Pharmacokinetic–Pharmacodynamic Modeling of Methotrexate-Induced Toxicity in Mice

• Published in: Journal of pharmaceutical sciences Vol. 92; no. 8; pp. 1654 - 1664
• Main Authors: Lobo, Evelyn D., Balthasar, Joseph P.
• Format: Journal Article
• Language: English
• Published: Hoboken Elsevier Inc 01.08.2003; Wiley Subscription Services, Inc., A Wiley Company; Wiley; American Pharmaceutical Association
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; General aspects; Male; Medical sciences; methotrexate; Methotrexate - blood; Methotrexate - pharmacokinetics; Methotrexate - toxicity; Mice; modeling; Models, Chemical; pharmacodynamic; pharmacokinetic; Pharmacology. Drug treatments; toxicity; Weight Loss - drug effects; Weight Loss - physiology; toxicity; methotrexate; pharmacodynamic; modeling; pharmacokinetic; Antineoplastic agent; Intraperitoneal administration; Toxicity; Body weight; Rodentia; Weight loss; Biological activity; Vertebrata; Mammalia; Mouse; Animal; Mathematical model; Methotrexate; Pharmacokinetics
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.10431

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