Effect of Renal Impairment on the Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Ertugliflozin in Participants With Type 2 Diabetes Mellitus (MK-8835-009)

NCT01948986 | Completed Phase 1 Results FDA Drug

• 3 other identifiers: 8835-009B1521023MK-8835-009
• Study Type: interventional
• Target: 36
• Locations: 0 countries
• Sites: N/A

Brief Summary

This is a study to evaluate the effect of renal impairment on the pharmacokinetics, pharmacodynamics, safety and tolerability of ertugliflozin in participants with type 2 diabetes mellitus (T2DM) and in healthy participants with normal renal function.

Conditions

Renal Impairment; Type 2 Diabetes Mellitus

Outcome Measures

Primary Outcomes (29)

• Area Under the Plasma Concentration-Time Profile for Ertugliflozin From Time 0 Extrapolated to Infinite Time (AUCinf)

  Area under the plasma concentration-time profile from Time 0 extrapolated to infinite time. Blood samples were taken at pre-dose up to 96 hours post-dose, from which the concentration of ertugliflozin was determined. Geometric Coefficient of Variation was reported as a percent.

  Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose

• Area Under the Plasma Concentration-Time Profile for Ertugliflozin From Time 0 to the Time of the Last Quantifiable Concentration (AUClast)

  Area under the plasma concentration-time profile from Time 0 to the time of the last quantifiable concentration (Clast). Blood samples were taken at pre-dose up to 96 hours post-dose, from which the concentration of ertugliflozin was determined. Geometric Coefficient of Variation was reported as a percent.

  Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose

• Apparent Clearance (CL/F) for Plasma Ertugliflozin

  CL/F is a calculation of the rate at which a drug is removed from the body via renal, hepatic and other clearance pathways, expressed as volume (milliliters) per unit of time (minutes). Blood samples were taken at pre-dose up to 96 hours post-dose, from which the concentration of ertugliflozin was determined. Geometric Coefficient of Variation was reported as a percent.

  Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose

• Maximum Observed Plasma Concentration (Cmax) for Ertugliflozin

  Cmax is a measure of the maximum amount of drug in the plasma after the dose is given. Blood samples were taken at pre-dose up to 96 hours post-dose, from which the concentration of ertugliflozin was determined. Geometric Coefficient of Variation was reported as a percent.

  Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose

• Time for Cmax (Tmax) for Plasma Ertugliflozin

  Tmax is a measure of the time to reach the maximum concentration in the plasma after the drug dose and is observed directly from data as time of first occurrence. Blood samples were taken at pre-dose up to 96 hours post-dose, from which the concentration of ertugliflozin was determined.

  Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose

• Terminal Half-Life (t1/2) for Plasma Ertugliflozin

  T1/2 is the time required for a given drug concentration in the plasma to decrease by 50%. T1/2 = Loge(2)/kel, where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Blood samples were taken at pre-dose up to 96 hours post-dose, from which the concentration of ertugliflozin was determined.

  Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose

• Apparent Volume of Distribution Following Oral Administration (Vz/F) for Plasma Ertugliflozin

  VzF is the apparent volume of distribution during terminal phase after oral / extravascular administration. VzF = Dose/(AUCinf × kel) where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Blood samples were taken at pre-dose up to 96 hours post-dose, from which the concentration of ertugliflozin was determined. Geometric Coefficient of Variation was reported as a percent.

  Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose

• Unbound Fraction (Fu) for Plasma Ertugliflozin

  Fraction of unbound (not protein-bound) drug in plasma. Fu is determined using in vitro equilibrium dialysis method: concentration in buffer at equilibrium/concentration in plasma at equilibrium. Blood samples were taken at pre-dose up to 96 hours post-dose, from which the concentration of ertugliflozin was determined.

  Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose

• Cumulative Amount of Drug Recovered Unchanged in Urine to 96 Hours Post Dose (Ae96)

  Urine samples were taken at pre-dose up to 96 hours post-dose, from which the concentration of ertugliflozin was determined. Ae96 = Sum of \[urine concentration × sample volume\] for each collection interval from 0 to 96 hours post dose. Geometric Coefficient of Variation was reported as a percent.

  0-4, 4-8, 8-12, 12-24, 24-48, 48-72, and 72-96 hours after dosing on Day 1

• Percent of Dose Recovered Unchanged in Urine From 0 to 96 Hours Postdose (for Ertugliflozin Only) (Ae96%)

  Urine samples were taken at pre-dose up to 96 hours post-dose, from which the concentration of ertugliflozin was determined. Ae96% = Ae96 / Dose × 100 Ae96 = Sum of \[urine concentration × sample volume\] for each collection interval from 0 to 96 hours post dose. Geometric Coefficient of Variation was reported as a percent.

