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

Sahasrabudhe, Vaishali; Saur, Didier; Matschke, Kyle; Terra, Steven G.; Hickman, Anne; Huyghe, Isabelle; Shi, Huidong; Cutler, David L.

doi:10.1002/cpdd.421

Cited by 14 publications

(14 citation statements)

References 20 publications

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“…This phase 1 study enrolled healthy subjects and evaluated the PK of ertugliflozin. The PK findings reported here in Chinese subjects residing in China are comparable with those observed in other populations [15][16][17][18][19][20][21][22] and are supported by results from a recently conducted phase 3 study exploring the efficacy and safety of ertugliflozin in Asian patients with T2DM. 32 This longer-term study (with the same ertugliflozin doses of 5 mg and 15 mg assessed in the current phase 1 study) demonstrated that ertugliflozin improved glycemic control and reduced body weight and systolic blood pressure in Asian patients with T2DM inadequately controlled on metformin monotherapy, including Chinese patients from mainland China.…”

Section: Discussionsupporting

confidence: 88%

“…19 The terminal elimination half-life (t ½ ) of ertugliflozin ranges from 11 to 17 hours. 5,6,[15][16][17][18][19][20][21][22] The PK of ertugliflozin are similar in healthy subjects and in patients with T2DM. 20 The major clearance pathway of ertugliflozin is metabolism via glucuronidation (86%) with minor contribution from oxidative metabolism (12%).…”

mentioning

confidence: 96%

“…[7][8][9][10][11][12][13][14] Ertugliflozin is rapidly absorbed following oral administration, with maximal plasma concentration (C max ) occurring after approximately 1 hour when administered in the fasted state. 6,[15][16][17][18][19] The absolute bioavailability of ertugliflozin is approximately 100% 15 ; its exposure increases in a dose-proportional manner over a dose range of 0.5 to 300 mg 5,6 ; and administration with food does not have a clinically meaningful effect on pharmacokinetics (PK). 19 The terminal elimination half-life (t ½ ) of ertugliflozin ranges from 11 to 17 hours.…”

mentioning

confidence: 99%

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Pharmacokinetic Properties of Single and Multiple Doses of Ertugliflozin, a Selective Inhibitor of SGLT2, in Healthy Chinese Subjects

Shi

et al. 2019

Clinical Pharm in Drug Dev

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Ertugliflozin, a sodium-glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus, prevents renal glucose reabsorption resulting in urinary glucose excretion. This open-label, parallel cohort, randomized study conducted in healthy Chinese adults residing in China assessed the pharmacokinetics, tolerability, and safety of 5 mg and 15 mg of ertugliflozin following single (fasted condition) and multiple-dose (fed condition) administration. Sixteen subjects were randomized and completed the study. Ertugliflozin absorption was rapid, with maximum plasma concentrations observed 1 hour after dosing under fasted conditions and 2 to 4 hours after dosing under fed conditions. Following single-and multiple-dose administration, ertugliflozin exhibited dose-proportional exposures with an apparent mean terminal halflife of approximately 9.5 to 11.9 hours. Steady state was reached after 4 once-daily doses. The accumulation ratio based on the area under the plasma concentration-time curve after multiple-dose administration was approximately 1.3 and 1.2 for ertugliflozin 5 mg and 15 mg, respectively. Ertugliflozin was generally well tolerated following administration of single and multiple oral doses of 5 mg and 15 mg in healthy Chinese subjects. Pharmacokinetic comparison with non-Asian subjects indicated that there are no clinically meaningful racial differences and no dose modification of ertugliflozin is required based on race or body weight.

