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Population pharmacokinetic model for irinotecan and two of its metabolites, SN‐38 and SN‐38 glucuronide
Author(s) -
Klein Cheri Enders,
Gupta Elora,
Reid Joel M.,
Atherton Pamela J.,
Sloan Jeff A.,
Pitot Henry C.,
Ratain Mark J.,
Kastrissios Helen
Publication year - 2002
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1067/mcp.2002.129502
Subject(s) - irinotecan , pharmacokinetics , glucuronide , metabolite , sn 38 , active metabolite , population , chemistry , volume of distribution , pharmacology , disposition , medicine , biochemistry , psychology , cancer , social psychology , colorectal cancer , environmental health
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. Conclusion 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. Clinical Pharmacology & Therapeutics (2002) 72 , 638–647; doi: 10.1067/mcp.2002.129502