  0-4, 4-8, 8-12, 12-24, 24-48, 48-72, and 72-96 hours after dosing on Day 1

• Renal Clearance (CLr) for Urinary Ertugliflozin

  Urine samples were taken at pre-dose up to 96 hours post-dose, from which the concentration of ertugliflozin was determined. CLr is Renal Clearance (Ae96 / AUC96), where Ae96 is the cumulative amount of drug recovered unchanged in urine to 96 hours post dose and AUC96 was the area under the concentration-time profile form time 0 to 96 hours. Geometric Coefficient of Variation was reported as a percent.

  0-4, 4-8, 8-12, 12-24, 24-48, 48-72, and 72-96 hours after dosing on Day 1

• Number of Participants Who Experienced an Adverse Event (AE)

  An adverse event (AE) is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study.

  Up to 19 days

• Number of Participants Who Discontinued Study Due to an AE

  An adverse event (AE) is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study.

  Up to 5 days

• Area Under the Plasma Concentration-Time Profile for Glucuronide Metabolite PF-06481944 From Time 0 Extrapolated to Infinite Time (AUCinf)

  Area under the plasma concentration-time profile from Time 0 extrapolated to infinite time. Blood samples were taken at pre-dose up to 96 hours post-dose, from which the concentration of glucuronide metabolite PF 06481944 was determined. Geometric Coefficient of Variation was reported as a percent.

  Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose

• Area Under the Plasma Concentration-Time Profile for Glucuronide Metabolite PF-06481944 From Time 0 to the Time of the Last Quantifiable Concentration (AUClast)

  Area under the plasma concentration-time profile from Time 0 to the time of the last quantifiable concentration (Clast). Blood samples were taken at pre-dose up to 96 hours post-dose, from which the concentration of glucuronide metabolite PF 06481944 was determined. Geometric Coefficient of Variation was reported as a percent.

  Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose

• Maximum Observed Plasma Concentration (Cmax) for Glucuronide Metabolite PF-06481944

  Cmax is a measure of the maximum amount of drug in the plasma after the dose is given. Blood samples were taken at pre-dose up to 96 hours post-dose, from which the concentration of glucuronide metabolite PF 06481944 was determined. Geometric Coefficient of Variation was reported as a percent.

  Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose

• Time for Cmax (Tmax) for Plasma Glucuronide Metabolite PF-06481944

  Tmax is a measure of the time to reach the maximum concentration in the plasma after the drug dose and is observed directly from data as time of first occurrence. Blood samples were taken at pre-dose up to 96 hours post-dose, from which the concentration of glucuronide metabolite PF 06481944 was determined.

  Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose

• Terminal Half-life (t1/2) for Plasma Glucuronide Metabolite PF-06481944

  T1/2 is the time required for a given drug concentration in the plasma to decrease by 50%. T1/2 = Loge(2)/kel, where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Blood samples were taken at pre-dose up to 96 hours post-dose, from which the concentration of glucuronide metabolite PF 06481944 was determined.

  Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose

• Cumulative Amount of Drug Recovered Unchanged in Urine to 96 Hours Post Dose (Ae96) for Glucuronide Metabolite PF-06481944

  Urine samples were taken at pre-dose up to 96 hours post-dose, from which the concentration of ertugliflozin was determined. Ae96 = Sum of \[urine concentration × sample volume\] for each collection interval from 0 to 96 hours post dose. Geometric Coefficient of Variation was reported as a percent.

  0-4, 4-8, 8-12, 12-24, 24-48, 48-72, and 72-96 hours after dosing on Day 1

• CLr for Urinary Glucuronide Metabolite PF-06481944

  Urine samples were taken at pre-dose up to 96 hours post-dose, from which the concentration of ertugliflozin was determined. CLr is Renal Clearance (Ae96 / AUC96), where Ae96 is the cumulative amount of drug recovered unchanged in urine to 96 hours post dose and AUC96 was the area under the concentration-time profile form time 0 to 96 hours. Geometric Coefficient of Variation was reported as a percent.

  0-4, 4-8, 8-12, 12-24, 24-48, 48-72, and 72-96 hours after dosing on Day 1

• Area Under the Plasma Concentration-Time Profile for Glucuronide Metabolite PF-06685948 From Time 0 Extrapolated to Infinite Time (AUCinf)

  Area under the plasma concentration-time profile from Time 0 extrapolated to infinite time. Blood samples were taken at pre-dose up to 96 hours post-dose, from which the concentration of glucuronide metabolite PF-06685948 was determined. Geometric Coefficient of Variation was reported as a percent.

  Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose

• Area Under the Plasma Concentration-Time Profile for Glucuronide Metabolite PF-06685948 From Time 0 to the Time of the Last Quantifiable Concentration (AUClast)

  Area under the plasma concentration-time profile from Time 0 to the time of the last quantifiable concentration (Clast). Blood samples were taken at pre-dose up to 96 hours post-dose, from which the concentration of glucuronide metabolite PF-06685948 was determined. Geometric Coefficient of Variation was reported as a percent.

  Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose

• Maximum Observed Plasma Concentration (Cmax) for Glucuronide Metabolite PF-06685948

  Cmax is a measure of the maximum amount of drug in the plasma after the dose is given. Blood samples were taken at pre-dose up to 96 hours post-dose, from which the concentration of glucuronide metabolite PF-06685948 was determined. Geometric Coefficient of Variation was reported as a percent.

  Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose

• Time for Cmax (Tmax) for Plasma Glucuronide Metabolite PF-06685948

  Tmax is a measure of the time to reach the maximum concentration in the plasma after the drug dose and is observed directly from data as time of first occurrence. Blood samples were taken at pre-dose up to 96 hours post-dose, from which the concentration of glucuronide metabolite PF-06685948 was determined.

  Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose

• Terminal Half-life (t1/2) for Plasma Glucuronide Metabolite PF-06685948

  T1/2 is the time required for a given drug concentration in the plasma to decrease by 50%. T1/2 = Loge(2)/kel, where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Blood samples were taken at pre-dose up to 96 hours post-dose, from which the concentration of glucuronide metabolite PF-06685948 was determined.

  Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose

• Cumulative Amount of Drug Recovered Unchanged in Urine to 96 Hours Post Dose (Ae96) for Glucuronide Metabolite PF-06685948

  Urine samples were taken at pre-dose up to 96 hours post-dose, from which the concentration of ertugliflozin was determined. Ae96 = Sum of \[urine concentration × sample volume\] for each collection interval from 0 to 96 hours post dose. Blood samples were taken at pre-dose up to 96 hours post-dose, from which the concentration of glucuronide metabolite PF-06685948 was determined. Geometric Coefficient of Variation was reported as a percent.

  0-4, 4-8, 8-12, 12-24, 24-48, 48-72, and 72-96 hours after dosing on Day 1

• Renal Clearance (CLr) for Urinary Glucuronide Metabolite PF-06685948

  Urine samples were taken at pre-dose up to 96 hours post-dose, from which the concentration of ertugliflozin was determined. CLr is Renal Clearance (Ae96 / AUC96), where Ae96 is the cumulative amount of drug recovered unchanged in urine to 96 hours post dose and AUC96 was the area under the concentration-time profile form time 0 to 96 hours. Blood samples were taken at pre-dose up to 96 hours post-dose, from which the concentration of glucuronide metabolite PF-06685948 was determined. Geometric Coefficient of Variation was reported as a percent.

  0-4, 4-8, 8-12, 12-24, 24-48, 48-72, and 72-96 hours after dosing on Day 1

• Change From Baseline in 24 Hour Inhibition of Glucose Reabsorption

  Inhibition of Glucose Reabsorption = 100 \* urinary glucose excretion / (eGFR(ML/MIN) \* Weighted Mean Plasma Glucose \* 0.0144). 0.0144 is a unit conversion factor used to make the ratio unitless. Geometric Coefficient of Variation was reported as a percent.

  Baseline and 24 Hours

• Change From Baseline in 24 Hour Fluid Balance

  Fluid balance = fluid intake - urine output.

  For 24 hours before Baseline (-48 to -24 hours) and up to 24 hours after dosing on Day 1 (Up to 24 hours)

Secondary Outcomes (1)

• Urinary Glucose Excretion Over 24 Hours (UGE0-24hr) for Ertugliflozin

  0-4, 4-8, 8-12, 12-24 hours after dosing on Day 1

Study Arms (5)

Ertugliflozin 15 mg (T2DM with Normal Renal Function)

EXPERIMENTAL

Ertugliflozin (15 mg), oral, administered in participants with T2DM and with normal renal function

Drug: Ertugliflozin

Ertugliflozin 15 mg (T2DM with Mild Renal Impairment)

EXPERIMENTAL

Ertugliflozin (15 mg), oral, administered in participants with T2DM and with mild renal impairment

Drug: Ertugliflozin

Ertugliflozin 15 mg (T2DM with Moderate Renal Impairment)

EXPERIMENTAL

Ertugliflozin (15 mg), oral, administered in participants with T2DM and with moderate renal impairment

Drug: Ertugliflozin

Ertugliflozin 15 mg (T2DM with Severe Renal Impairment)

EXPERIMENTAL

Ertugliflozin (15 mg), oral, administered in participants with T2DM and with severe renal impairment

Drug: Ertugliflozin

Ertugliflozin, 15 mg (Healthy Part. with Normal Renal Funct.)

