High-dose methotrexate in pediatric osteosarcoma patients. Implementing a population pharmacokinetic/pharmacogenetic study in Argentina

SCHAIQUEVICH P; CACERES GUIDO P; LICCIARDONE N; ARAOZ V; LAGOMARSINO E; ROSE A; CHERTKOFF L; ZUBIZARRETA P; CACCIAVILLANO W

Congreso; 12 th international congress of therapeutic drug monitoring and clinical toxicology; 2011

Background: Osteosarcoma is the most common pediatric bone tumor. In Argentina and bordering countries 20 new cases are reported every year. Chemotherapy treatment includes high-dose methotrexate (HDMTX). MTX plasma monitoring is used to reduce the incidence of severe toxicity (1). An association between MTX systemic exposure and clinical outcome has been proposed in developed countries but still there is no consensus (2-6). We aimed to characterize HDMTX pharmacokinetics/pharmacogenetics (PK/PG) and to evaluate possible associations with safety and efficacy in Latin-American osteosarcoma patients.Methods: Pediatric osteosarcoma patients receive 12 courses of HDMTX (12 g/m2) as a 4-hour i.v infusion with concomitant chemotherapy according to the protocol (GATLO). Patient demographic, clinical and biochemical characteristics are collected. MTX plasma samples are collected at: the end of the 4h-infusion, 24, 48 and 72 h after the start of the infusion and MTXconcentrations are determined by FPIA. Genetic polymorphisms of the 5,10-MTHFR included C677T and A1298C (7,8).Efficacy of treatment is evaluated according to overall survival, % tumor necrosis (TN) and toxicity is classified according to NCI CTCAE (9).Results: 6 patients with osteosarcoma of extremities and 3 lung metastasis were evaluated during 47 HD-MTX cycles. The median age and dose (range) was 14.8 years (5.7-16.1) and 16 g (7,4-22.2), respectively.162 plasma samples were obtained. The median (range) plasma concentration at the end of the 4-h infusion was 1100 miM (714-1735). The estimated population PK parameters (Monolix) included (mean; s.e): Vd (17.4 L; 3), Ke (0.273 h-1; 0.015). All patients were WT for C677T and 77 % were HET with one WT for A1298C polymorphism. Mucositis (G2/3), hematologic (G3) and hepatic (G3/4) toxicity was observed in 2, 1 and 5 cycles, respectively. 1 patient was a good responder (99% TN). Conclusion: This is the first PK/PG study in pediatric osteosarcoma patients implemented in Argentina. We emphasize the importance of PK/PG characterization to optimize chemotherapy (efficacy and safety of HDMTX treatment) taking into account that there is neither previous data nor other ongoing studies in our population.The results obtained so far are comparable to published reports even if disease-free or overall survival could not still be evaluated. Further characterization in a larger population is needed to translate the observations into the therapeutic monitoring of MTX.