Rescue after intermediate and high-dose methotrexate: background, rationale, and current practice

Abstract

Pharmacologic rescue methods used in combination with intermediate and high-dose methotrexate therapy are reviewed, with special emphasis on rescue with nucleosides and folinic acid. The mechanism of action, pharmacokinetics, and clinical applications of the rescue agents are described in detail in view of the literature and also of the own findings of the authors. In spite of the promising results of the in vitro studies and in vivo experiments in animal models, the clinical value of thymidine as a rescue agent remains to be determined. Currently, the only indication to use thymidine instead of folinic acid following high-dose methotrexate is to prevent toxicity related to extremely high methotrexate levels in patients with delayed elimination of methotrexate. In spite of the widespread application of folinic acid rescue, the exact mechanism of its action is not fully understood. The rescue dose and schedule in the majority of clinical protocols is empirical, and the start of the rescue administration is too early, allowing less than 36 to 42 hours of exposure to methotrexate. Clinical and laboratory findings indicate that while the early start of FA administration is unnecessary for protecting normal cells, it is potentially dangerous in terms of reduction of the antitumor effect of methotrexate. Our findings suggest that less than the most widely used 12-15 mg/m2 per dose rescue may be sufficient in preventing methotrexate related toxicity in patients with normal elimination of the drug. In addition, reducing the dose of the rescue may be beneficial to achieve better therapeutic results with high-dose methotrexate. Due to methodological problems, the pharmacokinetics of folinic acid rescue has not been excessively studied in humans. Recent data indicate that the pharmacokinetics of folinic acid in children is characterized by great intra- and interpatient variability. The effect of food on the bioavailability of folinic acid has not yet been studied, though it is most frequently administered orally. The introduction of the pure l-stereoisomer of the rescue agent in the clinical practice may eliminate potential interactions with the d-isomer, and may also simplify the introduction of therapeutic drug monitoring for folinic acid as well. This could lead to more rational clinical use of folinic acid as a rescue agent following intermediate and high-dose methotrexate therapy.