Pharmacokinetic individualization of high-dose methotrexate chemotherapy for the treatment of localized osteosarcoma.
Individualization of high-dose methotrexate (MTX) dosing is important to achieve therapeutic levels (700-1,000 microM) for osteosarcoma. Therefore we developed a pharmacokinetically (PK) individualized dosage regimen to maintain MTX concentrations of 700 microM (1 h bolus followed by 5 h maintenance infusion) and evaluated its safety and efficacy. Loading and maintenance doses were calculated by the PK parameters based on 2-compartment model analysis. Thirty-two courses of chemotherapy were performed in 9 patients with osteosarcoma. The maximum concentrations during maintenance infusion in 31 courses (97%) were above 700 microM. Only 1 patient developed severe hepatotoxicity as adverse effect. Total body clearance of MTX decreased in 4 patients when weekly MTX chemotherapy was performed for 3 consecutive weeks. Although the clearance was changed, the average MTX concentrations were maintained at about 700 microM by the PK individualization. The 5-year survival rate was 77.8% (7 of 9 patients), and all of them have survived for more than 9 years. This PK individualization is safe and useful for tailoring high-dose MTX therapy to achieve therapeutic levels.
Fujita
Y
Y
Department of Pharmacy, Gunma University Hospital, Gunma, Japan.
Nakamura
T
T
Aomori
T
T
Nishiba
H
H
Shinozaki
H
H
Yanagawa
T
T
Takagishi
K
K
Watanabe
H
H
Okada
Y
Y
Nakamura
K
K
Horiuchi
R
R
Yamamoto
K
K
D000293:Adolescent; D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002648:Child; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D012516:Osteosarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015996:Survival Rate; D014018:Tissue Distribution; D016896:Treatment Outcome; D055815:Young Adult
D000964:Antimetabolites, Antineoplastic; D008727:Methotrexate