Aim: To investigate the pharmacokinetic plausibility of capped body surface area (BSA) dosing in obese and overweight adult non-Hodgkin lymphoma (NHL) patients being treated with high-dose methotrexate (HD MTX).

Methods: A HD MTX population pharmacokinetic model incorporating renal function and body size was developed from retrospectively collected observations of 108 adults who received HD MTX as part of the Hyper-CVAD chemotherapy for aggressive NHL during 2002 to 2012 at a tertiary referral metropolitan hospital. The model was used to simulate MTX plasma concentrations and overall exposure in a virtual population of 1000 individuals, randomly sampled with stratification for body size from the National Health and Nutrition Examination databases. Simulations were conducted with MTX dosing (200mg/m² over 2 hours followed by 800mg/m² over 22 hours) based on i) actual BSA, and ii) dose capped at 2m² in individuals with a BSA >2m².

Results: Simulated MTX plasma concentrations in obese and overweight individuals did not differ significantly from normal weight patients (p=0.024 and p=0.114 respectively) and with 95% of the simulated concentrations falling below the toxicity levels at 48 and 72 hours. Dose capped obese individuals displayed a reduced mean MTX exposure compared to dose capped overweight individuals (278μmol*hr/L versus 297μmol*hr/L). Renal function demonstrated a clear impact on the pharmacokinetics in all individuals and the best methods for estimation of renal function to guide HD MTX dosing in a population of diverse weights were determined.

Conclusions: Pharmacokinetic changes with HD MTX in NHL appear to be marginal in obese and overweight individuals, suggesting dose capping purely based on body size may be unnecessary. Instead dosing adjustments in extremes of body size should appropriately account for renal function to avoid toxicity.