Evaluation of Pharmacokinetics, Safety, And Tolerability Of Ertugliflozin (PF-04971729, MK-8835) In Japanese And Western Healthy Participants (MK-8835-041)

A Phase 1, Randomized, Double Blind, Placebo-Controlled, Parallel Cohort, Single Dose Escalation And Multiple Dose Study In Japanese Healthy Subjects, And Open Label, Single Dose Escalation Study In Western Healthy Subjects To Investigate The Safety, Tolerability, Pharmacokinetics, And Pharmacodynamics Of PF-04971729

This study is to characterize the pharmacokinetics, safety, tolerability, and pharmacodynamics of single and multiple oral doses (SD, MD) of ertugliflozin (PF-04971729, MK-8835) in Japanese healthy participants. The secondary objective is to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single doses of ertugliflozin in Western healthy participants as compared to Japanese healthy participants.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: Drug: Ertugliflozin; Drug: Placebo; Drug: Ertugliflozin; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy male and/or female subjects of non-childbearing potential, between the ages of 18 and 55 years, inclusive
• Body Mass Index (BMI) of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lbs).
• Japanese subjects must have four Japanese grandparents who were born in Japan.
• Mean body weight and the body weight range of Western subjects are similar to those of Japanese subjects with a 10% plus and minus error.
• An informed consent document signed and dated by the subject.
• Subjects who are willing and able to comply with scheduled visits, treatment plan,laboratory tests, and other study procedures.

Exclusion Criteria:

• Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease
• Asian or Polynesian subjects in Western subject groups.
• Any condition possibly affecting drug absorption (eg, gastrectomy).
• A positive urine drug screen.
• History of regular alcohol consumption exceeding 7 drinks/week for females or 14 drinks/week for males within 6 months of screening.
• History or evidence of habitual use of tobacco or nicotine containing products within 3 months of Screening, with the exception of light smoking (up to 5 cigarettes per day or the equivalent).
• Treatment with an investigational drug within 30 days or 5 half-lives preceding the first dose of study medication.
• 12-lead ECG demonstrating QTc >450 msec at screening.
• Subjects with ANY of the following abnormalities on safety laboratory tests):
• Evidence of glycosuria, as defined by a positive urine dipstick test;
• Fasting serum triglyceride >300 mg/dL;
• Fasting LDL-cholesterol > than or equal to 190 mg/dL.
• Fasting serum glucose >125 mg/dL.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Single Dose Japanese Cohort; This will be a single dose Cohort in which Japanese healthy participants will receive 3 ascending single doses (1 mg, 5 mg, and 25 mg) of ertugliflozin or placebo through 3 dosing periods. A minimum wash out period of 7-days will be set between each dose administration.	Drug: Ertugliflozin; Dose escalation of 1, 5, and 25 mg Ertugliflozin administered in the fasted state; Drug: Placebo; Placebo tablets to Ertugliflozin administered in the fasted state; Drug: Ertugliflozin; Ertugliflozin 25 mg tablets administered once daily in the fed state for 7 days; Drug: Placebo; Placebo tablets administered once daily in the fed state for 7 days
Experimental: Single dose Western cohort; This will be a single dose Cohort in which Western healthy participants will receive 3 ascending single doses (1 mg, 5 mg, and 25 mg) of ertugliflozin through 3 dosing periods. A minimum wash out period of 7-days will be set between each dose administration.	Drug: Ertugliflozin; Dose escalation of 1, 5, and 25 mg Ertugliflozin administered in the fasted state; Drug: Ertugliflozin; Ertugliflozin 25 mg tablets administered once daily in the fed state for 7 days
Experimental: Multiple Dose Japanese Cohort; This will be a multiple dose Cohort in which Japanese healthy participants will receive once-daily 25 mg ertugliflozin or placebo for 7 days.	Drug: Ertugliflozin; Dose escalation of 1, 5, and 25 mg Ertugliflozin administered in the fasted state; Drug: Placebo; Placebo tablets to Ertugliflozin administered in the fasted state; Drug: Ertugliflozin; Ertugliflozin 25 mg tablets administered once daily in the fed state for 7 days; Drug: Placebo; Placebo tablets administered once daily in the fed state for 7 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Maximum plasma concentration (Cmax) of ertugliflozin for the Single Dose Cohort	Up to Day 4 of each treatment period
Time taken to reach the maximum observed plasma concentration (Tmax) of ertugliflozin for the Single Dose Cohort	Up to Day 4 of each treatment period
Area under the plasma concentration-time curve (AUC) from time 0 to time of the last quantifiable concentration (AUClast) for ertugliflozin for the Single Dose Cohort	Up to Day 4 of each treatment period
AUC from Hour 0 to infinity (AUCinf) for ertugliflozin for the Single Dose Cohort	Up to Day 4 of each treatment period
Ertugliflozin half life (t1/2) for the Single Dose Cohort	Up to Day 4 of each treatment period
Apparent clearance (CL/F) of ertugliflozin for the Single Dose Cohort	Up to Day 4 of each treatment period
Apparent volume of distribution (Vz/F) for the Single Dose Cohort	Up to Day 4 of each treatment period
Accumulation Ratio of Area Under the Curve for the dosing interval of ertugliflozin (Rac) for the Single Dose Cohort	Up to Day 4 of each treatment period
Number of participants who experienced an adverse event (AE) for the Single Dose Cohort	Up to 10 days after the final dose of study drug (Up to Day 11)
Number of participants who discontinued study drug due to an AE for the Single Dose Cohort	Up to Day 1 of each treatment period
Urinary Glucose Excretion over 24 hours for the Single Dose Cohort	Up to 24 hours postdose (Up to Day 2)
Cmax of ertugliflozin for the Multiple Dose Cohort	Up to Day 10
Tmax of ertugliflozin for the Multiple Dose Cohort	Up to Day 10
AUClast for ertugliflozin for the Multiple Dose Cohort	Up to Day 10
AUCinf for ertugliflozin for the Multiple Dose Cohort	Up to Day 10
t1/2 for the Multiple Dose Cohort	Up to Day 10
CL/F of ertugliflozin for the Multiple Dose Cohort	Up to Day 10
Vz/F for the Multiple Dose Cohort	Up to Day 10
Rac for the Single Dose Cohort	Up to Day 10
Number of participants who experienced an AE for the Multiple Dose Cohort	Up to 10 days after the final dose of study drug (Up to Day 17)
Number of participants who discontinued study drug due to an AE for the Multiple Dose Cohort	Up to Day 7
Urinary Glucose Excretion over 24 hours for the Multiple Dose Cohort	Up to 24 hours postdose (Up to Day 8)

