title: Individual adaptive dosing of topotecan in ovarian cancer.
abstract: 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.
authors.affiliation: Institut Claudius-Regaud, 20-24 rue du Pont-St-Pierre, F-31052 Toulouse, France.
authors.forename: Ashraf
authors.initials: A
authors.lastname: Montazeri
authors.forename: Stéphane
authors.initials: S
authors.lastname: Culine
authors.forename: Brigitte
authors.initials: B
authors.lastname: Laguerre
authors.forename: Frédéric
authors.initials: F
authors.lastname: Pinguet
authors.forename: François
authors.initials: F
authors.lastname: Lokiec
authors.forename: Nicolas
authors.initials: N
authors.lastname: Albin
authors.forename: Alain
authors.initials: A
authors.lastname: Goupil
authors.forename: Régine
authors.initials: R
authors.lastname: Déporte-Féty
authors.forename: Roland
authors.initials: R
authors.lastname: Bugat
authors.forename: Pierre
authors.initials: P
authors.lastname: Canal
authors.forename: Etienne
authors.initials: E
authors.lastname: Chatelut
mesh_terms: 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
chemical_list: D000970:Antineoplastic Agents; D019772:Topotecan; D003404:Creatinine