Population pharmacokinetic model for irinotecan and two of its metabolites, SN-38 and SN-38 glucuronide.
OBJECTIVE
The objective of the study was to develop and validate a population pharmacokinetic model for irinotecan and 2 of its metabolites, SN-38 and SN-38 glucuronide (SN-38G).


METHODS
Plasma concentrations were obtained during and up to 48 hours after a 90-minute continuous intravenous infusion of irinotecan (100-340 mg/m(2)) in 78 patients. Data splitting was used to create model-building and model-validation data sets. Pharmacokinetic parameter estimates were obtained by compartmental methods to describe the disposition of metabolites that are dependent on the disposition of the parent compound. Relationships between patient attributes and estimates of clearance (CL) and volume of the central compartment for irinotecan, as well as CL and volume of the central compartment adjusted for the fraction metabolized for SN-38 and SN-38G, were explored by use of generalized additive models and graphic analysis. Selected covariates were introduced into the final population model by stepwise additions or deletions with the likelihood ratio test.


RESULTS
SN-38 and SN-38G were shown to be formation rate-limited and were characterized by first-order rate constants of formation and elimination. Two subpopulations of SN-38 disposition were identified, presumably because of differences in the fraction of metabolite formed from the parent compound. Estimated irinotecan CL (25.2 L/h) was similar to that determined in other studies. Age and performance status were found to be important predictors of irinotecan CL, whereas variability in systemic exposure to the active metabolite, SN-38, was predicted by sex and hepatic function.


CONCLUSIONS
The validated population pharmacokinetic model describing the disposition of irinotecan and 2 of its metabolites should facilitate the design of future studies to elucidate the relative contributions of the parent compound and SN-38 to the pharmacologic and toxic effects of irinotecan therapy.
Klein
Cheri Enders
CE
University of Illinois, Chicago 60612, USA.
Gupta
Elora
E
Reid
Joel M
JM
Atherton
Pamela J
PJ
Sloan
Jeff A
JA
Pitot
Henry C
HC
Ratain
Mark J
MJ
Kastrissios
Helen
H
D000328:Adult; D000469:Alkaline Phosphatase / Q000097:blood; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001663:Bilirubin / Q000097:blood; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D003404:Creatinine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring / Q000379:methods / Q000592:standards*; D005260:Female; D005965:Glucuronates / Q000097:blood; D006801:Humans; D007262:Infusions, Intravenous; D000077146:Irinotecan; D007677:Kidney Function Tests; D008111:Liver Function Tests; D008297:Male; D010088:Oxidoreductases / Q000097:blood; D011237:Predictive Value of Tests; D015203:Reproducibility of Results
C114685:7-ethyl-10-hydroxycamptothecin beta-glucuronide; D000972:Antineoplastic Agents, Phytogenic; D005965:Glucuronates; D000077146:Irinotecan; D003404:Creatinine; D010088:Oxidoreductases; D000469:Alkaline Phosphatase; D001663:Bilirubin; D002166:Camptothecin