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC
• Collaborators: Pfizer

Publications and helpful links

General Publications

• Fediuk DJ, Sahasrabudhe V, Dawra VK, Zhou S, Sweeney K. Population Pharmacokinetic Analyses of Ertugliflozin in Select Ethnic Populations. Clin Pharmacol Drug Dev. 2021 Nov;10(11):1297-1306. doi: 10.1002/cpdd.970. Epub 2021 Jul 2.
• 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.
• Li Y, Nucci G, Yamamoto Y, Fediuk DJ, Sahasrabudhe V. Pharmacokinetics and Pharmacodynamics of Ertugliflozin in Healthy Japanese and Western Subjects. Clin Pharmacol Drug Dev. 2021 Jul;10(7):765-776. doi: 10.1002/cpdd.908. Epub 2021 Jan 12.

Study record dates

Study Major Dates

• Study Start: October 1, 2010
• Primary Completion (Actual): February 1, 2011
• Study Completion (Actual): February 1, 2011

Study Registration Dates

• First Submitted: October 13, 2010
• First Submitted That Met QC Criteria: October 17, 2010
• First Posted (Estimate): October 19, 2010

Study Record Updates

• Last Update Posted (Estimate): May 20, 2016
• Last Update Submitted That Met QC Criteria: May 19, 2016
• Last Verified: May 1, 2016

More Information

Terms related to this study

• Keywords: pharmacokinetics; pharmacodynamics; Ertugliflozin; Japanese and Western population
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; 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: 8835-041

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No