A Phase 1 Study of Ertugliflozin in Healthy Male Participants (MK-8835-020)

A Phase 1, Open-Label, Non-Randomized, 2-Period, Fixed Sequence, Study to Assess the Absolute Bioavailability and Fraction Absorbed of Ertugliflozin in Health Male Subjects Using a 14^C-Microdose Approach

This study will evaluate the absolute oral bioavailability (F) and fraction absorbed (Fa) of ertugliflozin following oral administration of unlabeled ertugliflozin (MK-8835) and intravenous (IV) and oral administration of 14^C-labeled ertugliflozin in healthy male participants.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus
• Intervention / Treatment: Drug: Unlabeled ertugliflozin for oral use; Drug: 14^C-labeled ertugliflozin for IV use; Drug: 14^C-labeled ertugliflozin for oral use

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Healthy male subjects between the ages of 18 and 65 years.
• Body Mass Index (BMI) of 17.5 to 30.5 kg/m^2; and a total body weight >50 kg (110 lbs.)

Exclusion Criteria:

• Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies).
• Any clinically significant malabsorption condition (eg, gastrectomy, bowel resection).
• A positive urine drug screen for drugs of abuse or recreational drugs.
• Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) results.
• History of abuse of alcohol or binge drinking and/or any other illicit drug use or dependence within 6 months of Screening.
• Current smokers and those who have smoked any substance within the last 12 months.
• Treatment with an investigational drug within 1 month preceding the first dose of study medication.
• Have participated in any clinical study with exposure to 14^C in the last 12 months.
• Any radiation exposure, including that which is projected to result from the present study, excluding background radiation but including diagnostic x-rays and other medical exposures. No occupationally exposed worker, as defined in the Ionising Radiation Regulation 1999, shall participate in the study.
• Use of prescription or nonprescription drugs (including vitamins and dietary supplements) within 7 days prior to the first dose of study medication.
• 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.
• Participants who have previously participated in a clinical trial for ertugliflozin.
• Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Ertugliflozin; Period 1: Oral dose of 15 mg unlabeled ertugliflozin + intravenous (IV) dose of 100 µg 14^C-labeled ertugliflozin containing approximately 400 nCi 14^C. The 14^C IV dose will be administered as an infusion over approximately 5 minutes starting at 55 minutes after the unlabeled oral dose. → Period 2: Oral dose 15 mg unlabeled ertugliflozin + oral dose of 100 µg 14^C-labeled ertugliflozin containing approximately 400 nCi 14^C. Both the unlabeled and 14^C-ertugliflozin will be administered at the same time (no more than 5 minutes apart). Dosing in Periods 1 and 2 will be separated by a washout of at least 11 days.

