Summary
A phase 1, open-label, non-randomized, single center study was conducted to determine the pharmacokinetics, distribution, metabolism, elimination, and mass balance of patupilone in patients with advanced solid tumors. Five patients with advanced solid tumors received 10 mg/m2 (1.1 MBq) of 14 C–radiolabeled patupilone at cycle 1 as a 20-minute intravenous infusion every 3 weeks until disease progression. Sequential samples of blood/plasma were taken for 3 weeks and urine and fecal samples were collected for seven days after the first dose of patupilone. Patupilone blood levels decreased rapidly after the infusion. The compound showed a large volume of distribution (Vss: 2242 L). The main radiolabeled component in blood was patupilone itself, accompanied by the lactone hydrolysis products that are unlikely to contribute to the pharmacological effect of patupilone. The blood clearance of patupilone was relatively low at 14 L/h. The administered radioactivity dose was excreted slowly (46 % of dose up to 168 h) but ultimately accounted for 91 % of the dose by extrapolation. The fecal excretion of radioactivity was 2–3 times higher than the urinary excretion consistent with hepato-biliary elimination. Three patients had progressive disease and two patients had stable disease as their best response. Patupilone was generally well tolerated in patients with advanced solid tumors with no newly occurring safety events compared to previous clinical studies. In adult solid tumor patients, intravenous radiolabeled patupilone undergoes extensive metabolism with fecal excretion of radioactive metabolites predominating over renal excretion.
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References
Lee JJ, Swain SM (2008) The epothilones: translating from the laboratory to the clinic. Clin Cancer Res 14(6):1618–24
Goodin S (2008) Novel cytotoxic agents: epothilones. Am J Health Syst Pharm 65(10 Suppl 3):S10–5
Cortes J, Baselga J (2007) Targeting the microtubules in breast cancer beyond taxanes: the epothilones. Oncologist 12(3):271–80
Kowalski RJ, Giannakakou P, Hamel E (1997) Activities of the microtubule-stabilizing agents epothilones A and B with purified tubulin and in cells resistant to paclitaxel (Taxol(R)). J Biol Chem 272(4):2534–41
O’Reilly T, Wartmann M, Brueggen J, Allegrini PR, Floersheimer A, Maira M et al (2008) Pharmacokinetic profile of the microtubule stabilizer patupilone in tumor-bearing rodents and comparison of anti-cancer activity with other MTS in vitro and in vivo. Cancer Chemother Pharmacol 62(6):1045–54
Bollag DM, McQueney PA, Zhu J, Hensens O, Koupal L, Liesch J et al (1995) Epothilones, a new class of microtubule-stabilizing agents with a taxol-like mechanism of action. Cancer Res 55(11):2325–33
O’Reilly T, Wartmann M, Maira SM, Hattenberger M, Vaxelaire J, Muller M et al (2005) Patupilone (epothilone B, EPO906) and imatinib (STI571, Glivec) in combination display enhanced antitumour activity in vivo against experimental rat C6 glioma. Cancer Chemother Pharmacol 55(4):307–17
Altmann KH, Wartmann M, O’Reilly T (2000) Epothilones and related structures—a new class of microtubule inhibitors with potent in vivo antitumor activity. Biochim Biophys Acta 1470(3):M79–91
O'Reilly T, McSheehy PM, Wenger F, Hattenberger M, Muller M, Vaxelaire J et al (2005) Patupilone (epothilone B, EPO906) inhibits growth and metastasis of experimental prostate tumors in vivo. Prostate 65(3):231–40
Clarke R, Leonessa F, Trock B (2005) Multidrug resistance/P-glycoprotein and breast cancer: review and meta-analysis. Semin Oncol 32(6 Suppl 7):S9–15
Kelley MJ, Li S, Harpole DH (2001) Genetic analysis of the beta-tubulin gene, TUBB, in non-small-cell lung cancer. J Natl Cancer Inst 93(24):1886–8
Rubin EH, Rothermel J, Tesfaye F, Chen T, Hubert M, Ho YY et al (2005) Phase I dose-finding study of weekly single-agent patupilone in patients with advanced solid tumors. J Clin Oncol 23(36):9120–9
Sefkow M, Kiffe M, Hofle G (1998) Derivatization of the C12-C13 functional groups of epothilones A, B and C. Bioorg Med Chem Lett 8(21):3031–6
Melichar B, Casado E, Bridgewater J, Bennouna J, Campone M, Vitek P et al (2011) Clinical activity of patupilone in patients with pretreated advanced/metastatic colon cancer: results of a phase I dose escalation trial. Br J Cancer 105(11):1646–53
Chi KN, Beardsley E, Eigl BJ, Venner P, Hotte SJ, Winquist E et al (2012) A phase 2 study of patupilone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel: Canadian Urologic Oncology Group study P07a. Ann Oncol 23(1):53–8
Ten Bokkel Huinink WW, Sufliarsky J, Smit WM, Spanik S, Wagnerova M, Hirte HW et al (2009) Safety and efficacy of patupilone in patients with advanced ovarian, primary fallopian, or primary peritoneal cancer: a phase I, open-label, dose-escalation study. J Clin Oncol 27(19):3097–103
Fogh S, Machtay M, Werner-Wasik M, Curran WJ Jr, Bonanni R, Axelrod R et al (2010) Phase I trial using patupilone (epothilone B) and concurrent radiotherapy for central nervous system malignancies. Int J Radiat Oncol Biol Phys 77(4):1009–16
Conflict of interest
Markus Zollinger, Frédéric Lozac’h, Eugene Tan, Felix Waldmeier, Patrick Urban, Suraj Anand, Yanfeng Wang and Piet Swart are employees of Novartis Pharmaceuticals Corporation.
Kevin R. Kelly, Alain Mita, Chris Takimoto and Monica Mita do not have a conflict of interest to declare.
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Kelly, K.R., Zollinger, M., Lozac’h, F. et al. Metabolism of patupilone in patients with advanced solid tumor malignancies. Invest New Drugs 31, 605–615 (2013). https://doi.org/10.1007/s10637-012-9838-2
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DOI: https://doi.org/10.1007/s10637-012-9838-2