Eribulin mesylate pharmacokinetics in patients with solid tumors receiving repeated oral ketoconazole
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Purpose To study the influence of repeated oral administration of ketoconazole, a potent CYP3A4 inhibitor, on the plasma pharmacokinetics of eribulin mesylate administered by single-dose intravenous infusion. Eribulin mesylate is a non-taxane microtubule dynamics inhibitor that is currently under development in phase I-III trials for the treatment of solid tumors. Experimental design A randomized, open-label, two treatments, two sequences, crossover phase I study was performed in patients with advanced solid tumors. Treatments were given on day 1 and day 15 and consisted of 1.4 mg/m2 eribulin mesylate alone or 0.7 mg/m2 eribulin mesylate plus 200 mg ketoconazole on the day of eribulin mesylate administration and the following day. Pharmacokinetic sampling for determination of eribulin plasma concentration was performed up to 144 h following administration of eribulin mesylate. Also safety and anti-tumor activity were determined. Results Pharmacokinetic sampling and analysis was completed in ten patients. Statistical analysis of dose-normalized log-transformed AUC0-∞ and Cmax indicated that single-dose exposure of eribulin was not statistically different when co-administered with ketoconazole (ratio of geometric least square means: 0.95 (90%CI: 0.80–1.12) and 0.97 (90%CI: 0.83–1.12), respectively) in patients with solid tumors. Ketoconazole had no effect on eribulin clearance and elimination half-life. The most frequently reported treatment related adverse events were fatigue and nausea, each reported in 8/12 patients. Seven patients (58.3 %) achieved stable disease as best overall response. Conclusions The results indicate that eribulin mesylate can be safely co-administered with ketoconazole. Drug-drug interactions are not expected with other CYP3A4 inhibitors.
KeywordsPharmacokinetics Drug-drug interaction Ketoconazole CYP3A4 induction Eribulin mesylate Microtubule dynamics inhibitor
This study was funded by Eisai Ltd. Part of this study was presented in poster format at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, Berlin, Germany, November 16–19, 2010 (abstract 574).
J.W., A.J. and W.C. were formerly employed by Eisai Ltd. G.E. was paid by Eisai Ltd. for statistician consultancy services. L.R. and F.P. are employees of Eisai Inc. The institute of J.H.B. has received funds for research from Eisai. All remaining authors have declared no conflicts of interest.
- 2.Towle MJ, Salvato KA, Budrow J, Wels BF, Kuznetsov G, Aalfs KK, Welsh S, Zheng W, Seletsk BM, Palme MH, Habgood GJ, Singer LA, Dipietro LV, Wang Y, Chen JJ, Quincy DA, Davis A, Yoshimatsu K, Kishi Y, Yu MJ, Littlefield BA (2001) In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B. Cancer Res 61:1013–1021PubMedGoogle Scholar
- 7.U.S.National Institute of Health.http://www.clinicaltrials.gov. Accessed on 26 April 2011
- 8.Vahdat LT, Pruitt B, Fabian CJ, Rivera RR, Smith DA, Tan-Chiu E, Wright J, Tan AR, Dacosta NA, Chuang E, Smith J, O’Shaughnessy J, Shuster DE, Meneses NL, Chandrawansa K, Fang F, Cole PE, Ashworth S, Blum JL (2009) Phase II study of eribulin mesylate, a halichondrin B analog, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol 27:2954–2961PubMedCrossRefGoogle Scholar
- 9.Cortes J, Vahdat L, Blum JL, Twelves C, Campone M, Roche H, Bachelot T, Awada A, Paridaens R, Goncalves A, Shuster DE, Wanders J, Fang F, Gurnani R, Richmond E, Cole PE, Ashworth S, Allison MA (2010) Phase II study of the halichondrin B analog eribulin mesylate in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline, a taxane, and capecitabine. J Clin Oncol 28:3922–3928PubMedCrossRefGoogle Scholar
- 10.Cortes J, O’Shaughnessy J, Loesch D, Blum JL, Vahdat LT, Petrakova K, Chollet P, Manikas A, Dieras V, Delozier T, Vladimirov V, Cardoso F, Koh H, Bougnoux P, Dutcus CE, Seegobin S, Mir D, Meneses N, Wanders J, Twelves C (2011) Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet 377:914–923PubMedCrossRefGoogle Scholar
- 11.Goel S, Mita AC, Mita M, Rowinsky EK, Chu QS, Wong N, Desjardins C, Fang F, Jansen M, Shuster DE, Mani S, Takimoto CH (2009) A phase I study of eribulin mesylate (E7389), a mechanistically novel inhibitor of microtubule dynamics, in patients with advanced solid malignancies. Clin Cancer Res 15:4207–4212PubMedCrossRefGoogle Scholar
- 14.Reyderman L, Gupta A, Pelletier R, Wong N: Eribulin and cytochrome P450 effectors: in vitro studies and population pharmacokinetic-pharmacodynamic analysis. Abstract 573 presented at the EORTC-NCI-AACR Symposium on Molecular Targets and Therapeutics, Berlin, Germany, November 16–19 2010Google Scholar
- 15.European Medicines Agency Committee for medicinal products for human use (CHMP); Guideline on the investigation of drug interactions CPMP/EWP/560/95/Rev.1-Corr. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/05/WC500090112.pdf. 2010,
- 16.U.S.Food and Drug Administration; Guidance for industry. In vivo drug metabolism/drug interaction studies - study design, data analysis, and recommendations for dosing and labeling http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072119.pdf. 1999
- 19.Summary of products characteristics for Nizoral. http://www.medicines.org.uk/emc/document.aspx?documentId=912. 2010
- 20.Summary of products characteristics for Halaven. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002084/WC500105112.pdf. 2011
- 21.Cancer Therapy Evaluation Program NCI Common Terminology Criteria AE Version 3.0 (NCI-CTCAE v3.0). 2006Google Scholar
- 22.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 92:205–216PubMedCrossRefGoogle Scholar
- 23.Dubbelman AC, Rosing H, Thijssen B, Lucas L, Copalu W, Wanders J, Schellens JH, Beijnen JH (2011) Validation of high-performance liquid chromatography-tandem mass spectrometry assays for the quantification of eribulin (E7389) in various biological matrices. J Chromatogr B Analyt Technol Biomed Life Sci 879:1149–1155PubMedCrossRefGoogle Scholar
- 26.Dubbelman AC, Rosing H, Jansen RS, Mergui-Roelvink M, Huitema AD, Koetz B, Lymboura M, Reyderman L, Lopez-Anaya A, Schellens JH, Beijnen JH (2012) Mass balance study of 14C-eribulin in patients with advanced solid tumours. Drug Metab Dispos 40:313–321Google Scholar
- 27.Goel S, Cohen M, Comezoglu SN, Perrin L, Andre F, Jayabalan D, Iacono L, Comprelli A, Ly VT, Zhang D, Xu C, Humphreys WG, McDaid H, Goldberg G, Horwitz SB, Mani S (2008) The effect of ketoconazole on the pharmacokinetics and pharmacodynamics of ixabepilone: a first in class epothilone B analogue in late-phase clinical development. Clin Cancer Res 14:2701–2709PubMedCrossRefGoogle Scholar