Individual adaptive dosing of topotecan in ovarian cancer.
OBJECTIVE
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.


METHODS
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 nM.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) nM.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.


CONCLUSIONS
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.
Montazeri
Ashraf
A
Institut Claudius-Regaud, 20-24 rue du Pont-St-Pierre, F-31052 Toulouse, France.
Culine
Stéphane
S
Laguerre
Brigitte
B
Pinguet
Frédéric
F
Lokiec
François
F
Albin
Nicolas
N
Goupil
Alain
A
Déporte-Féty
Régine
R
Bugat
Roland
R
Canal
Pierre
P
Chatelut
Etienne
E
D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D003404:Creatinine / Q000652:urine; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D013997:Time Factors; D019772:Topotecan / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D019772:Topotecan; D003404:Creatinine