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Section: Discussionsupporting

confidence: 88%

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confidence: 96%

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confidence: 99%

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Pharmacokinetic Properties of Single and Multiple Doses of Ertugliflozin, a Selective Inhibitor of SGLT2, in Healthy Chinese Subjects

Shi

et al. 2019

Clinical Pharm in Drug Dev

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“…To evaluate the potential effects of a supratherapeutic dose of ertugliflozin on prolongation of the cardiac QT interval, a randomized, three-treatment, six-sequence, three-period, crossover, placebo-and active-controlled study was conducted in 42 healthy subjects where fasted subjects received a single oral dose of ertugliflozin 100 mg (~ 6.7-fold greater than the highest ertugliflozin dose of 15 mg used in phase III studies), moxifloxacin 400 mg as a positive control, or placebo [45]. Following treatment with ertugliflozin, the maximum least squares mean (90% CI) difference in QT interval corrected for heart rate (QTc) using the Fridericia correction (QTcF) observed between ertugliflozin and placebo was 2.99 ms, which was less than the threshold of potential clinical concern of 5 ms.…”

Section: Thorough Qtc Studymentioning

confidence: 99%

Overview of the Clinical Pharmacology of Ertugliflozin, a Novel Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor

et al. 2020

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Ertugliflozin, a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), is approved in the US, EU, and other regions for the treatment of adults with type 2 diabetes mellitus (T2DM). This review summarizes the ertugliflozin pharmacokinetic (PK) and pharmacodynamic data obtained during phase I clinical development, which supported the registration and labeling of this drug. The PK of ertugliflozin was similar in healthy subjects and patients with T2DM. Oral absorption was rapid, with time to peak plasma concentrations (T max) occurring at 1 h (fasted) and 2 h (fed) postdose. The terminal phase half-life ranged from 11 to 18 h and steady-state concentrations were achieved by 6 days after initiating once-daily dosing. Ertugliflozin exposure increased in a dose-proportional manner over the tested dose range of 0.5-300 mg. Ertugliflozin is categorized as a Biopharmaceutical Classification System Class I drug with an absolute bioavailability of ~ 100% under fasted conditions. Administration of the ertugliflozin 15 mg commercial tablet with food resulted in no meaningful effect on ertugliflozin area under the plasma concentration-time curve (AUC), but decreased peak concentrations (C max) by 29%. The effect on C max is not clinically relevant and ertugliflozin can be administered without regard to food. Mild, moderate, and severe renal impairment were associated with a ≤ 70% increase in ertugliflozin exposure relative to subjects with normal renal function, and no dose adjustment in renal impairment patients is needed based on PK results. Consistent with the mechanism of action of SGLT2 inhibitors, 24-h urinary glucose excretion decreased with worsening renal function. In subjects with moderate hepatic impairment, a decrease in AUC (13%) relative to subjects with normal hepatic function was observed and not considered clinically relevant. Concomitant administration of metformin, sitagliptin, glimepiride, or simvastatin with ertugliflozin did not have clinically meaningful effects on the PK of ertugliflozin or the coadministered medications. Coadministration of rifampin decreased ertugliflozin AUC and C max by 39% and 15%, respectively, and is not expected to affect efficacy in a clinically meaningful manner. This comprehensive evaluation supports administration to patients with T2DM without regard to prandial status and with no dose adjustments for coadministration with commonly prescribed drugs, or in patients with renal impairment or mild-to-moderate hepatic impairment based on ertugliflozin PK.

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“…Detailed methodology for the ertugliflozin and metformin assay procedures have been previously published. 9,23 The following plasma ertugliflozin and metformin PK parameters were calculated for each subject for each treatment using noncompartmental analysis of plasma concentration-time data: C max , t max , area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration (AUC last ), AUC inf , and t 1/2 . Samples below the LLOQ were set to zero for analysis.…”

Section: Pharmacokinetic Sample Assessmentsmentioning

confidence: 99%

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

Fediuk

Matschke

Liang

et al. 2019

Clinical Pharm in Drug Dev

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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.

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

Cited by 14 publications

References 20 publications

Pharmacokinetic Properties of Single and Multiple Doses of Ertugliflozin, a Selective Inhibitor of SGLT2, in Healthy Chinese Subjects

Pharmacokinetic Properties of Single and Multiple Doses of Ertugliflozin, a Selective Inhibitor of SGLT2, in Healthy Chinese Subjects

Overview of the Clinical Pharmacology of Ertugliflozin, a Novel Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor

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

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