Pharmacokinetics of eribulin mesylate in cancer patients with normal and impaired renal function

Antoinette R Tan, John Sarantopoulos, Lucy Lee, Larisa Reyderman, Yi He, Martin Olivo, Sanjay Goel, Antoinette R Tan, John Sarantopoulos, Lucy Lee, Larisa Reyderman, Yi He, Martin Olivo, Sanjay Goel

Abstract

Purpose: To evaluate the effect of renal impairment on eribulin mesylate pharmacokinetics following a single dose in adults with advanced solid tumors.

Methods: Patients were grouped by renal function: moderate impairment (creatinine clearance [CrCl] 30-50 mL/min), severe impairment (CrCl 15-29 mL/min), or normal (CrCl ≥80 mL/min). During each 21-day cycle, eribulin mesylate doses (days 1 and 8) were administered intravenously: moderate, 1.1 mg/m(2) (except cycle 1 day 1, 1.4 mg/m(2)); severe, 0.7 mg/m(2); normal, 1.4 mg/m(2).

Results: Nineteen patients were enrolled (normal, n = 6; moderate, n = 7; severe, n = 6). Renal impairment was associated with an increased mean dose-normalized area under the concentration-time curve (ratios for moderate/normal and severe/normal: 1.49; 90 % confidence interval [CI] 0.9, 2.45). CrCl and renal function correlated positively, with a numerically small slope (0.0184; 90 % CI -0.00254, 0.0394). A simulated dose reduction to eribulin 1.1 mg/m(2) in patients with moderate or severe renal impairment achieved the same exposure as 1.4 mg/m(2) in those with normal renal function. All groups had similar toxicity profiles, with no unexpected adverse events.

Conclusions: Renal impairment decreased eribulin clearance and increased exposure. Pharmacokinetic evaluation supports an eribulin dose reduction to 1.1 mg/m(2) in patients with moderate or severe renal impairment. CLINICALTRIALS.

Gov identifier: NCT01418677.

Keywords: Cancer patients; Eribulin; Pharmacokinetics; Renal function; Renal impairment.

Figures

Fig. 1
Fig. 1
a Linear and b semi-log plots of mean (±standard deviation) eribulin plasma concentration versus time following a single intravenous administration of eribulin mesylate 1.4 mg/m2 to patients with normal renal function, 1.4 mg/m2 to patients with moderate renal impairment, and 0.7 mg/m2 to patients with severe renal impairment. Data shown as mean ± standard deviation
Fig. 2
Fig. 2
Individual eribulin plasma clearance (a) and log-transformed dose-normalized Cmax (b), AUC(0–t) (c) and AUC(0–inf) (d) versus creatinine clearance. AUC area under the concentration–time curve, AUC0–t AUC from time 0 to the last measurable concentration, AUC(0–inf) area under the concentration–time curve from time zero extrapolated to infinity, CI confidence interval, CLtot total clearance, Cmax maximum plasma concentration, SE standard error
Fig. 3
Fig. 3
Eribulin exposure in patients with normal renal function at a dose of 1.4 mg/m2 and predicted eribulin exposure at a dose of 1.1 mg/m2 in patients with moderate or severe renal impairment. AUC area under the curve, CI confidence interval

