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

Primary Purpose

Renal Impairment, Type 2 Diabetes Mellitus

Status
Completed
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
Ertugliflozin
Sponsored by
Merck Sharp & Dohme LLC
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Renal Impairment

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • 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
  • Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease including clinically relevant and significant drug allergies
  • Use of prescription drugs (hormonal methods of birth control are allowed), vitamins and dietary supplements within 7 days of study participation
  • For T2DM participants, history of type 1 diabetes mellitus or a history of ketoacidosis
  • For T2DM participants, clinically significant electrocardiogram abnormality
  • For T2DM participants, history of myocardial infarction, unstable angina, coronary revascularization, stroke or transient ischemic attack within 3 months of study participation
  • For T2DM participants, heart failure defined as New York Heart Association Functional Class III-IV
  • For T2DM participants, renal allograft recipients
  • For T2DM participants, requiring dialysis
  • For T2DM participants, strict fluid restriction
  • For T2DM participants, urinary incontinence
  • For T2DM participants, acute renal disease
  • For T2DM participants, significant hepatic, cardiac, or pulmonary disease or clinically nephrotic
  • For T2DM participants, prescription and over-the-counter medication that is not taken according to a stable regimen for 7 days before study participation
  • For T2DM participants, on metformin should not be enrolled if their baseline renal function is outside the approved product labeling
  • For T2DM participants receiving any of the following medications within 7 days of study participation: 1. Other SGLT2 inhibitors (eg, dapagliflozin, canagliflozin, empagliflozin); 2. Other injectable anti-hyperglycemic agents including pramlintide or Glucagon-like peptide-1 (GLP-1) analogues; 3. Any immunosuppressive drugs, including cyclosporine, tacrolimus, sirolimus; 4. Oral corticosteroids (note that inhaled, nasal and topical corticosteroids are permitted); 5. Any potent drug-metabolizing enzyme-inducing drug, including rifampin, phenytoin, and carbamazepine; 6. Probenecid, valproic acid, gemfibrozil.

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm 3

    Arm 4

    Arm 5

    Arm Type

    Experimental

    Experimental

    Experimental

    Experimental

    Experimental

    Arm Label

    Ertugliflozin 15 mg (T2DM with Normal Renal Function)

    Ertugliflozin 15 mg (T2DM with Mild Renal Impairment)

    Ertugliflozin 15 mg (T2DM with Moderate Renal Impairment)

    Ertugliflozin 15 mg (T2DM with Severe Renal Impairment)

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

    Arm Description

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

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

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

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

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

    Outcomes

    Primary Outcome Measures

    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.
    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.
    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.
    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 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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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 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.
    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.
    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.
    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.
    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.
    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.
    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 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.
    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.
    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.
    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.
    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.
    Change From Baseline in 24 Hour Fluid Balance
    Fluid balance = fluid intake - urine output.

    Secondary Outcome Measures

    Urinary Glucose Excretion Over 24 Hours (UGE0-24hr) for Ertugliflozin
    Participants were asked to void at the end of each prescribed interval with forced voids prior to start and at the end of each interval.

    Full Information

    First Posted
    September 20, 2013
    Last Updated
    October 11, 2018
    Sponsor
    Merck Sharp & Dohme LLC
    Collaborators
    Pfizer
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    1. Study Identification

    Unique Protocol Identification Number
    NCT01948986
    Brief Title
    Effect of Renal Impairment on the Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Ertugliflozin in Participants With Type 2 Diabetes Mellitus (MK-8835-009)
    Official Title
    A Phase 1, Non-Randomized, Open-Label, Single Dose Study to Evaluate the Effect of Renal Impairment on the Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Ertugliflozin in Subjects With Type 2 Diabetes Mellitus
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    October 2018
    Overall Recruitment Status
    Completed
    Study Start Date
    October 1, 2013 (Actual)
    Primary Completion Date
    October 6, 2014 (Actual)
    Study Completion Date
    October 16, 2014 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Merck Sharp & Dohme LLC
    Collaborators
    Pfizer

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    Yes
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    No

    5. Study Description

    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.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Renal Impairment, Type 2 Diabetes Mellitus