EXPERIMENTAL

Ertugliflozin (15 mg), oral, administered in participants with healthy participants and with normal renal function

Drug: Ertugliflozin

Interventions

Ertugliflozin DRUG

Single oral administration of 3 X 5 mg tablets.

Also known as: MK-8835

Ertugliflozin 15 mg (T2DM with Mild Renal Impairment); Ertugliflozin 15 mg (T2DM with Moderate Renal Impairment); Ertugliflozin 15 mg (T2DM with Normal Renal Function); Ertugliflozin 15 mg (T2DM with Severe Renal Impairment); Ertugliflozin, 15 mg (Healthy Part. with Normal Renal Funct.)

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Body Mass Index (BMI) of approximately 18 to 40 kg/m\^2
• Stable renal function
• Male or female not of reproductive potential
• Female of reproductive potential must agree or have their partner agree to use 2 acceptable methods of contraception
• Healthy subjects determined to be healthy by investigator screening
• T2DM participants have a diagnosis of T2DM as per American Diabetes Association guidelines
• T2DM participants to be on a stable anti-hyperglycemic regimen with no new drug or drug dosage within 8 weeks of study participation. Variations in daily dose of insulin up to 10% are permitted.

You may not qualify if:

• A positive urine drug screen for drugs of abuse or recreational drugs
• Pregnant or nursing females
• History of abuse of alcohol or illicit drugs
• Significant renal or urinary disease within 6 months of study participation
• History of malignancy within the past 5 years basal cell carcinoma of the skin or cervical cancer in situ
• History of human immunodeficiency virus (HIV)
• History of blood dyscrasias or any disorders causing hemolysis or unstable red blood cells
• Any acute disease state (eg, , vomiting, fever, diarrhea) within 7 days before study participation
• Treatment with an investigational drug within 30 days of study participation
• Use of herbal supplements within 28 days prior to study participation
• Any clinically significant malabsorption condition
• Blood donation (excluding plasma donations) of approximately 1 pint within 56 days prior to study participation
• History of sensitivity to ertugliflozin or other Sodium-Glucose co-Transporter 2 (SGLT2) inhibitors
• History of sensitivity to heparin or heparin-induced thrombocytopenia
• Unwilling or unable to comply with the study Lifestyle Guidelines

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead
• Pfizer: collaborator

Related Publications (3)

• Sahasrabudhe V, Terra SG, Hickman A, Saur D, Shi H, O'Gorman M, Zhou Z, Cutler DL. The Effect of Renal Impairment on the Pharmacokinetics and Pharmacodynamics of Ertugliflozin in Subjects With Type 2 Diabetes Mellitus. J Clin Pharmacol. 2017 Nov;57(11):1432-1443. doi: 10.1002/jcph.955. Epub 2017 Jul 13.

  PMID: 28703316 RESULT

• Fediuk DJ, Sahasrabudhe V, Dawra VK, Zhou S, Sweeney K. Population Pharmacokinetic Analyses of Ertugliflozin in Select Ethnic Populations. Clin Pharmacol Drug Dev. 2021 Nov;10(11):1297-1306. doi: 10.1002/cpdd.970. Epub 2021 Jul 2.

  PMID: 34213819 DERIVED

• Marshall JC, Liang Y, Sahasrabudhe V, Tensfeldt T, Fediuk DJ, Zhou S, Krishna R, Dawra VK, Wood LS, Sweeney K. Meta-Analysis of Noncompartmental Pharmacokinetic Parameters of Ertugliflozin to Evaluate Dose Proportionality and UGT1A9 Polymorphism Effect on Exposure. J Clin Pharmacol. 2021 Sep;61(9):1220-1231. doi: 10.1002/jcph.1866. Epub 2021 Jun 19.

  PMID: 33813736 DERIVED

MeSH Terms

Conditions

Renal Insufficiency; Diabetes Mellitus, Type 2

Interventions

ertugliflozin

Condition Hierarchy (Ancestors)

Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 20, 2013
• First Posted: September 24, 2013
• Study Start: October 1, 2013
• Primary Completion: October 6, 2014
• Study Completion: October 16, 2014
• Last Updated: February 18, 2019
• Results First Posted: February 18, 2019

Record last verified: 2018-10

Data Sharing

• IPD Sharing: Will share