Sparse-data set analysis for irinotecan and SN-38 pharmacokinetics in cancer patients co-treated with cisplatin.
The clinical pharmacokinetics of the antineoplastic agent irinotecan (CPT-11) are associated with substantial interpatient variability. The degree to which this variability in CPT-11 exposure impacts upon the response and toxicity of the drug has not yet been properly determined. In general, the area under the plasma concentration-time curve (AUC) is an appropriate indicator of exposure, but requires collection of up to 17 timed blood samples. This presents difficulties if large-scale population samplings are required. The present study involved the development and validation of a strategy to estimate the AUCs of the lactone and total (i.e. lactone plus carboxylate) forms of CPT-11 and its active metabolite SN-38 from a limited number of blood samples in patients co-treated with cisplatin. Using data from 24 patients, univariate and multivariate regression analyses were employed to generate the models. The best predictive models for simultaneous estimation of CPT-11 and SN-38 AUCs were obtained with three time points at 0.5, 1.67 and 5.50 h after start of the 90 min i.v. infusion of CPT-11. The models were tested separately in another group of 24 patients receiving the same combination treatment. This validation set demonstrated that CPT-11 and SN-38 AUCs after standard dose administration could be predicted sufficiently unbiased and precisely with three timed samples to warrant clinical application.
Mathijssen
R H
RH
Department of Medical Oncology, Rotterdam Cancer Institute, The Netherlands.
van Alphen
R J
RJ
de Jonge
M J
MJ
Verweij
J
J
de Bruijn
P
P
Loos
W J
WJ
Nooter
K
K
Vernillet
L
L
Stoter
G
G
Sparreboom
A
A
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D002945:Cisplatin / Q000008:administration & dosage; D005260:Female; D006801:Humans; D000077146:Irinotecan; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy*; D011237:Predictive Value of Tests; D015203:Reproducibility of Results
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D002945:Cisplatin; D002166:Camptothecin