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Effect of valspodar on the pharmacokinetics of unbound paclitaxel

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Abstract

The aim of this multicenter study was to determine whether valspodar (Amdray™; code designation, SDZ PSC 833), a potent P-glycoprotein (P-gp) inhibitor, affects the pharmacokinetics of unbound paclitaxel (C u). Data were obtained from 31 patients with advanced breast cancer. Thirteen patients were treated with paclitaxel alone (3-h infusion at 175mg/m2) and another 18 received paclitaxel (3-h infusion at 70mg/m2) in combination with a 21-day cycle of oral valspodar (5mg/kg given four times a day) starting 1 day before administration of paclitaxel. Serial blood samples were taken in the first course and C u in plasma determined using equilibrium dialysis with a [G-3H]paclitaxel tracer. The apparent clearance of C u was not significantly different between the two groups, with mean ± standard deviation (±SD) values of 230 ± 56.0 and 202 ± 49.9L/h/m2 in the absence and presence of valspodar, respectively (P = 0.17). The volume of C u distribution was slightly larger in the presence of valspodar (1160 ± 474 vs. 1620 ± 552L/m2; P = 0.025), which contributed to a minor difference in the terminal disposition half-life (6.12 ± 3.42 vs. 8.50 ± 2.06h; P = 0.028). These data indicate that (i) valspodar lacks the significant interaction with paclitaxel observed previously with other P-gp modulators, (ii) the majority of the increased toxicity of the combination does not appear to be attributable to increased levels of C u, and (iii) provide further evidence of the conjecture that the plasma concentration of paclitaxel may not be an appropriate measure to monitor the impact of P-gp inhibition.

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Author notes

  1. Alex Sparreboom

    Present address: National Cancer Institute, Bethesda, MD, 20892

Authors and Affiliations

  1. Erasmus MC – Daniel den Hoed Cancer Center, Department of Medical Oncology, Rotterdam, The Netherlands

    Albert J. ten Tije & Jaap Verweij

  2. City of Hope Cancer Center, Duarte, CA

    Timothy W. Synold & James H. Doroshow

  3. USC/Norris Comprehensive Cancer Center, Los Angeles, CA

    Darcy Spicer

  4. Erasmus, Department of Medical Oncology, MC – Daniel den Hoed Cancer Center, Rotterdam, The Netherlands

    Alex Sparreboom

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ten Tije, A.J., Synold, T.W., Spicer, D. et al. Effect of valspodar on the pharmacokinetics of unbound paclitaxel. Invest New Drugs 21, 291–298 (2003). https://doi.org/10.1023/A:1025412509730

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