Concepts in use of high-dose methotrexate therapy

In cancer chemotherapy, routine monitoring of drug concentrations has been practical only for methotrexate (MTX). The primary setting for pharmacokinetic monitoring of MTX is its use in high doses (HDMTX) for adjuvant therapy of osteosarcoma, for single-agent treatment of intracranial lymphomas, and in combination therapy of childhood leukemia as well as adult and pediatric non-Hodgkin lymphomas. Typically, HDMTX is infused in doses of 3-15 g/m2 over a period of 6-24 h. Precautions must be taken to ensure a high urine flow and an alkaline urine pH, so as to prevent precipitation of MTX in urine. Patients with decreased renal function, advanced in age, and taking nonsteroidal anti-inflammatory drugs or nephrotoxic agents are at increased risk of developing renal dysfunction during MTX infusion, thus being placed at high risk for toxicity. At the end of HDMTX infusion, and periodically thereafter for 24-48 h, drug concentrations are measured to assure that the disappearance rate of MTX from plasma is occurring at a normal rate. Also, at the end of HDMTX infusion, the patient is given leucovorin (5-formyl-tetrahydrofolic acid; LV), which replenishes intracellular stores of reduced folate and attenuates the toxicity secondary to HDMTX. In the presence of inappropriately high concentrations of MTX, routine doses of LV will be ineffective; the dose of LV required must be increased in proportion to the MTX concentration it faces in plasma. In practice, routine monitoring of plasma MTX concentrations allows early detection of abnormal clearance, as well as institution of early and effective countermeasures, including the use of increased and prolonged LV rescue.