The orally administered P-glycoprotein inhibitor R101933 does not alter the plasma pharmacokinetics of docetaxel

Lia Van Zuylen*, Alex Sparreboom, Ate Van Der Gaast, Maria E.L. Van Der Burg, Vera Van Beurden, Cornelis J. Bol, Robert Woestenborghs, Peter A. Palmer, Jaap Verweij

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


This Phase I study was performed to assess the feasibility of combining docetaxel with the new P-glycoprotein inhibitor R101933 and to determine the dose limiting toxicity of this combination. Fifteen patients received oral R101933 alone at a dose escalated from 200 to 300 mg twice dally (b.i.d.; cycle 0), an escalating i.v. dose of docetaxel (60, 75, and 100 mg/m2) as a 1-h infusion (cycle 1), and the combination (cycle 2 and further). Dose limiting toxicity consisting of mucositis and neutropenic fever was reached at the combination of docetaxel, 100 mg/m2, and R101933, 300 mg b.i.d., and the maximum tolerated dose was established at docetaxel, 100 mg/m2, and R101933, 200 mg b.i.d. Plasma concentrations of R101933 achieved in patients were in the same range as required in preclinical rodent models to overcome paclitaxel resistance. The plasma pharmacokinetics of docetaxel were not influenced by the R101933 regimen at any dose level tested, as indicated by plasma clearance values of 26.5 ± 7.78 liters/h/m2 and 23.4 ± 4.52 liters/h/m2 (P = 0.15) in cycles 1 and 2, respectively. These findings indicate that the contribution of a P-glycoprotein inhibitor to the activity of anticancer chemotherapy can now be assessed in patients for the first time independent of its effect on drug pharmacokinetics.

Original languageEnglish
Pages (from-to)1365-1371
Number of pages7
JournalClinical Cancer Research
Issue number4
Publication statusPublished - 1 Apr 2000
Externally publishedYes

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