Bioequivalence of Ertugliflozin/Metformin Fixed‐Dose Combination Tablets and Coadministration of Respective Strengths of Individual Components

Abstract

A fixed-dose combination (FDC) of ertugliflozin, a selective sodium-glucose cotransporter 2 inhibitor, and immediaterelease metformin is approved for the treatment of type 2 diabetes mellitus in the United States and European Union. Four open-label, randomized, 2-period, single-dose, crossover studies were conducted under fasted conditions in healthy subjects to demonstrate bioequivalence of the ertugliflozin/metformin FDC tablets and coadministration of the individual components at respective strengths. In each study, 32 or 34 subjects received an ertugliflozin/metformin FDC tablet (2.5 mg/500 mg, 7.5 mg/850 mg, or 7.5 mg/1000 mg) and the respective doses of individual components (ertugliflozin with US-or EU-sourced metformin [Glucophage]). Plasma samples for ertugliflozin and metformin concentrations were collected for 72 hours in each period. For both ertugliflozin and metformin, the 90% confidence intervals for the adjusted geometric mean ratio (FDC : coadministration) for area under the plasma concentration-time profile from time zero extrapolated to infinity and maximum observed plasma concentration were within acceptance criteria for bioequivalence. The majority of adverse events were mild in intensity. The studies demonstrated that each strength of FDC tablet is bioequivalent to respective doses of coadministered individual components, supporting that safety and efficacy can be bridged to the individual components used in phase 3 studies evaluating ertugliflozin in combination with metformin.

Bioequivalence of Metformin in Ertugliflozin/Metformin Fixed‐Dose Combination Tablets to Canadian‐Sourced Metformin Coadministered With Ertugliflozin Under Fasted and Fed States

“…Estimates for the adjusted (least-squares) mean differences and 90% confidence intervals (CIs) and estimates of the ratio of adjusted geometric means (test:reference [FDC:coadministered]) and 90%CI for the ratio were obtained using previously described methods. 28 For each FDC strength, the FDC tablet will be considered bioequivalent to coadministration if the 90%CIs for the geometric mean ratios (GMRs) for metformin AUC last and C max fell within 80% and 125%. PK parameters were calculated using electronic noncompartmental analysis (eNCA, version 2.2.4), a Pfizer internally validated software.…”

“…In addition, multimedia dissolution tests showed that both FDC tablets (2.5/500 or 7.5/850 mg) dissolved rapidly, showing > 85% release in 15 minutes. 28 Therefore, both strengths of the ertugliflozin/metformin FDC tablets (2.5/500 and 7.5/850 mg) can be considered bioequivalent to the respective strengths of ertugliflozin and metformin when coadministered.…”

“…Consequently, 2.5 and 7.5 mg twice-daily doses of ertugliflozin, which is half the approved oncedaily doses, were used for the FDC formulation. To bridge phase 3 efficacy and safety data of ertugliflozin and metformin 7 with the FDC tablet formulation, 4 28 Here we report 2 additional phase 1 randomized, open-label, 2-period, 2-sequence, single-dose crossover studies in healthy participants to assess the bioequivalence of the metformin component in the ertugliflozin/metformin FDC tablets at doses of 2.5/500 or 7.5/850 mg compared with the respective doses of Canadian-sourced metformin (Glucophage)hereafter, referred to as metformin coadministered with ertugliflozin. As metformin has nonlinear PK with saturable absorption and dose-dependent absolute bioavailability that decreases with increasing dose, 25 the bioequivalence studies were conducted with the lower 2 doses of metformin (500 and 850 mg) in both fed and fasted conditions as per Health Canada guidance.…”

“…Consequently, 2.5 and 7.5 mg twice‐daily doses of ertugliflozin, which is half the approved once‐daily doses, were used for the FDC formulation. To bridge phase 3 efficacy and safety data of ertugliflozin and metformin 7 with the FDC tablet formulation, 4 crossover phase 1 single‐dose studies that were randomized and open‐label with 2 periods and 2 sequences were conducted in healthy participants in the fasted state and demonstrated the bioequivalence of ertugliflozin and metformin in the ertugliflozin/metformin FDC tablets at doses of 2.5/500, 7.5/850, or 7.5/1000 mg to the corresponding doses of the individual components (United States‐ or European Union‐sourced metformin [Glucophage]) when coadministered with ertugliflozin 2 . 8…”

“…As a 1000‐mg strength of the reference metformin product is not available in Canada, a bioequivalence study for the FDC containing 1000 of mg metformin was not conducted. Bioequivalence of the ertugliflozin component was not evaluated in these studies, as bioequivalence of ertugliflozin in the ertugliflozin/metformin FDC has already been established at 2.5‐ and 7.5‐mg doses of ertugliflozin when coadministered with either 500, 850, or 1000 mg metformin 28 . Ertugliflozin also meets requirements for biowaiver as a BCS class I drug.…”