Individual Adaptive Dosing of Topotecan in Ovarian Cancer

• Published in: Clinical cancer research 2002-02, Vol.8 (2), p.394-399
• Main Authors: MONTAZERI, Ashraf, CULINE, Stéphane, CHATELUT, Etienne, LAGUERRE, Brigitte, PINGUET, Frédéric, LOKIEC, Francois, ALBIN, Nicolas, GOUPIL, Alain, DEPORTE-FETY, Régine, BUGAT, Roland, CANAL, Pierre
• Format: Article
• Language: English
• Subjects: Aged; Antineoplastic agents; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Area Under Curve; Biological and medical sciences; Chemotherapy; Creatinine - urine; Dose-Response Relationship, Drug; Female; Humans; Medical sciences; Middle Aged; Neutrophils - drug effects; Neutrophils - metabolism; Ovarian Neoplasms - drug therapy; Pharmacology. Drug treatments; Time Factors; Topotecan - pharmacokinetics; Topotecan - therapeutic use; Treatment Outcome
• ISSN: 1078-0432; 1557-3265

Purpose: To take into account relationships between topotecan area under the plasma concentration (AUC) versus time curve and percentage decrease of neutrophil count previously shown when topotecan is administered on a 5-day, daily schedule. A multicentric clinical trial with individualized dosing of topotecan was performed in patients with platinum-refractory ovarian cancer. The primary goal of this study was to evaluate the toxicity of topotecan when the interindividual variability in plasma drug exposure is decreased. Experimental Design: A total of 39 patients were evaluable. In cycle 1, the daily dose for the last 2 days was dependent on the observed topotecan AUC at day 1; the general objective was to constrain the overall AUC ( i.e ., from day 1 to day 5) within 37,500–75,000 n m ·min. A pharmacokinetic study was also performed on day 5 of cycle 1 and day 1 of cycle 2 to evaluate the intrapatient pharmacokinetic variability both within cycle 1 and between cycles. Results: The dose of topotecan was decreased for 20 patients and increased for only 1 patient within cycle 1. The total administered dose was correlated to the creatinine clearance. The dose adjustments allowed control of the topotecan exposure: mean (±SD) observed AUC of 70,697 (±12,364) n m ·min. Fourteen cases of dose-limiting toxicity were observed, mainly in patients who previously received two different regimens of chemotherapy without a washout period before topotecan treatment. An overall response rate of 21% was observed in the 33 patients evaluable. Conclusion : Dose adjustments are required not only in patients with creatinine clearance below 40 ml/min, but also in those with values between 40 and 60 ml/min (recommended starting dose is 1.2 mg/m 2 ). By performing drug monitoring and taking into consideration the past treatment of each patient, better dose individualization can be obtained.