A phase I/II study of infusional vinblastine with the P-glycoprotein antagonist valspodar (PSC 833) in renal cell carcinoma

Susan E. Bates*, Susan Bakke, Min Kang, Robert W. Robey, Suoping Zhai, Paul Thambi, Clara Chen, Sheela Patil, Tom Smith, Seth M. Steinberg, Maria Merino, Barry Goldspiel, Beverly Meadows, Wilfred D. Stein, Peter Choyke, Frank Balis, William D. Figg, Tito Fojo

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

69 Scopus citations


Purpose: P-glycoprotein (Pgp) inhibitors have been under clinical evaluation for drug resistance reversal for over a decade. Valspodar (PSC 833) inhibits Pgp-mediated efflux but delays drug clearance, requiring reduction of anticancer drug dosage. We designed an infusional schedule for valspodar and vinblastine to mimic infusional vinblastine alone. The study was designed to determine the maximally tolerated dose of vinblastine, while attempting to understand the pharmacokinetic interactions between vinblastine and valspodar and to determine the response rate in patients with metastatic renal cell cancer. Patients and Methods: Thirty-nine patients received continuous infusion valspodar and vinblastine. Vinblastine was administered for 3 days to compensate for the expected delay in clearance and the required dose reduction. Valspodar was administered initially at a dose of 10 mg/kg/d; the dose of vioblastine varied. Results: The maximum-tolerated dose of vinblastine was 1.3 mg/m 2/d. As suggested previously, serum valspodar concentrations exceeded those needed for Pgp inhibition. Consequently, the dose of valspodar was reduced to 5 mg/kg, allowing a vinblastine dose of 2.1 mg/m2/d to be administered. Pharmacodynamic studies demonstrated continued inhibition of Pgp at lower valspodar doses by functional assay in Pgp-expressing CD56+ cells and by 99mTc-sestamibi imaging. A 15-fold range in cytochrome P450 activity was observed, as measured by midazolam clearance. No major responses were observed. Conclusions: These results suggest that the pharmacokinetic impact of cytochrome P450 inhibition by valspodar can be reduced although not eliminated, while preserving Pgp inhibition, thus separating the pharmacokinetic and pharmacodynamic activities of valspodar.

Original languageEnglish
Pages (from-to)4724-4733
Number of pages10
JournalClinical Cancer Research
Issue number14
StatePublished - 15 Jul 2004
Externally publishedYes


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