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Phase I study of docetaxel and topotecan in patients with advanced malignancies

Department of Medicine, Medical Oncology Section, University of Wisconsin Comprehensive Cancer Center, Madison, WI, USA

Paul Hutson, PharmD

Department of Pharmacy, University of Wisconsin, Madison, WI, USA

Dona Alberti, BSN

Department of Medicine, Medical Oncology Section, University of Wisconsin Comprehensive Cancer Center, Madison, WI, USA

Rhoda Arzoomanian, BSN

Department of Medicine, Medical Oncology Section, University of Wisconsin Comprehensive Cancer Center, Madison, WI, USA

Kim Binger, BSN

Department of Medicine, Medical Oncology Section, University of Wisconsin Comprehensive Cancer Center, Madison, WI, USA

Jennifer Volkman, BSN

Department of Medicine, Medical Oncology Section, University of Wisconsin Comprehensive Cancer Center, Madison, WI, USA

Chris Feierabend, BSN

Department of Medicine, Medical Oncology Section, University of Wisconsin Comprehensive Cancer Center, Madison, WI, USA

George Wilding, MD

Department of Medicine, Medical Oncology Section, University of Wisconsin Comprehensive Cancer Center, Madison, WI, USA

Joan H Schiller, MD

Department of Medicine, Medical Oncology Section, University of Wisconsin Comprehensive Cancer Center, Madison, WI, USA

Background. Docetaxel and topotecan are drugs with different mechanisms of action and significant activity against various tumour types. Topotecan may influence docetaxel metabolism by inhibiting the CYP3A4 enzyme. We designed a phase I study to evaluate the maximum tolerated dose of this combination and to assess the impact of pharmaco-kinetic interactions of the two drugs on toxicity.

Methods. Docetaxel and topotecan were administered intravenously on day 1, and days 1- 5 respectively, using a phase I dose escalation design. Plasma samples were analysed to determine docetaxel and topotecan concentration by HPLC with subsequent pharmacokinetic analysis using NONMEM.

Results. Of the 17 patients enrolled in the trial, 11 had grade 3 and 4 neutropenia and 1 had grade 4 thrombocytopenia. Nonhaematological toxicities were less frequent. The maximum tolerated dose for docetaxel and topotecan were 60 mg/m² on day 1 and 0.75 mg/m² days 1- 5, respectively. One patient had stable disease. Subjects with grade]3 haematologic toxicity had higher plasma docetaxel or topotecan area under the curve (AUC) (docetaxel 1.0390.11 mg-hr/L versus 0.7390.13 mghr/L; topotecan 65.8914.6 mcg-hr/L versus 41.6913.9 mcg-hr/L). There was no additive effectoftheAUCofthetwodrugsonthe likelihood of grade]3 haematologic toxicity by multiple logistic regression.

Conclusion. The dose-limiting toxicity seen with the combination of docetaxel and topotecan was myelosuppression. Future trials will require growth factor support if this combination is pursued.

Key Words: docetaxel • pharmacodynamics • pharmacokinetics • phase I • topotecan

Journal of Oncology Pharmacy Practice, Vol. 11, No. 4, 132-138 (2005)
DOI: 10.1191/1078155205jp161oa


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