This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mielke, S. Articles by Mross, K. Search for Related Content PubMed PubMed Citation Articles by Mielke, S. Articles by Mross, K.

Association of Paclitaxel Pharmacokinetics with the Development of Peripheral Neuropathy in Patients with Advanced Cancer

Authors' Affiliations: ¹ Department of Hematology and Oncology, University of Freiburg Medical Center, Freiburg, Germany; ² Tumor Biology Center of Freiburg at the Albert-Ludwigs University, Freiburg, Germany; ³ Clinical Pharmacology Research Core, and ⁴ Center for Cancer Research, Biostatistics and Data Management Section, National Cancer Institute, NIH, Bethesda, Maryland; ⁵ Department of Medical Oncology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, the Netherlands; and ⁶ Department of Medical Oncology, Leiden University Medical Center, Leiden, the Netherlands

Requests for reprints: Stephan Mielke, Stem Cell Allogeneic Transplant Section, Hematology Branch, DIR/NHLBI, NIH, Building 10 CRC, Room 3-5288, 10 Center Drive, MSC 1202, Bethesda, MD 20892-1202. Phone: 301-402-3294; Fax: 301-496-8396; E-mail: mielkes{at}nhlbi.nih.gov.

Purpose: The shortening of infusion time from 3 to 1 hour decreases the systemic exposure (area under the curve, AUC) of total and unbound paclitaxel but increases the AUC of its vehicle Cremophor EL, whereas the time above total paclitaxel concentrations of 0.05 µmol/L (T_>0.05) remains almost constant. As both Cremophor EL and paclitaxel are neurotoxic, we evaluated their pharmacodynamic effects on the development of peripheral neuropathy as the most important nonhematologic toxicity.

Experimental Design: Patients with advanced cancer of different origin were randomized to receive a maximum of 12 weekly-given 1- or 3-hour infusions of 100 mg/m² paclitaxel (Taxol). Twenty-four patients were assessable for both pharmacokinetics and peripheral neuropathy development evaluated by a clinical scoring system including sensory symptoms, strength, tendon reflexes, and vibratory sense.

Results: Patients with peripheral neuropathy development (n = 14) received more weeks of therapy (P = 0.056) and showed significantly higher T_>0.05 (P = 0.022) and overall systemic drug exposures (weeks of therapy x AUC) for total paclitaxel (P = 0.002) and unbound paclitaxel (P = 0.003) than those without peripheral neuropathy. In Kaplan-Meier analyses, T_>0.05 10.6 hours (P = 0.023), AUC of total paclitaxel 4.7 µg/mL x hour (P = 0.047), and AUC of unbound paclitaxel 0.375 µg/mL x hour (P = 0.095) were identified as being potential factors for peripheral neuropathy development. In a Cox regression analysis, only T_>0.05 10.6 hours remained as an independent risk factor (relative risk, 18.43; P = 0.036) after adjusting for prior vincamycin (relative risk, 11.28; P = 0.038).

Conclusions: From the results obtained in this study, it is concluded that exposure to paclitaxel but not Cremophor EL is associated with peripheral neuropathy development.

This article has been cited by other articles:

				S. Goel, G. L. Goldberg, D. Y.-S. Kuo, F. Muggia, J. Arezzo, and S. Mani Novel neurosensory testing in cancer patients treated with the epothilone B analog, ixabepilone Ann. Onc., December 1, 2008; 19(12): 2048 - 2052. [Abstract] [Full Text] [PDF]

				B. Hosten, C. Abbara, B. Petit, A. Dauvin, F. Bourasset, R. Farinotti, P. Gonin, and L. Bonhomme-Faivre Effect of Interleukin-2 Pretreatment on Paclitaxel Absorption and Tissue Disposition after Oral and Intravenous Administration in Mice Drug Metab. Dispos., August 1, 2008; 36(8): 1729 - 1735. [Abstract] [Full Text] [PDF]

				J. R. Murillo Jr, J. E. Cox, and M. S. Oholendt An Overview of Chemotherapy-Induced Peripheral Neuropathy Journal of Pharmacy Practice, April 1, 2008; 21(2): 138 - 145. [Abstract] [PDF]

				N. Denduluri, J. A. Low, J. J. Lee, A. W. Berman, J. M. Walshe, U. Vatas, C. K. Chow, S. M. Steinberg, S. X. Yang, and S. M. Swain Phase II Trial of Ixabepilone, an Epothilone B Analog, in Patients With Metastatic Breast Cancer Previously Untreated With Taxanes J. Clin. Oncol., August 10, 2007; 25(23): 3421 - 3427. [Abstract] [Full Text] [PDF]

				L. E. Broker, S. A. Veltkamp, E. I. Heath, B. C. Kuenen, H. Gall, L. Astier, S. Parker, L. Kayitalire, P. M. Lorusso, J. H.M. Schellens, et al. A Phase I Safety and Pharmacologic Study of a Twice Weekly Dosing Regimen of the Oral Taxane BMS-275183 Clin. Cancer Res., July 1, 2007; 13(13): 3906 - 3912. [Abstract] [Full Text] [PDF]

				W. Boehmerle, K. Zhang, M. Sivula, F. M. Heidrich, Y. Lee, S.-E. Jordt, and B. E. Ehrlich Chronic exposure to paclitaxel diminishes phosphoinositide signaling by calpain-mediated neuronal calcium sensor-1 degradation PNAS, June 26, 2007; 104(26): 11103 - 11108. [Abstract] [Full Text] [PDF]

				H. Wang, H. Huang, H. Li, D. G. Teotico, M. Sinz, S. D. Baker, J. Staudinger, G. Kalpana, M. R. Redinbo, and S. Mani Activated Pregnenolone X-Receptor Is a Target for Ketoconazole and Its Analogs Clin. Cancer Res., April 15, 2007; 13(8): 2488 - 2495. [Abstract] [Full Text] [PDF]

				J. J. Lee and S. M. Swain Peripheral Neuropathy Induced by Microtubule-Stabilizing Agents J. Clin. Oncol., April 1, 2006; 24(10): 1633 - 1642. [Abstract] [Full Text] [PDF]

				A. Sparreboom, S. D. Baker, and J. Verweij Paclitaxel Repackaged in an Albumin-Stabilized Nanoparticle: Handy or Just a Dandy? J. Clin. Oncol., November 1, 2005; 23(31): 7765 - 7767. [Full Text] [PDF]