Phase I and pharmacokinetic study of the novel MDR1 and MRP1 inhibitor biricodar administered alone and in combination with doxorubicin

R. A. Peck, J. Hewett, M. W. Harding, Y. M. Wang, P. R. Chaturvedi, A. Bhatnagar, H. Ziessman, F. Atkins, M. J. Hawkins

Research output: Contribution to journalArticle

Abstract

Purpose: To evaluate the safety, tolerability, and pharmacokinetics of biricodar (VX-710), an inhibitor of P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP1), alone and with doxorubicin in patients with advanced malignancies. The effect of VX-710 on the tissue distribution of 99mTc-sestamibi, a P-gp and MRP1 substrate, was also evaluated. Patients and Methods: Patients with solid malignancies refractory to standard therapy first received a 96-hour infusion of VX-710 alone at 20 to 160 mg/m2/h. After a 3-day washout, a second infusion of VX-710 was begun, on the second day of which doxorubicin 45 mg/m2 was administered. Cycles were repeated every 21 to 28 days. 99mTc-sestamibi scans were performed before and during administration of VX-710 alone. Results: Of the 28 patients who enrolled, 25 patients were eligible for analysis. No dose-limiting toxicity (DLT) was observed in the nine assessable patients who received 120 mg/m2/h or less. Among seven patients receiving VX-710 160 mg/m2/h, two DLTs were seen: reversible CNS toxicity and febrile neutropenia. All other adverse events were mild to moderate and reversible. Plasma concentrations of VX-710 in patients who received at 120 and 160 mg/m2/h were two- to fourfold higher than concentrations required to fully reverse drug resistance in vitro. VX-710 exhibited linear pharmacokinetics with a harmonic mean half-life of 1.1 hours. VX-710 enhanced hepatic uptake and retention of 99mTc-sestamibi in all patients. Conclusion: A 96-hour infusion of VX-710 at 120 mg/m2/h plus doxorubicin 45 mg/m2 has acceptable toxicity in patients with refractory malignancies. The safety and pharmacokinetics of VX-710 plus doxorubicin warrant efficacy trials in malignancies expressing P-gp and/or MRP1.

Original languageEnglish (US)
Pages (from-to)3130-3141
Number of pages12
JournalJournal of Clinical Oncology
Volume19
Issue number12
DOIs
StatePublished - Jun 15 2001
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Peck, R. A., Hewett, J., Harding, M. W., Wang, Y. M., Chaturvedi, P. R., Bhatnagar, A., Ziessman, H., Atkins, F., & Hawkins, M. J. (2001). Phase I and pharmacokinetic study of the novel MDR1 and MRP1 inhibitor biricodar administered alone and in combination with doxorubicin. Journal of Clinical Oncology, 19(12), 3130-3141. https://doi.org/10.1200/JCO.2001.19.12.3130