Methotrexate administered by 6-h and 24-h infusion: a pharmacokinetic comparison

The pharmacokinetics of 8 g/m2 methotrexate (MTX) was compared following short (6 h) and long (24 h) infusions of the drug to 11 children with osteogenic sarcoma (OS; 42 infusion) and 28 children with acute lymphoblastic leukemia (ALL: 118 infusions), respectively. No difference was observed in the first-phase half-life, in systemic clearance or in the volume of distribution of the drug (P greater than 0.05). The concentration of MTX at the end of the infusion was approximately 4-fold higher when the drug was given over only 6 h. However, patients receiving 24-h infusions had approximately 9-fold higher levels by 24 h after the beginning of the infusion. The area under the data curve from start of the MTX infusion until the beginning of folinic acid rescue administration was significantly higher in patients with osteogenic sarcoma (6-h infusions), while the area under the log-data curve was significantly longer in the ALL group (24-h infusions) for the same period. The latter parameter is considered to be characteristic for the concentration-time-effect relationship. The longer duration of MTX administration (with delayed rescue) is thought to be more beneficial from the pharmacokinetic aspect. Patients with osteogenic sarcoma had significantly lower concentrations of MTX at the end of their last treatment with MTX than at the end of the first infusion. Patients developing MTX toxicity had shorter half-lives of MTX in the beta phase. It is suggested that cisplatin induced tubular loss of MTX and folinic acid is responsible for these observations. A wider application of clinical pharmacologic findings in the practice of the administration of cytostatics is indicated.