Body Surface Area Dosing of High-Dose Methotrexate Should Be Reconsidered, Particularly in Overweight, Adult Patients

Background: High-dose methotrexate is used for treating several types of cancer. However, it is associated with a high risk of acute kidney injury (AKI), especially in patients with high MTX concentrations. Although therapeutic drug monitoring is performed to monitor MTX concentrations, it is unclear what concentration should be considered critical, thus requiring rescue protocols to prevent nephrotoxicity. Methods: Patients treated with high-dose methotrexate for lymphoma or acute lymphoblastic leukemia and those benefited from therapeutic drug monitoring were included. The relationship between MTX concentrations and the presence or absence of AKI was assessed. MTX concentrations were analyzed using a population pharmacokinetic approach. Specific attention was given to morphological covariates because MTX doses are individualized according to body surface area (BSA). Results: In total, 328 patients and 657 cycles of treatment were analyzed. Higher MTX concentrations were observed in the AKI+ group. For cycle 1, all patients showing an MTX concentration >6 µM at 36 hours or >2 µM at 48 hours after infusion developed nephrotoxicity. The final pharmacokinetic model had 2 compartments and included the effect of age on clearance (CL) and of body weight on peripheral distribution volume. None of the morphological covariates tested on CL led to significant improvement in the model. Higher MTX concentrations were observed in patients with extreme BSA values (≥2 m 2 ) or body mass index (≥25 kg/m 2 ). Patients with AKI who received at least 1 cycle had higher BSA and BMI. Conclusions: The results from this study provide additional information on the relationship between MTX concentration and nephrotoxicity. Patients with a plasma MTX concentration >6 µM at 36 hours were more likely to manifest AKI. In addition, the results suggest that overweight patients have a high AKI risk and that BSA-based adjustment of MTX dose is not appropriate.