High dose methotrexate in adult patients with osteosarcoma: Clinical and pharmacokinetic results
Open Access
- 1 January 2005
- journal article
- research article
- Published by Medical Journals Sweden AB in Acta Oncologica
- Vol. 44 (4), 406-411
- https://doi.org/10.1080/02841860510029770
Abstract
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: Cmax (maximum MTX concentration) 1149.5 µM (692 – 2 200), AUCtot (total area under curve) 6 955.1 µmol*h/l (3 477 – 12 681). Cmax>1 000 µM 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 (Kel). Toxicity was mild: only two reversible G4 events were observed, related to AUCtot >12 000 µmol*h/l (p < 0.001). HDMTX pk and interpatient variability in adults are comparable to those in children. No correlation between Cmax/AUCtot 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 Cmax, while severe toxicity depends on highest AUCtot values.Keywords
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