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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/m2) 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/m2 of HDMTX infused over 24 hours. Plasma methotrexate concentrations were measured at 24, 42, and 48 hours. At 48 hours, ≥0.4 μmol/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.