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 evaluat ed the pharmacokinetics and pharmacodynamics of docetaxel and topotecan whe n coadministered on two different sequences of administration. Patients and Methods: On cycle 1, docetaxel wets administered as a 1-hour i nfusion 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 mea surement of docetaxel (Cl-DOC) and topotecan (CLTPT) total clearance were o btained on day 1 of cycle 1 and day 4 of cycle 2. CLDOC and CLTPT were calc ulated using compartmental methods. Results: Mean +/- SD CLDOC in cycles 1 and 2 were 75.9 +/- 79.0 L/h/m(2) an d 29.2 +/- 19.3 L/h/m(2), respectively (P < .046). Mean +/- SD CLTPT in cyc les 1 and 2 were 8.5 +/- 4.4 L/h/m(2) and 9.3 +/- 3.4 L/h/m(2), respectivel y (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 Cli nical Oncology.