Pharmacokinetic and pharmacodynamic study of the combination of docetaxel and topotecan in patients with solid tumors

Purpose: The sequence in which chemotherapeutic agents are administered can alter their pharmacokinetics, therapeutic effect, and toxicity. We evaluated the pharmacokinetics and pharmacodynamics of docetaxel and topotecan when coadministered on two different sequences of administration. Patients and Methods: On cycle 1, docetaxel wets administered as a 1-hour infusion at 60 mg/m(2) without filgrastim and at 60, 70, and 80 mg/m(2) with filgrastim on day 1, and topotecan was administered at 0.75 mg/m(2) as a 0.5-hour infusion on days 1 to 4. On cycle 2, topotecan was administered on days 1 to 4, and docetaxel was administered on day 4. Cycles were repeated every 21 days. Blood samples for high-performance liquid chromatography measurement of docetaxel (Cl-DOC) and topotecan (CLTPT) total clearance were obtained on day 1 of cycle 1 and day 4 of cycle 2. CLDOC and CLTPT were calculated using compartmental methods. Results: Mean +/- SD CLDOC in cycles 1 and 2 were 75.9 +/- 79.0 L/h/m(2) and 29.2 +/- 19.3 L/h/m(2), respectively (P < .046). Mean +/- SD CLTPT in cycles 1 and 2 were 8.5 +/- 4.4 L/h/m(2) and 9.3 +/- 3.4 L/h/m(2), respectively (P > .05), Mean +/- SD neutrophil nadir in cycles 1 and 2 were 4,857 +/- 6,738/mu L and 2,808 +/- 4,518/mu L, respectively (P = .02). Conclusion: Administration of topotecan on days 1 to 4 and docetaxel on day 4 resulted in an approximately 50% decrease in docetaxel clearance and war associated with increased neutropenia. (C) 2000 by American Society of Clinical Oncology.