Prediction of the systemic exposure to oral 9-amino-20(S)-camptothecin using single-sample analysis
The purpose of this study was to develop and validate limited-sampling strategies for prediction of the area under the plasma-concentration time curves (AUCs) of the lactone and total (i. e., lactone plus carboxylate) forms of the novel topoisomerase-I inhibitor 9-amino-20(S)-camptothecin (9-AC). Complete pharmacokinetic curves for both drug species were obtained from 32 patients who received the drug orally in a clinical phase I setting at dose levels ranging from 0.25 to 1.10 mg/m2. The concentrations of the lactone and carboxylate forms of 9-AC in plasma were measured by HPLC. Using data from 20 randomly selected patients, forward-stepwise multivariate regression analysis was used to generate modeling strategies incorporating data from one, two, or three plasma samples. The simultaneous optimal prediction of both 9-AC lactone and 9-AC total AUCs was obtained with sample time points at 0.33, 3.0, and 11.0 h after drug dosing. Validation of the models on an independent data set comprising data of the remaining 12 patients demonstrated that 9-AC lactone and 9-AC total AUCs could be predicted sufficiently unbiased and precise using one and two time points: [AUC (ng. h/ml) = 7.103*C3 + 4.333] for 9-AC lactone and [AUC (ng. h/ml) = 9.612*C3 + 13.77*C11 - 44.11] for 9-AC total, where C3 and C11 represent the 9-AC plasma concentrations in ng/ml at 3 and 11 h after drug dosing. Application of the proposed models will be valuable in the determination of 9-AC population pharmacokinetics and permits treatment optimization for patients on the basis of individual pharmacokinetic characteristics through restricted drug monitoring in clinical routines.
|Keywords||Adolescent, Adult, Aged, Antineoplastic Agents/blood/*pharmacokinetics, Area Under Curve, Camptothecin/*analogs & derivatives/blood/pharmacokinetics, Chromatography, High Pressure Liquid, Female, Humans, Male, Middle aged|
Sparreboom, A., de Jonge, M.J.A., Punt, C.J., Loos, W.J., Nooter, K., Stoter, G., … Verweij, J.. (1999). Prediction of the systemic exposure to oral 9-amino-20(S)-camptothecin using single-sample analysis. Drug Metabolism and Disposition: the biological fate of chemicals. Retrieved from http://hdl.handle.net/1765/9128