Comparative Bioavailability of a Single Dose of Trametinib (TMT212) Containing 9% vs 11% Dimethyl Sulfoxide in Randomized Healthy Volunteers to Assess Long‐Term Storage at Room Temperature

Storage of trametinib tablets outside of 2‐8°C protected from moisture may lead to loss of dimethyl sulfoxide (DMSO) and adversely impact trametinib bioavailability. In this open‐label, phase 1, single‐dose, randomized, 2‐treatment, 2‐period crossover study in healthy volunteers, bioavailability of a single 2‐mg tablet of trametinib containing 9% DMSO (test formulation), corresponding to the lowest DMSO content in the tablet after storage at 25°C for 36 months, was evaluated vs bioavailability of a 2‐mg tablet containing 11% DMSO (reference formulation). Sixty‐five percent of subjects (n = 39/65) were men, and mean (standard deviation) age was 45.6 (11.17) years. Time to reach maximum plasma concentration occurred at 1.5 hours after dosing. The geometric mean ratio (90%CI) comparing 2‐mg trametinib containing 9% DMSO with 2‐mg trametinib containing 11% DMSO for area under the concentration‐time curve from time 0 to the last measurable plasma concentration sampling time was 0.890 (0.848‐0.935), suggesting the 2 formulations have similar bioavailability. The majority of adverse events were mild, with 1 subject experiencing 1 grade 3 headache. These results indicated that storage of trametinib at room temperatures ≤25°C during the overall shelf life of 36 months would not negatively impact trametinib bioavailability.