Relative bioavailability of ertugliflozin tablets containing the amorphous form versus tablets containing the cocrystal form

Abstract

Objectives: Ertugliflozin is a selective sodium-glucose cotransporter 2 inhibitor approved for the treatment of type 2 diabetes in adults. In its natural form, ertugliflozin exists as an amorphous solid with physicochemical properties that prevent commercial manufacture. The commercial product was developed as an immediate-release tablet, consisting of an ertugliflozin-L-pyroglutamic acid cocrystal of 1 : 1 molar stoichiometry as the active pharmaceutical ingredient. The ertugliflozin cocrystal may partially dissociate when exposed to high humidity for extended periods, leading to the formation of free amorphous ertugliflozin. Therefore, a study was conducted to estimate the relative bioavailability of ertugliflozin when administered in non-commercial formulated tablets containing the amorphous form vs. the cocrystal form. Materials and methods: In this phase 1, open-label, randomized, two-period, two-sequence, single-dose crossover study, 16 healthy subjects received 15 mg immediate-release ertugliflozin in its amorphous and cocrystal forms under fasted conditions, separated by a washout period of ≥ 7 days. Blood samples were collected post-dose for 72 hours to determine plasma ertugliflozin concentrations. Results: Mean ertugliflozin plasma concentration-time profiles were nearly superimposable following administration of the amorphous and cocrystal forms. The 90% confidence intervals for the geometric mean ratios for AUCinf and Cmax were wholly contained within the pre-specified criteria for similarity (70 – 143%), as well as the acceptance range for bioequivalence (80 – 125%). Most adverse events were mild in intensity. Conclusion: Any dissociation of ertugliflozin to the amorphous form that occurs in tablets containing the cocrystal will not have any clinically meaningful impact on the oral bioavailability of ertugliflozin.