High dose methotrexate in adult patients with osteosarcoma: clinical and pharmacokinetic results.
High dose methotrexate (HDMTX) with folinic acid rescue is widely used to treat osteosarcoma, which predominantly afflicts children; the study investigated HDMTX pharmacokinetics (pk) in adult subjects in neoadjuvant/adjuvant settings. Twenty five patients with advanced osteosarcoma (11 females--14 males, median age 26.0 years) were treated by 12 g/m2 HDMTX 4 hour iv infusion (64 total courses, range 1-7 courses). Pk was determined by non-compartmental analysis and population pk modeling. Median (range) bioavailability pk parameters were: C(max) (maximum MTX concentration) 1149.5 microM (692-2,200), AUC(tot) (total area under curve) 6,955.1 micromol*h/l (3,477-12,681). C(max)>1,000 microM gave increased histological responses (p < 0.05). Six covariates (height-weight-hemoglobin-AST-ALT-creatinine) were found to influence MTX volume of distribution (V) and elimination rate constant (K(el)). Toxicity was mild: only two reversible G4 events were observed, related to AUC(tot) >12,000 micromol*h/l (p < 0.001). HDMTX pk and interpatient variability in adults are comparable to those in children. No correlation between C(max)/AUC(tot) and subject age/sex was found, even in the population pk model. The excretion mechanism is not affected by sex/age differences. HDMTX can safely be administered to adults: as in younger patients, a good clinical response can be predicted by C(max), while severe toxicity depends on highest AUC(tot) values.
Comandone
Alessandro
A
Divisione di Oncologia Medica, Ospedale Gradenigo, Torino, Italy.
Passera
Roberto
R
Boglione
Antonella
A
Tagini
Valentina
V
Ferrari
Stefano
S
Cattel
Luigi
L
D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001859:Bone Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008727:Methotrexate / Q000493:pharmacokinetics* / Q000627:therapeutic use; D020360:Neoadjuvant Therapy; D012516:Osteosarcoma / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism*; D011379:Prognosis; D015996:Survival Rate
D008727:Methotrexate