Drug: Unlabeled ertugliflozin for oral use; 15 mg oral (3 x 5 mg tablets); Drug: 14^C-labeled ertugliflozin for IV use; 100 µg (10 µg/mL solution IV) containing approximately 400 nCi 14^C (ie, radiolabeled ertugliflozin); Drug: 14^C-labeled ertugliflozin for oral use; 100 µg (10 µg/mL solution oral) containing approximately 400 nCi 14^C (ie, radiolabeled ertugliflozin)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Plasma Concentration-Time Profile From Time Zero to Time of the Last Quantifiable Concentration (AUC Last) (Dose Normalized to 1 mg) and Absolute Oral Bioavailability (F) (Period 1)	AUC0-inf is a measure of the mean concentration levels of drug in the plasma after the drug dose. An absolute bioavailability provides information on the amount of a drug reaching the systemic circulation and can be determined by comparing the plasma concentration-time-curves (area under the curve) of a compound after oral application of that compound to that after intravenous application of the same compound.	Oral: 0, 15 and 30 min., and at 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hrs. after oral dose; IV: -5 min. (predose), 0 (end of infusion), and at 10, 20, 30, and 45 min. and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 11, 23, 47, 71, and 95 hrs. after end of infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Plasma Concentration-Time Profile From Time Zero to Time of the Last Quantifiable Concentration (AUC Last) Following Administration of Unlabeled Ertugliflozin 15 mg Oral + 14^C-Ert. 100 ug IV (Period 1) (Dose Not Normalized to 1 mg)	AUC0-last is a measure of the total amount of drug in the plasma from time zero to time of the last measurable concentration. Geometric coefficient of variation is given as the percent coefficient of variation.	Oral: 0, 15 and 30 min., and at 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hrs. after oral dose; IV: -5 min. (predose), 0 (end of infusion), and at 10, 20, 30, and 45 min. and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 11, 23, 47, 71, and 95 hrs. after end of infusion
Pharmacokinetic Parameter: (AUC Inf) Following Administration of Unlabeled Ertugliflozin 15 mg Oral + 14^C-Ertugliflozin 100 ug IV (Period 1)	AUC0-inf is a measure of the mean concentration levels of drug in the plasma after the dose. Geometric coefficient of variation is given as the percent coefficient of variation.	Oral: 0, 15 and 30 min., and at 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hrs. after oral dose; IV: -5 min. (predose), 0 (end of infusion), and at 10, 20, 30, and 45 min. and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 11, 23, 47, 71, and 95 hrs. after end of infusion
Pharmacokinetic Parameter: Maximum Plasma Concentration (Cmax) Following Administration of Unlabeled Ertugliflozin 15 mg Oral + 14^C-Ertugliflozin 100 ug IV (Period 1) (Dose Normalized to 1 mg)	Cmax is a measure of the maximum amount of drug in the plasma after the dose is given. Geometric coefficient of variation is given as the percent coefficient of variation.	Oral: 0, 15 and 30 min., and at 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hrs. after oral dose; IV: -5 min. (predose), 0 (end of infusion), and at 10, 20, 30, and 45 min. and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 11, 23, 47, 71, and 95 hrs. after end of infusion
Pharmacokinetic Parameter: Time for Cmax (Tmax) Following Administration of Unlabeled Ertugliflozin 15 mg Oral + 14^C-Ertugliflozin 100 ug IV (Period 1)	Tmax is a measure of the time to reach the maximum concentration in the plasma after the drug dose. The confidence intervals displayed are minimums to maximums.	Oral: 0, 15 and 30 min., and at 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hrs. after oral dose; IV: -5 min. (predose), 0 (end of infusion), and at 10, 20, 30, and 45 min. and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 11, 23, 47, 71, and 95 hrs. after end of infusion
Pharmacokinetic Parameter: Terminal Elimination Half-Life (t1/2) Following Administration of Unlabeled Ertugliflozin 15 mg Oral + 14^C-Ertugliflozin 100 ug IV (Period 1)	T1/2 is the time required for a given drug concentration in the plasma to decrease by 50%.	Oral: 0, 15 and 30 min., and at 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hrs. after oral dose; IV: -5 min. (predose), 0 (end of infusion), and at 10, 20, 30, and 45 min. and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 11, 23, 47, 71, and 95 hrs. after end of infusion
Pharmacokinetic Parameter: Apparent Oral Total Plasma Clearance (CL/F) - Oral, Following Administration of Unlabeled Ertugliflozin 15 mg Oral + 14^C-Ertugliflozin 100 ug IV (Period 1)	Apparent clearance is a calculation of the rate at which a drug is removed from plasma after oral administration via renal, hepatic and other clearance pathways, expressed as volume (milliliters) per unit of time (minutes). Geometric coefficient of variation is given as the percent coefficient of variation. This outcome measure is for the Ertugliflozin oral drug profile only so no participants were analyzed in the 14^C-Ertugliflozin 100 ug IV arm.	Oral: 0, 15 and 30 min., and at 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hrs. after oral dose; IV: -5 min. (predose), 0 (end of infusion), and at 10, 20, 30, and 45 min. and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 11, 23, 47, 71, and 95 hrs. after end of infusion
