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Modeling Plasma and Saliva Topotecan Concentration Time Course Using a Population Approach

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The purpose of this study was to develop a pharmacokinetic model simultaneously accounting for topotecan concentrations in plasma and saliva. Thirteen patients with metastatic epithelial ovarian cancer received topotecan. During the first and the second courses of treatment, each patient underwent pharmacokinetic evaluation. Data were analyzed using the nonlinear mixed-effect model program. The saliva concentrations were associated to a peripheral compartment while the central compartment described the plasma concentration time course. Thus, a three-compartment model was used; the basic parameters were: total clearance (CL), initial volume of distribution (V1), transfer rate constants (k12/k21 and k13/k31). The interoccasion variability was taken into account in the model. Data analysis was performed using a three-step approach; in step 2, a close relationship was found between creatinine CL and topotecan CL. The inclusion of this second stage model significantly improved the fit. Large interindividual variability in pharmacokinetic parameters occurred (CL varied from 10.4 to 23 L/h) while interoccasion variability was limited (6%). Seven additional courses were used for model validation. A limited sampling strategy using Bayesian estimation based on two sampling times (saliva at 25 min and plasma plus saliva at 8.5 h after the start of infusion) was developed. This study shows that salivary concentrations can be effectively used for drug monitoring.

Keywords: Key words: Topotecan; Plasma; Saliva; Population p

Document Type: Research Article


Affiliations: 1: †Oncopharmacology Department, Pharmacy service, Val d'Aurelle Anticancer Centre, parc Euromédecine, Montpellier, France 2: ‡Department of Medicine, Val d'Aurelle Anticancer Centre, parc Euromédecine, Montpellier, France 3: *Clinical Pharmacokinetic Laboratory, Faculty of Pharmacy, University Montpellier I, 15 Avenue Ch. Flahault, BP 14 491, 34093 Montpellier Cedex 5, France

Publication date: January 1, 2002

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  • Formerly: Oncology Research Incorporating Anti-Cancer Drug Design
    Oncology Research Featuring Preclinical and Clincal Cancer Therapeutics publishes research of the highest quality that contributes to an understanding of cancer in areas of molecular biology, cell biology, biochemistry, biophysics, genetics, biology, endocrinology, and immunology, as well as studies on the mechanism of action of carcinogens and therapeutic agents, reports dealing with cancer prevention and epidemiology, and clinical trials delineating effective new therapeutic regimens.

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