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

• Published in: International journal of clinical pharmacology and therapeutics Vol. 60; no. 7; pp. 317 - 326
• Main Authors: Sahasrabudhe, Vaishali, Matschke, Kyle, Shi, Haihong, Hickman, Anne, Kong, Angela, Rodríguez Spong, Barbara, Nickerson, Beverly, Arora, Kapildev K
• Format: Journal Article
• Language: English
• Published: Germany Dustri - Verlag Dr. Karl Feistle GmbH & Co. KG 01.07.2022; Dustri-Verlag Dr. Karl Feistle
• Subjects: Bioavailability; Pharmacology
• DOI: 10.5414/CP204212
• ISSN: 0946-1965

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. 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. 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 AUC and C 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. 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.