In:
Clinical Pharmacology & Therapeutics, Wiley, Vol. 72, No. 3 ( 2002-09), p. 265-275
Abstract:
Our objective was to build population pharmacokinetic models that describe plasma concentrations of irinotecan (CPT‐11) and its metabolites 7‐ethyl‐10‐hydroxycamptothecin (SN‐38) and SN‐38 glucuronide (SN‐38G) and to investigate the pharmacokinetic‐pharmacodynamic relationships between drug exposure and diarrhea, the major dose‐limiting toxicity. Methods Data were obtained from 109 patients (65 men and 44 women) who received 1.5‐hour (range, 0.75‐ to 2.25‐hour) intravenous infusions of irinotecan at doses that ranged from 100 to 350 mg/m 2 ; 44 patients had a second course. The population pharmacokinetic models were developed to describe plasma concentration‐time profiles. The area under the concentration‐time curve from time zero to 60 hours [AUC (0–60)] was used as a measure of drug exposure to model the probabilities of diarrhea with use of a logistic regression model. Results A 3‐compartment pharmacokinetic model best described the disposition of irinotecan, whereas SN‐38 and SN‐38G showed 2‐compartmental characteristics. The population estimate of clearance for irinotecan was 31.6 L/h, and the volume of distribution at steady‐state (V SS ) was 263 L. The clearance divided by formation fraction (F m ) was 712 L/h and 66.8 L/h for SN‐38 and SN‐38G, respectively. The V SS /F m was 72,000 L for SN‐38 and 85.4 L for SN‐38G. The frequencies of diarrhea scores in this study were 46% (grade 0), 28% (grade 1), 20% (grade 2), 4% (grade 3), and 2% (grade 4). Significant correlations between AUC(0–60) and diarrhea scores were found for irinotecan ( P 〈 .05) and SN‐38G ( P 〈 .01) but not for SN‐38 or the biliary index. Conclusions In this population analysis, irinotecan and SN‐38G AUC values were appropriate predictors of the risk for diarrhea, and SN‐38G AUC showed the stronger relationship of the two. The developed population models may be useful in further clinical development of this agent. Clinical Pharmacology & Therapeutics (2002) 72 , 265–275; doi: 10.1067/mcp.2002.126741
Type of Medium:
Online Resource
ISSN:
0009-9236
,
1532-6535
DOI:
10.1067/mcp.2002.126741
Language:
English
Publisher:
Wiley
Publication Date:
2002
detail.hit.zdb_id:
2040184-X
detail.hit.zdb_id:
123793-7
SSG:
15,3
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