Effect of Food on the Pharmacokinetics of Ertugliflozin and Its Fixed‐Dose Combinations Ertugliflozin/Sitagliptin and Ertugliflozin/Metformin

Abstract

Ertugliflozin, an inhibitor of sodium‐glucose cotransporter 2, is approved in the United States and European Union for the treatment of type 2 diabetes in adults, both as monotherapy and as part of fixed‐dose combination (FDC) therapies with either sitagliptin or immediate‐release metformin. The effect of a standard, high‐fat breakfast on the pharmacokinetics of the highest strengths of ertugliflozin monotherapy (15 mg), ertugliflozin/sitagliptin FDC (15‐/100‐mg), and ertugliflozin/metformin FDC (7.5‐/1000‐mg) tablets was evaluated. In 3 separate open‐label, 2‐period, 2‐sequence, single‐dose, crossover studies, 14 healthy subjects per study were randomized to receive either ertugliflozin monotherapy or FDC tablets comprising ertugliflozin and sitagliptin or ertugliflozin and metformin under fasted and fed (or vice versa) conditions. Food did not meaningfully affect the pharmacokinetics of ertugliflozin, sitagliptin, or metformin. For FDCs, the effect of food was consistent with that described for individual components. All treatments were well tolerated. Ertugliflozin and ertugliflozin/sitagliptin FDC tablets can be administered without regard to meals. As metformin is administered with meals because of its gastrointestinal side effects, the ertugliflozin/metformin FDC should also be administered with meals.

A Phase 1, Randomized, Placebo‐ and Active‐Controlled Crossover Study to Determine the Effect of Single‐Dose Ertugliflozin on QTc Interval in Healthy Volunteers

“…Log‐linear regression analyses suggested that mean area under the plasma concentration‐time profile (AUC) values for patients with renal impairment were ≤70% higher compared with those in subjects with normal renal function, although this increase in exposure is not expected to be clinically meaningful . A 2‐period, single‐dose crossover phase 1 study demonstrated that there is no effect of food on the pharmacokinetics of ertugliflozin in healthy volunteers and that ertugliflozin 15 mg can be administered without regard to meal consumption . The potential for ertugliflozin to be a victim or perpetrator of clinically meaningful drug interactions is low: a number of phase 1 studies have shown that there is no clinically relevant drug‐drug interaction between ertugliflozin and metformin, sitagliptin, glimepiride, simvastatin, or rifampin…”

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

“…45 Indeed, a recent study has shown that ertugliflozin 15 mg and sitagliptin 100 mg FDC tablets can be administered without regard to meals. 6 Bioequivalence was demonstrated for the 4 assessed strengths of ertugliflozin/sitagliptin FDC tablet and the individual components: for both ertugliflozin and sitagliptin, the 90%CIs for the ratios (FDC/ coadministration) of geometric means for AUC inf and C max were within the acceptance criteria for bioequivalence (80% to 125%). Although caution should be taken when drawing conclusions regarding the general clinical applicability of data from single-dose studies in healthy volunteers, all treatment combinations of ertugliflozin and sitagliptin (FDC or when coadministered) were well tolerated: no serious AEs, severe AEs, or temporary or permanent discontinuations due to AEs were observed in any of the 4 single-dose studies.…”

“…Because both agents are Biopharmaceutical Classification System class 1 compounds, a clinically meaningful food effect on exposure is unlikely due to their high solubility and permeability . Indeed, a recent study has shown that ertugliflozin 15 mg and sitagliptin 100 mg FDC tablets can be administered without regard to meals …”

“…SGLT2 inhibitors reduce renal glucose reabsorption and lower the renal threshold for glucose excretion, thereby increasing urinary glucose excretion and reducing plasma glucose and glycated hemoglobin (A 1c ) . Oral absorption of ertugliflozin is rapid, with median time to maximum plasma concentration (T max ) occurring at ∼1 hour postdose in the fasted state and at ∼2 hours postdose in the fed state . The area under the plasma concentration‐time curve (AUC) for ertugliflozin increases in a dose‐proportional manner over the dose range of 0.5 to 300 mg …”

“…4,5 Oral absorption of ertugliflozin is rapid, with median time to maximum plasma concentration (T max ) occurring at ß1 hour postdose in the fasted state and at ß2 hours postdose in the fed state. 6 The area under the plasma concentration-time curve (AUC) for ertugliflozin increases in a dose-proportional manner over the dose range of 0.5 to 300 mg. 7 Absolute bioavailability of ertugliflozin is ß100%. 8 The terminal-phase half-life (t ½ ) is in the range of 11 to 17 hours.…”