High dose methotrexate in adult patients with osteosarcoma: Clinical and pharmacokinetic results

被引:44
作者
Comandone, A
Passera, R
Boglione, A
Tagin, V
Ferrar, S
Cattel, L
机构
[1] Univ Turin, Dipartimento Sci & Tecnol Farmaco, I-10125 Turin, Italy
[2] Osped Gradenigo, Div Med Oncol, Turin, Italy
[3] Ist Ortoped Rizzoli, Sez Chemioterapia Tumori Apparato Locomotore, Bologna, Italy
关键词
D O I
10.1080/02841860510029770
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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/m(2) 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 mu M (692 - 2 200) AUC(tot) (total area under curve) 6 955.1 mu mol*h/l (3 477 - 12 681). C-max > 1 000 mu M 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 mu mol*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.
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页码:406 / 411
页数:6
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