Effect of Body Fat on Population Pharmacokinetics of High-Dose Methotrexate in Pediatric Patients With Acute Lymphoblastic Leukemia

Nearly all international regimens for pediatric acute lymphoblastic leukemia (ALL) incorporate intravenous "high-dose" methotrexate (HDMTX, >= 1 g/m(2)) to penetrate the central nervous system. Dosing is routinely adjusted for body surface area (BSA), but limited data describe the pharmacokinetics of HDMTX, particularly in obese and/or large patients. To understand the impact of body size (BSA) and body fat percentage (BFP) on HDMTX pharmacokinetics, we performed a secondary analysis of 36 children and adolescents 10-21 years old treated for newly diagnosed ALL and who were enrolled in a prospective study examining body composition. All patients received 5 g/m(2) of HDMTX infused over 24 hours. Plasma methotrexate concentrations were measured at 24, 42, and 48 hours. At 48 hours, >= 0.4 mu mol/L was defined as "delayed elimination," necessitating prolonged supportive care. BFP was measured using dual-energy x-ray absorptiometry. A nonparametric population pharmacokinetic model was constructed with subsequent simulations to explore effects of BSA and BFP extremes. Despite standard BSA-adjusted dosing, we found significant intrapatient variability in mean MTX concentration (38%; range, 1.2%-86%). BSA and BFP were not linearly associated with increased area under the curve (AUC, P = 0.74 and P = 0.12), but both larger size (BSA) and greater obesity (BFP) were associated with an approximately 2-fold higher risk for delayed elimination at 48 hours. HDMTX AUC was not associated with toxicity. MTX pharmacokinetics vary among and even within patients despite BSA-adjusted dosing. Obesity and large size are identified as new risk factors for delayed elimination, requiring further investigation.