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

Phase 1

Completed

• Conditions: Hepatic Impairment; Type 2 Diabetes Mellitus
• Interventions: Drug: Ertugliflozin 15 mg

• Registration Number: NCT02115347
• Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary

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).

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2014-04-14
• Study First Submitted QC: 2014-04-14
• Study First Posted: 2014-04-16
• Study Start: 2014-09-19
• Primary Completion: 2015-01-10
• Study Completion: 2015-01-19
• Results First Submitted: 2017-11-01
• Results First Submitted QC: 2017-11-01
• Status Verified: 2018-08
• Results First Posted: 2018-08-03
• Last Update Submitted: 2018-08-17
• Last Update Posted: 2018-08-20

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 16

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Ertugliflozin 15 mg - Moderate Hepatic Impairment	Ertugliflozin 15 mg	Participants receive a single 15 mg oral dose (tablet) of ertugliflozin
Ertugliflozin 15 mg - Healthy Participants	Ertugliflozin 15 mg	Participants receive a single 15 mg oral dose (tablet) of ertugliflozin
Ertugliflozin 15 mg - Mild Hepatic Impairment	Ertugliflozin 15 mg	Participants receive a single 15 mg oral dose (tablet) of ertugliflozin

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
AUClast for Fraction of Ertugliflozin Unbound in Plasma (AUClast,u)	Hour 0 (predose), and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours	Area under the plasma concentration-time profile from time zero to time of the last quantifiable concentration (Clast) for unbound drug (ertugliflozin only).
Maximum Plasma Concentration (Cmax) of Ertugliflozin	Hour 0 (predose), and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours	Cmax is a measure of the maximum amount of drug in the plasma after the dose is given.
Cmax for Fraction of Ertugliflozin Unbound in Plasma (Cmax,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 for unbound drug (ertugliflozin only).
AUCinf for Fraction of Ertugliflozin Unbound in Plasma (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	Area under the plasma concentration-time profile from time zero extrapolated to infinite time for unbound drug (ertugliflozin only) (AUCinf, u).
Number of Participants Who Experienced an Adverse Event	Up to 19 days	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.