Pharmacokinetics, Safety, and Tolerability of Ertugliflozin (MK-8835/PF-04971729) in Participants With Hepatic Impairment and in Healthy Participants (MK-8835-014)

Study Overview
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Brief Summary
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This is a study to assess the pharmacokinetics and safety of ertugliflozin (MK-8835, PF-04971729) in participants with hepatic impairment versus healthy participants. In Part 1 of the study, participants with moderate hepatic impairment (Child-Pugh score 7-9) and matched healthy participants will be enrolled; depending on results in Part 1, Part 2 may be conducted and will enroll participants with mild hepatic impairment (Child-Pugh score 5-6).

Official Title
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A Phase 1, Non-randomized, Open-label, Single Dose Study to Evaluate the Pharmacokinetics, Safety and Tolerability of Ertugliflozin (MK-8835/PF-04971729) in Subjects With Hepatic Impairment and the Healthy Subjects With Normal Hepatic Function

Conditions
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Type 2 Diabetes Mellitus, Hepatic Impairment

Intervention / Treatment
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* Drug: Ertugliflozin 15 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ALL PARTICIPANTS: Body Mass Index (BMI) of 18 to 40 kg/m^2; and a total body weight >50 kg (110 lbs) Male or female not of reproductive potential If a female of reproductive potential, agrees to remain abstinent from heterosexual activity or agree to use or have their partner use 2 methods of acceptable contraception to prevent pregnancy while the participant is receiving study medication and for 14 days after the last dose of study medication PARTICIPANTS WITH NORMAL HEPATIC FUNCTION Healthy with normal hepatic function PARTICIPANTS WITH HEPATIC IMPAIRMENT Satisfy the criteria for Child-Pugh classification [moderate (Part 1): Child-Pugh Scores 7-9 points, mild (Part 2): Child-Pugh Scores 5-6 points] within 14 days before administration of study medication A diagnosis of hepatic impairment due to primary liver disease and not secondary to other diseases Stable hepatic impairment, defined as no clinically-significant change in disease status within the last 30 days On a stable dose of medication and/or treatment regimen used to manage hepatic disease for at least 4 weeks prior to study start Exclusion Criteria: ALL PARTICIPANTS A known hypersensitivity or intolerance to ertugliflozin or any other Sodium-Glucose co-Transporter 2 (SGLT2) inhibitor (i.e., canagliflozin [Invokana], dapagliflozin [Farxiga], empagliflozin, or ipragliflozin) Febrile illness within 5 days prior to the first dose of study medication Any clinically significant malabsorption condition A positive urine drug screen for drugs of abuse or recreational drugs Abuse of alcohol or binge drinking and/or any other illicit drug use or dependence within 6 months of study start Treatment with an investigational drug within 30 days preceding the first dose of study medication Pregnant or breastfeeding females Use of herbal supplements within 28 days prior to the first dose of study medication Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or more within 56 days prior to dosing History of sensitivity to heparin or heparin-induced thrombocytopenia PARTICIPANTS WITH NORMAL HEPATIC FUNCTION Use of prescription drugs (hormonal methods of birth control are allowed), vitamins, and dietary supplements within 7 days prior to the first dose of study medication Positive serology for Hepatitis B or C PARTICIPANTS WITH HEPATIC IMPAIRMENT Hepatic carcinoma and hepatorenal syndrome or life expectancy less than 1 year Undergone portal-caval shunt surgery History of gastrointestinal hemorrhage due to esophageal varices or peptic ulcers less than 1 month prior to study entry Signs of significant hepatic encephalopathy Severe ascites and/or pleural effusion A transplanted kidney, heart or liver Received any of the following medications within 7 days prior to the first dose of study medication or during the study: other SGLT2 inhibitors (eg, dapagliflozin, canagliflozin, empagliflozin, and ipragliflozin); any potent drug-metabolizing enzyme-inducing drug, including rifampin, phenytoin, and carbamazepine; probenecid, valproic acid, gemfibrozil

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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 - Moderate Hepatic Impairment<br>Participants receive a single 15 mg oral dose (tablet) of ertugliflozin | Drug: Ertugliflozin 15 mg<br>* Tablet<br>|
| Other: Ertugliflozin 15 mg - Healthy Participants<br>Participants receive a single 15 mg oral dose (tablet) of ertugliflozin | Drug: Ertugliflozin 15 mg<br>* Tablet<br>|
| Experimental: Ertugliflozin 15 mg - Mild Hepatic Impairment<br>Participants receive a single 15 mg oral dose (tablet) of ertugliflozin | Drug: Ertugliflozin 15 mg<br>* Tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Concentration-Time Curve From Time 0 to Time of the Last Quantifiable Concentration (AUClast) for Ertugliflozin | Area under the plasma concentration-time profile from time zero to time of the last quantifiable concentration (AUClast). | Hour 0 (predose), and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours | 
| AUC From Hour 0 to Infinity (AUCinf) for Ertugliflozin | Area under the plasma concentration-time profile from time zero extrapolated to infinite time (AUCinf). | Hour 0 (predose), and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUClast for Fraction of Ertugliflozin Unbound in Plasma (AUClast,u) | Area under the plasma concentration-time profile from time zero to time of the last quantifiable concentration (Clast) for unbound drug (ertugliflozin only). | Hour 0 (predose), and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours | 
| AUCinf for Fraction of Ertugliflozin Unbound in Plasma (AUCinf,u) | Area under the plasma concentration-time profile from time zero extrapolated to infinite time for unbound drug (ertugliflozin only) (AUCinf, u). | Hour 0 (predose), and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours | 
| Maximum Plasma Concentration (Cmax) of Ertugliflozin | Cmax is a measure of the maximum amount of drug in the plasma after the dose is given. | Hour 0 (predose), and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours | 
| Cmax for Fraction of Ertugliflozin Unbound in Plasma (Cmax,u) | Maximum plasma concentration for unbound drug (ertugliflozin only). | Hour 0 (predose), and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours | 
| Number of Participants Who Experienced an Adverse Event | 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 |