns, Nancy E. Davidson, Sharyn D. Baker & Antonio C. Wolff

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  1. Roisin M. Connolly
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Correspondence to Antonio C. Wolff.

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Connolly, R.M., Rudek, M.A., Garrett-Mayer, E. et al. Docetaxel metabolism is not altered by imatinib: findings from an early phase study in metastatic breast cancer. Breast Cancer Res Treat 127, 153–162 (2011). https://doi.org/10.1007/s10549-011-1413-6

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