A prospective, open-label, randomized, crossover study to compare the pharmacokinetics of crushed methotrexate with that of the tablet formulation in patients with head-and-neck cancer

ABSTRACT Background: Crushing solid dosage forms is often required in patients with swallowing difficulties; however, the pharmacokinetic (PK) impact of this alteration is not well-studied. Objective: The primary objective was to compare the PK of crushed methotrexate tablets suspended in water versus whole tablets in patients with head-and-neck cancer. The secondary objective was to evaluate the effect of nasogastric/polyethylene glycol (PEG) tube administration on PK parameters. Materials and Methods: In this randomized crossover study, patients received methotrexate as either a crushed tablet in water or a whole tablet, followed by alternate formulation after 1-week washout. Serial blood samples were collected post-administration. PK parameters were derived using noncompartmental analysis in PUMAS. Bioequivalence was assessed using 90% confidence intervals (CIs) of the geometric mean ratio (GMR) for C max and area under the curve (AUC 0-∞ ) with equivalence defined as 80%-125%. Results: Thirteen patients were enrolled; 11 completed both study periods. High interindividual variability (>40%) was observed for both formulations. Crushed tablets achieved T max approximately 16 minutes earlier. Mean C max and AUC 0-∞ for whole versus crushed formulations were 447.04 ± 180.91 vs. 447.70 ± 224.71 ng/mL and 1704.29 ± 808.93 vs. 1907.47 ± 1012.24 ng.h/mL, respectively, with no statistical significance. The GMR for crushed versus whole tablets was 103.3% for C max and 112.2% for AUC 0-∞ . However, their 90% CIs (76%-139% for C max and 93%-134% for AUC 0-∞ ) indicated lack of bioequivalence. Conclusion: Although not bioequivalent, crushed methotrexate tablets produced similar systemic exposure and a shorter T max . Despite high variability, crushed administration may be an acceptable PK alternative for patients unable to swallow tablets, without dose adjustment.