Pharmacokinetic–Pharmacodynamic Modeling of Methotrexate-Induced Toxicity in Mice
The prediction of chemotherapeutic efficacy is complicated by “protocol dependencies” in dose-effect and dose-toxicity relationships. It has been proposed that pharmacokinetic–pharmacodynamic mathematical models may allow characterization of chemotherapeutic protocol dependencies, and may facilitate...
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Published in | Journal of pharmaceutical sciences Vol. 92; no. 8; pp. 1654 - 1664 |
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Main Authors | , |
Format | Journal Article |
Language | English |
Published |
Hoboken
Elsevier Inc
01.08.2003
Wiley Subscription Services, Inc., A Wiley Company Wiley American Pharmaceutical Association |
Subjects | |
Online Access | Get full text |
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Summary: | The prediction of chemotherapeutic efficacy is complicated by “protocol dependencies” in dose-effect and dose-toxicity relationships. It has been proposed that pharmacokinetic–pharmacodynamic mathematical models may allow characterization of chemotherapeutic protocol dependencies, and may facilitate the prediction of chemotherapeutic efficacy; however, few demonstrations exist in the literature. The present study examines the pharmacokinetics and toxicodynamics of methotrexate (MTX), a commonly used anticancer agent, after intraperitoneal (i.p.) administration to mice. MTX was administered via bolus or infusion (24, 72, and 168 h), at doses of 2.5–1000mg/kg. MTX plasma and peritoneal pharmacokinetics were characterized through standard noncompartmental and compartmental techniques. Body weight loss was used as a measure of MTX-induced toxicity. We found that MTX pharmacokinetics were independent of dose (over a range of 3–600mg/kg) and independent of dosing mode (i.e., i.p. bolus vs. i.p. infusion). However, MTX-induced toxicity was shown to be highly dependent on the dosing protocol used. For example, the maximally tolerated dose (i.e., the dose related to a mean body weight loss of 10%) was 200-fold greater after bolus administration relative to that observed for 72-h infusion (760mg/kg vs. 3.8mg/kg). This profound protocol dependence in the relationship between MTX-induced toxicity and MTX exposure was characterized through the use of a time-dissociated pharmacokinetic–pharmacodynamic model (median prediction error: 3.9%). © 2003 Wiley-Liss, Inc. and the American Pharmacists Association |
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Bibliography: | ArticleID:JPS10431 ark:/67375/WNG-J8186K9N-8 istex:253C5754D306BEEA7495F6E46EF606B386C53DE2 |
ISSN: | 0022-3549 1520-6017 |
DOI: | 10.1002/jps.10431 |