Clinical trial NCT02115347: Pharmacokinetics, Safety, and Tolerability of Ertugliflozin (MK-8835/PF-04971729) in Participants With Hepatic Impairment and in Healthy Participants (MK-8835-014)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Type 2 Diabetes Mellitus
Hepatic Impairment
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
Collaborators: name: Pfizer
First posted: 2014-04-16
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).


Eligibility criteria: 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

Primary outcomes:
measure: Area Under the Plasma Concentration-Time Curve From Time 0 to Time of the Last Quantifiable Concentration (AUClast) for Ertugliflozin
timeFrame: Hour 0 (predose), and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours
measure: AUC From Hour 0 to Infinity (AUCinf) for Ertugliflozin
timeFrame: Hour 0 (predose), and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours
Secondary outcomes:
measure: AUClast for Fraction of Ertugliflozin Unbound in Plasma (AUClast,u)
timeFrame: Hour 0 (predose), and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours
measure: AUCinf for Fraction of Ertugliflozin Unbound in Plasma (AUCinf,u)
timeFrame: Hour 0 (predose), and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours
measure: Maximum Plasma Concentration (Cmax) of Ertugliflozin
timeFrame: Hour 0 (predose), and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours
measure: Cmax for Fraction of Ertugliflozin Unbound in Plasma (Cmax,u)
timeFrame: Hour 0 (predose), and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours
measure: Number of Participants Who Experienced an Adverse Event
timeFrame: Up to 19 days
Other outcomes:
Locations:
Study officials:
affiliation: Merck/Pfizer
name: Medical Director
role: STUDY_DIRECTOR
References:
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.
citation: 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.