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

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

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).

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus; Hepatic Impairment
• Intervention / Treatment: Drug: Ertugliflozin 15 mg

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ertugliflozin 15 mg - Moderate Hepatic Impairment; Participants receive a single 15 mg oral dose (tablet) of ertugliflozin	Drug: Ertugliflozin 15 mg; Tablet
Other: Ertugliflozin 15 mg - Healthy Participants; Participants receive a single 15 mg oral dose (tablet) of ertugliflozin	Drug: Ertugliflozin 15 mg; Tablet
Experimental: Ertugliflozin 15 mg - Mild Hepatic Impairment; Participants receive a single 15 mg oral dose (tablet) of ertugliflozin	Drug: Ertugliflozin 15 mg; Tablet

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC
• Collaborators: Pfizer
• Investigators: Study Director: Medical Director, Merck/Pfizer

Publications and helpful links

General Publications

• 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.
• Sahasrabudhe V, Terra SG, Hickman A, Saur D, Raje S, Shi H, Matschke K, Zhou S, Cutler DL. Pharmacokinetics of Single-dose Ertugliflozin in Patients With Hepatic Impairment. Clin Ther. 2018 Oct;40(10):1701-1710. doi: 10.1016/j.clinthera.2018.06.015. Epub 2018 Sep 14.

Study record dates

Study Major Dates

• Study Start (Actual): September 19, 2014
• Primary Completion (Actual): January 10, 2015
• Study Completion (Actual): January 19, 2015

Study Registration Dates

• First Submitted: April 14, 2014
• First Submitted That Met QC Criteria: April 14, 2014
• First Posted (Estimate): April 16, 2014

Study Record Updates

• Last Update Posted (Actual): August 20, 2018
• Last Update Submitted That Met QC Criteria: August 17, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Liver Diseases; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Ertugliflozin
• Other Study ID Numbers: 8835-014; MK-8835-014 (Other Identifier: Merck Study number); B1521024 (Other Identifier: Pfizer Study number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No