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 1
    Interventional Study Model
    Parallel Assignment
    Masking
    None (Open Label)
    Allocation
    Non-Randomized
    Enrollment
    36 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Ertugliflozin 15 mg (T2DM with Normal Renal Function)
    Arm Type
    Experimental
    Arm Description
    Ertugliflozin (15 mg), oral, administered in participants with T2DM and with normal renal function
    Arm Title
    Ertugliflozin 15 mg (T2DM with Mild Renal Impairment)
    Arm Type
    Experimental
    Arm Description
    Ertugliflozin (15 mg), oral, administered in participants with T2DM and with mild renal impairment
    Arm Title
    Ertugliflozin 15 mg (T2DM with Moderate Renal Impairment)
    Arm Type
    Experimental
    Arm Description
    Ertugliflozin (15 mg), oral, administered in participants with T2DM and with moderate renal impairment
    Arm Title
    Ertugliflozin 15 mg (T2DM with Severe Renal Impairment)
    Arm Type
    Experimental
    Arm Description
    Ertugliflozin (15 mg), oral, administered in participants with T2DM and with severe renal impairment
    Arm Title
    Ertugliflozin, 15 mg (Healthy Part. with Normal Renal Funct.)
    Arm Type
    Experimental
    Arm Description
    Ertugliflozin (15 mg), oral, administered in participants with healthy participants and with normal renal function
    Intervention Type
    Drug
    Intervention Name(s)
    Ertugliflozin
    Other Intervention Name(s)
    MK-8835
    Intervention Description
    Single oral administration of 3 X 5 mg tablets.
    Primary Outcome Measure Information:
    Title
    Area Under the Plasma Concentration-Time Profile for Ertugliflozin From Time 0 Extrapolated to Infinite Time (AUCinf)
    Description
    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 Frame
    Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose
    Title
    Area Under the Plasma Concentration-Time Profile for Ertugliflozin From Time 0 to the Time of the Last Quantifiable Concentration (AUClast)
    Description
    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 Frame
    Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose
    Title
    Apparent Clearance (CL/F) for Plasma Ertugliflozin
    Description
    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 Frame
    Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose
    Title
    Maximum Observed Plasma Concentration (Cmax) for Ertugliflozin
    Description
    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 Frame
    Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose
    Title
    Time for Cmax (Tmax) for Plasma Ertugliflozin
    Description
    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 Frame
    Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose
    Title
    Terminal Half-Life (t1/2) for Plasma Ertugliflozin
    Description
    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 Frame
    Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose
    Title
    Apparent Volume of Distribution Following Oral Administration (Vz/F) for Plasma Ertugliflozin
    Description
    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 Frame
    Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose
    Title
    Unbound Fraction (Fu) for Plasma Ertugliflozin
    Description
    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 Frame
    Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose
    Title
    Cumulative Amount of Drug Recovered Unchanged in Urine to 96 Hours Post Dose (Ae96)
    Description
    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.
    Time Frame
    0-4, 4-8, 8-12, 12-24, 24-48, 48-72, and 72-96 hours after dosing on Day 1
    Title
    Percent of Dose Recovered Unchanged in Urine From 0 to 96 Hours Postdose (for Ertugliflozin Only) (Ae96%)
    Description
    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.
    Time Frame
    0-4, 4-8, 8-12, 12-24, 24-48, 48-72, and 72-96 hours after dosing on Day 1
    Title
    Renal Clearance (CLr) for Urinary Ertugliflozin
    Description
    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.
    Time Frame
    0-4, 4-8, 8-12, 12-24, 24-48, 48-72, and 72-96 hours after dosing on Day 1
    Title
    Number of Participants Who Experienced an Adverse Event (AE)
    Description
    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.
    Time Frame
    Up to 19 days
    Title
    Number of Participants Who Discontinued Study Due to an AE
    Description
    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.
    Time Frame
    Up to 5 days
    Title
    Area Under the Plasma Concentration-Time Profile for Glucuronide Metabolite PF-06481944 From Time 0 Extrapolated to Infinite Time (AUCinf)
    Description
    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 Frame
    Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose
    Title
    Area Under the Plasma Concentration-Time Profile for Glucuronide Metabolite PF-06481944 From Time 0 to the Time of the Last Quantifiable Concentration (AUClast)
    Description
    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 Frame
    Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose
    Title
    Maximum Observed Plasma Concentration (Cmax) for Glucuronide Metabolite PF-06481944
    Description
    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 Frame
    Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose
    Title
    Time for Cmax (Tmax) for Plasma Glucuronide Metabolite PF-06481944
    Description
    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 Frame
    Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose
    Title
    Terminal Half-life (t1/2) for Plasma Glucuronide Metabolite PF-06481944
    Description
    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 Frame
    Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose
    Title
    Cumulative Amount of Drug Recovered Unchanged in Urine to 96 Hours Post Dose (Ae96) for Glucuronide Metabolite PF-06481944
    Description
    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.
    Time Frame
    0-4, 4-8, 8-12, 12-24, 24-48, 48-72, and 72-96 hours after dosing on Day 1
    Title
    CLr for Urinary Glucuronide Metabolite PF-06481944
    Description
    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.
    Time Frame
    0-4, 4-8, 8-12, 12-24, 24-48, 48-72, and 72-96 hours after dosing on Day 1
    Title
    Area Under the Plasma Concentration-Time Profile for Glucuronide Metabolite PF-06685948 From Time 0 Extrapolated to Infinite Time (AUCinf)
    Description
    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 Frame
    Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose
    Title
    Area Under the Plasma Concentration-Time Profile for Glucuronide Metabolite PF-06685948 From Time 0 to the Time of the Last Quantifiable Concentration (AUClast)
    Description
    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 Frame
    Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose
    Title
    Maximum Observed Plasma Concentration (Cmax) for Glucuronide Metabolite PF-06685948
    Description
    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 Frame
    Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose
    Title
    Time for Cmax (Tmax) for Plasma Glucuronide Metabolite PF-06685948
    Description
    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 Frame
    Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose
    Title
    Terminal Half-life (t1/2) for Plasma Glucuronide Metabolite PF-06685948
    Description
    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 Frame
    Time 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours post-dose
    Title
    Cumulative Amount of Drug Recovered Unchanged in Urine to 96 Hours Post Dose (Ae96) for Glucuronide Metabolite PF-06685948
    Description
    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.
    Time Frame
    0-4, 4-8, 8-12, 12-24, 24-48, 48-72, and 72-96 hours after dosing on Day 1
    Title
    Renal Clearance (CLr) for Urinary Glucuronide Metabolite PF-06685948
    Description
    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.
    Time Frame
    0-4, 4-8, 8-12, 12-24, 24-48, 48-72, and 72-96 hours after dosing on Day 1
    Title
    Change From Baseline in 24 Hour Inhibition of Glucose Reabsorption
    Description
    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.
    Time Frame
    Baseline and 24 Hours
    Title
    Change From Baseline in 24 Hour Fluid Balance
    Description
    Fluid balance = fluid intake - urine output.
    Time Frame
    For 24 hours before Baseline (-48 to -24 hours) and up to 24 hours after dosing on Day 1 (Up to 24 hours)
    Secondary Outcome Measure Information:
    Title
    Urinary Glucose Excretion Over 24 Hours (UGE0-24hr) for Ertugliflozin
    Description
    Participants were asked to void at the end of each prescribed interval with forced voids prior to start and at the end of each interval.
    Time Frame
    0-4, 4-8, 8-12, 12-24 hours after dosing on Day 1

