Tablet crushing, but not splitting, alters the pharmacokinetics of extended-release levetiracetam in dogs

Objective: To compare the pharmacokinetics of intact, split, and crushed levetiracetam (LEV) extended-release (LEV-XR) tablets in dogs. We hypothesized that splitting produces a pharmacokinetic profile similar to intact tablets, whereas crushing results in earlier and higher maximum concentrations. Methods: Healthy research dogs were administered 500 mg LEV-XR orally as intact, split, or crushed tablets in a randomized crossover design. Plasma LEV concentrations were measured over 12 hours by high-pressure liquid chromatography. Pharmacokinetic parameters were estimated using noncompartmental analysis and supplementary compartmental analysis and compared using linear mixed-effects models. Results: The study utilized 7 Beagles. Compared with intact tablets, crushed tablets resulted in higher maximum concentration (Cmax) values (61.5 vs 46.0 µg/mL; geometric mean ratio, 1.34; 95% CI, 1.08 to 1.65) and lower 8- to 12-hour exposure (30.0 vs 49.8 µg·h/mL; geometric mean ratio, 0.60; 95% CI, 0.47 to 0.77). Duration above the targeted concentration of 10 µg/mL was longer with intact than crushed tablets (10.9 vs 8.5 hours; mean difference, 2.37 hours; 95% CI, 1.02 to 3.72). Exploratory compartmental analysis estimated an earlier time to maximum concentration (Tmax) for crushed compared with intact tablets. No statistically significant differences were observed between intact and split tablets. Conclusions: Splitting LEV-XR tablets did not significantly alter the evaluated pharmacokinetic parameters, whereas crushing resulted in a higher Cmax, an earlier model-estimated Tmax, and reduced late exposure. Clinical Relevance: Splitting LEV-XR tablets may provide a practical option for dose adjustment in smaller dogs. Crushed LEV-XR warrants further evaluation as adjunct therapy during cluster seizures when immediate-release LEV is unavailable.