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Clinical pharmacoki...
Clinical pharmacokinetics of irinotecan and its metabolites in relation with diarrhea
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- Xie, Rujia (author)
- Uppsala universitet,Avdelningen för farmakokinetik och läkemedelsterapi
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Mathijssen, Ron H J (author)
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Sparreboom, Alex (author)
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Verweij, Jaap (author)
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- Karlsson, Mats O (author)
- Uppsala universitet,Avdelningen för farmakokinetik och läkemedelsterapi
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(creator_code:org_t)
- Springer Science and Business Media LLC, 2002
- 2002
- English.
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In: Clinical Pharmacology and Therapeutics. - : Springer Science and Business Media LLC. - 0009-9236 .- 1532-6535. ; 72:3, s. 265-275
- Related links:
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http://www.ncbi.nlm....
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
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- OBJECTIVES: 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
Keyword
- Adult
- Aged
- Antineoplastic Agents/adverse effects/blood/pharmacokinetics
- Area Under Curve
- Camptothecin/*adverse effects/*analogs & derivatives/blood/*pharmacokinetics
- Chi-Square Distribution
- Diarrhea/blood/*chemically induced
- Dose-Response Relationship; Drug
- Female
- Glucuronates/adverse effects/blood/pharmacokinetics
- Humans
- Male
- Middle Aged
- Research Support; Non-U.S. Gov't
- PHARMACY
- FARMACI
Publication and Content Type
- vet (subject category)
- art (subject category)
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