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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Renal Impairment, Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Ertugliflozin


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ertugliflozin 15 mg (T2DM with Normal Renal Function)<br>Ertugliflozin (15 mg), oral, administered in participants with T2DM and with normal renal function | Drug: Ertugliflozin<br>* Single oral administration of 3 X 5 mg tablets.<br>* Other names: MK-8835;|
| Experimental: Ertugliflozin 15 mg (T2DM with Mild Renal Impairment)<br>Ertugliflozin (15 mg), oral, administered in participants with T2DM and with mild renal impairment | Drug: Ertugliflozin<br>* Single oral administration of 3 X 5 mg tablets.<br>* Other names: MK-8835;|
| Experimental: Ertugliflozin 15 mg (T2DM with Moderate Renal Impairment)<br>Ertugliflozin (15 mg), oral, administered in participants with T2DM and with moderate renal impairment | Drug: Ertugliflozin<br>* Single oral administration of 3 X 5 mg tablets.<br>* Other names: MK-8835;|
| Experimental: Ertugliflozin 15 mg (T2DM with Severe Renal Impairment)<br>Ertugliflozin (15 mg), oral, administered in participants with T2DM and with severe renal impairment | Drug: Ertugliflozin<br>* Single oral administration of 3 X 5 mg tablets.<br>* Other names: MK-8835;|
| Experimental: Ertugliflozin, 15 mg (Healthy Part. with Normal Renal Funct.)<br>Ertugliflozin (15 mg), oral, administered in participants with healthy participants and with normal renal function | Drug: Ertugliflozin<br>* Single oral administration of 3 X 5 mg tablets.<br>* Other names: MK-8835;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 0-4, 4-8, 8-12, 12-24 hours after dosing on Day 1 |