PT  - JOURNAL ARTICLE
AU  - Sparreboom, Alex
AU  - de Jonge, Maja J. A.
AU  - Punt, Cornelis J. A.
AU  - Loos, Walter J.
AU  - Nooter, Kees
AU  - Stoter, Gerrit
AU  - Porro, Maria Grazia
AU  - Verweij, Jaap
TI  - Prediction of the Systemic Exposure to Oral 9-Amino-20(<em>S</em>)-Camptothecin Using Single-Sample Analysis
DP  - 1999 Jul 01
TA  - Drug Metabolism and Disposition
PG  - 816--820
VI  - 27
IP  - 7
4099  - http://dmd.aspetjournals.org/content/27/7/816.short
4100  - http://dmd.aspetjournals.org/content/27/7/816.full
SO  - Drug Metab Dispos1999 Jul 01; 27
AB  - 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 C11represent 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. The American Society for Pharmacology and Experimental Therapeutics