High dose methotrexate chemotherapy: pharmacokinetics, folate and toxicity in osteosarcoma patients

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • High dose methotrexate (HD MTX) is generally well tolerated, although unpredictable acute toxicities occur frequently. • Low overall toxicity in paediatric patients and increased liver toxicity in adults has been reported, but there are no reports addressing the relationship between acute liver toxicity and gender in patients treated with HD MTX. • Previous studies in animals suggested involvement of the 7-hydroxy-methotrexate metabolite in acute liver toxicity, but this has not been investigated in humans and the aetiology of acute liver toxicity remains unclear. WHAT THIS STUDY ADDS • Survival has increased dramatically over the past decades for patients with malignancies such as osteosarcoma and since these patients are frequently children or adolescents at the time of high dose methotrexate, identification of risk factors for toxicity increases the possibility for tailoring treatment. • Our study presents a detailed analysis of acute toxicity, folate concentrations and pharmacokinetics of both methotrexate and its major extracellular metabolite 7-hydroxy-methotrexate and identifies several factors that are highly correlated with acute liver toxicity. AIMS To investigate the relationships between pretreatment folate concentrations, MTX pharmacokinetics and acute toxicities following high dose methotrexate (HD MTX) therapy. METHODS MTX and its major extracellular metabolite 7-OH-MTX were measured in eight serum samples per HD MTX cycle in 65 consecutive osteosarcoma patients (288 cycles) and AUC (area under the blood concentration–time curve) was calculated. Pretreatment concentrations of folate in serum (S) and erythrocytes (ER) were determined. Hepatic, renal and haematological toxicities, assessed by routine laboratory parameters, as well as mucositis were graded according to National Cancer Institute Common Terminology Criteria for adverse events (CTCAE v.3.0). Dermatitis and pleuritis were reported as occurred or not. RESULTS S- and ER-folate pretreatment concentrations increased significantly with increasing number of HD MTX cycles (P < 0.001). ER-folate pretreatment concentrations were higher among males (median 610 nmol l⁻¹, 95% CI 550, 680) compared with females (median 465 nmol l⁻¹, 95% CI 430, 520, P < 0.001), but showed no correlation with MTX or 7-OH-MTX pharmacokinetics. We found correlations between alanine aminotransferase peak concentration (ALAT_max) and clearance of MTX (P < 0.001), gender (P < 0.001), age (P < 0.001) and 7-OH-MTX concentrations (P < 0.001), the latter being the main factor influencing ALAT_max. CONCLUSION Our results suggest that 7-OH-MTX is involved in the development of HD MTX hepatic toxicity and that young female patients are most affected.