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Maximum Age & Unit of Time
    80 Years
    Accepts Healthy Volunteers
    Accepts Healthy Volunteers
    Eligibility Criteria
    Inclusion Criteria: 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. Exclusion Criteria: 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 Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease including clinically relevant and significant drug allergies Use of prescription drugs (hormonal methods of birth control are allowed), vitamins and dietary supplements within 7 days of study participation For T2DM participants, history of type 1 diabetes mellitus or a history of ketoacidosis For T2DM participants, clinically significant electrocardiogram abnormality For T2DM participants, history of myocardial infarction, unstable angina, coronary revascularization, stroke or transient ischemic attack within 3 months of study participation For T2DM participants, heart failure defined as New York Heart Association Functional Class III-IV For T2DM participants, renal allograft recipients For T2DM participants, requiring dialysis For T2DM participants, strict fluid restriction For T2DM participants, urinary incontinence For T2DM participants, acute renal disease For T2DM participants, significant hepatic, cardiac, or pulmonary disease or clinically nephrotic For T2DM participants, prescription and over-the-counter medication that is not taken according to a stable regimen for 7 days before study participation For T2DM participants, on metformin should not be enrolled if their baseline renal function is outside the approved product labeling For T2DM participants receiving any of the following medications within 7 days of study participation: 1. Other SGLT2 inhibitors (eg, dapagliflozin, canagliflozin, empagliflozin); 2. Other injectable anti-hyperglycemic agents including pramlintide or Glucagon-like peptide-1 (GLP-1) analogues; 3. Any immunosuppressive drugs, including cyclosporine, tacrolimus, sirolimus; 4. Oral corticosteroids (note that inhaled, nasal and topical corticosteroids are permitted); 5. Any potent drug-metabolizing enzyme-inducing drug, including rifampin, phenytoin, and carbamazepine; 6. Probenecid, valproic acid, gemfibrozil.
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Medical Director
    Organizational Affiliation
    Merck Sharp & Dohme LLC
    Official's Role
    Study Director

    12. IPD Sharing Statement

    Plan to Share IPD
    Yes
    IPD Sharing Plan Description
    https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf
    IPD Sharing URL
    http://engagezone.msd.com/ds_documentation.php
    Citations:
    PubMed Identifier
    28703316
    Citation
    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.
    Results Reference
    result
    PubMed Identifier
    34213819
    Citation
    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.
    Results Reference
    derived
    PubMed Identifier
    33813736
    Citation
    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.
    Results Reference
    derived

    Learn more about this trial

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

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