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J Pharm Sci. 2003 Aug;92(8):1654-64.

Pharmacokinetic-pharmacodynamic modeling of methotrexate-induced toxicity in mice.

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Department of Pharmaceutical Sciences, University at Buffalo, The State University at New York, 521 Hochstetter Hall, Buffalo, New York 14260, USA.


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 2.5-1000 mg/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 3-600 mg/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 (760 mg/kg vs. 3.8 mg/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%).

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