References

    1. Hirata Y, Uemura D. Halichondrins—antitumor polyether macrolides from a marine sponge. Pure Appl Chem. 1986;58:701–710. doi: 10.1351/pac198658050701.
    1. Bai RL, Paull KD, Herald CL, Malspeis L, Pettit GR, Hamel E. Halichondrin B and homohalichondrin B, marine natural products binding in the vinca domain of tubulin. Discovery of tubulin-based mechanism of action by analysis of differential cytotoxicity data. J Biol Chem. 1991;266:15882–15889.
    1. Fodstad O, Breistol K, Pettit GR, Shoemaker RH, Boyd MR. Comparative antitumor activities of halichondrins and vinblastine against human tumor xenografts. J Exp Ther Oncol. 1996;1:119–125.
    1. Halaven (eribulin mesylate) injection [prescribing information] (2014) Eisai Inc., Woodcliff Lake
    1. Halaven 0.44 mg/ml solution for injection [summary of product characteristics]. Eisai Europe Limited, Hertfordshire
    1. Goel S, Mita AC, Mita M, Rowinsky EK, Chu QS, Wong N, Desjardins C, Fang F, Jansen M, Shuster DE, Mani S, Takimoto CH. A phase I study of eribulin mesylate (E7389), a mechanistically novel inhibitor of microtubule dynamics, in patients with advanced solid malignancies. Clin Cancer Res. 2009;15:4207–4212. doi: 10.1158/1078-0432.CCR-08-2429.
    1. Tan AR, Rubin EH, Walton DC, Shuster DE, Wong YN, Fang F, Ashworth S, Rosen LS. Phase I study of eribulin mesylate administered once every 21 days in patients with advanced solid tumors. Clin Cancer Res. 2009;15:4213–4219. doi: 10.1158/1078-0432.CCR-09-0360.
    1. Mukohara T, Nagai S, Mukai H, Namiki M, Minami H. Eribulin mesylate in patients with refractory cancers: a Phase I study. Invest New Drugs. 2012;30:1926–1933. doi: 10.1007/s10637-011-9741-2.
    1. Dubbelman AC, Rosing H, Jansen RS, Mergui-Roelvink M, Huitema AD, Koetz B, Lymboura M, Reyderman L, Lopez-Anaya A, Schellens JH, Beijnen JH. Mass balance study of [14C]eribulin in patients with advanced solid tumors. Drug Metab Dispos. 2012;40:313–321. doi: 10.1124/dmd.111.042762.
    1. Devriese LA, Witteveen PO, Marchetti S, Mergui-Roelvink M, Reyderman L, Wanders J, Jenner A, Edwards G, Beijnen JH, Voest EE, Schellens JH. Pharmacokinetics of eribulin mesylate in patients with solid tumors and hepatic impairment. Cancer Chemother Pharmacol. 2012;70:823–832. doi: 10.1007/s00280-012-1976-x.
    1. European Medicines Agency (2011) Assessment report for Halaven eribulin. Procedure No. EMEA/H/C/002084. . Accessed 27 April 2015
    1. Majid O, Gupta A, Reyderman L, Olivo M, Hussein Z. Population pharmacometric analyses of eribulin in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines and taxanes. J Clin Pharmacol. 2014;54:1134–1143. doi: 10.1002/jcph.315.
    1. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER) (2010) Guidance for industry: pharmacokinetics in patients with impaired renal function—study design, data analysis, and impact on dosing and labeling. Revision 1. . Accessed 27 April 2015
    1. DesJardins C Validation of LC/MS/MS methods for the determination of E7389 in human plasma and urine. Study Number: DSDB2004-004, Report Number DSD2004-36, Revision No. 3
    1. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer. 2009;45:228–247. doi: 10.1016/j.ejca.2008.10.026.
    1. Shetty N, Gupta S. Eribulin drug review. South Asian J Cancer. 2014;3:57–59. doi: 10.4103/2278-330X.126527.
    1. Swami U, Chaudhary I, Ghalib MH, Goel S. Eribulin—a review of preclinical and clinical studies. Crit Rev Oncol Hematol. 2012;81:163–184. doi: 10.1016/j.critrevonc.2011.03.002.
    1. Naud J, Michaud J, Boisvert C, Desbiens K, Leblond FA, Mitchell A, Jones C, Bonnardeaux A, Pichette V. Down-regulation of intestinal drug transporters in chronic renal failure in rats. J Pharmacol Exp Ther. 2007;320:978–985. doi: 10.1124/jpet.106.112631.
    1. Jain S, Cigler T. Eribulin mesylate in the treatment of metastatic breast cancer. Biologics. 2012;6:21–29.
    1. Synold TW, Tsao-Wei DD, Quinn DI, Groshen SG, Aparicio A, Twardowski P, Stadler WM, Gandara DR, Lara Jr P, Newman EM (2010) Phase I and pharmacokinetic (PK) study of eribulin (E7389) in patients (pts) with renal dysfunction (RD) and advanced urothelial cancer (UC): a California Cancer Consortium Trial [abstract]. J Clin Oncol 28(15 Suppl):abstract 2527
    1. Food and Drug Administration, Department of Health and Human Services (2014). Prior approval supplemental new drug application 201532/S-101

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