Pharmacokinetic Parameter: Systemic IV Total Plasma Clearance (CL) - IV, Following Administration of Unlabeled Ertugliflozin 15 mg Oral + 14^C-Ertugliflozin 100 ug IV (Period 1)	Systemic clearance is a calculation of the rate at which a drug is removed from plasma via renal, hepatic and other clearance pathways, expressed as volume (milliliters) per unit of time (minutes). Geometric coefficient of variation is given as the percent coefficient of variation. This outcome measure is for the Ertugliflozin intravenous drug profile only so no participants were analyzed in the Ertugliflozin oral arm.	Oral: 0, 15 and 30 min., and at 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hrs. after oral dose; IV: -5 min. (predose), 0 (end of infusion), and at 10, 20, 30, and 45 min. and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 11, 23, 47, 71, and 95 hrs. after end of infusion
Pharmacokinetic Parameter: Apparent Volume of Distribution (Vz/F) Following Oral Administration - Oral, Following Administration of Unlabeled Ertugliflozin 15 mg Oral + 14^C-Ertugliflozin 100 ug IV (Period 1)	Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose is influenced by the fraction absorbed. Geometric coefficient of variation is given as the percent coefficient of variation. This outcome measure is for the Ertugliflozin oral drug profile only so no participants were analyzed in the 14^C-Ertugliflozin 100 ug intravneous arm.	Oral: 0, 15 and 30 min., and at 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hrs. after oral dose; IV: -5 min. (predose), 0 (end of infusion), and at 10, 20, 30, and 45 min. and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 11, 23, 47, 71, and 95 hrs. after end of infusion
Pharmacokinetic Parameter: Steady-State Volume of Distribution (Vss) Following IV Infusion - IV, Following Administration of Unlabeled Ertugliflozin 15 mg Oral + 14^C-Ertugliflozin 100 ug IV (Period 1)	Steady-State Volume of Distribution is the theoretical volume that the total amount of administered drug would have to occupy (if it were uniformly distributed), to provide the same concentration as it is in blood plasma at steady state. Geometric coefficient of variation is given as the percent coefficient of variation. This outcome measure is for the Ertugliflozin intravenous drug profile only so no participants were analyzed in the Ertugliflozin oral arm.	Oral: 0, 15 and 30 min., and at 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hrs. after oral dose; IV: -5 min. (predose), 0 (end of infusion), and at 10, 20, 30, and 45 min. and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 11, 23, 47, 71, and 95 hrs. after end of infusion
Pharmacokinetic Parameter: Fraction Absorbed (Fa, Radioactivity in Urine) (Periods 1 and 2) (Dose Normalized)	Fraction absorbed is the fraction of the total ertugliflozin dose absorbed, regardless of the fate of that dose after absorption (i.e., metabolism, degradation, etc). Fraction Absorbed was estimated as the ratio of total radioactivity (dose normalized) excreted into the urine (from time zero to the time of last measurable concentration) following oral and IV administration of 14^C-ertugliflozin. Fraction of 14^C dose recovered in urine = 14^C total in urine in dpm/14^C total in dose in dpm	Part 1: pre- IV dose, 0-11 and 11-23 hrs. post IV dose, and 23 - 47, 47 - 71 and 71 - 95 hrs. until Day 5; Part 2: predose, 0-12 and 12-24 hrs. post dose, and then 24-hour intervals until Day 5
Number of Participants Who Experienced an Adverse Event (Periods 1 and 2)	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 approximately 33 days
Number of Participants Discontinuing Study Drug Due to Adverse Events (Periods 1 and 2)	An 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 approximately 16 days

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC
• Collaborators: 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.
• Raje S, Callegari E, Sahasrabudhe V, Vaz A, Shi H, Fluhler E, Woolf EJ, Schildknegt K, Matschke K, Alvey C, Zhou S, Papadopoulos D, Fountaine R, Saur D, Terra SG, Stevens L, Gaunt D, Cutler DL. Novel Application of the Two-Period Microtracer Approach to Determine Absolute Oral Bioavailability and Fraction Absorbed of Ertugliflozin. Clin Transl Sci. 2018 Jul;11(4):405-411. doi: 10.1111/cts.12549. Epub 2018 Mar 25.

Study record dates

Study Major Dates

• Study Start (Actual): October 29, 2014
• Primary Completion (Actual): January 30, 2015
• Study Completion (Actual): February 9, 2015

Study Registration Dates

• First Submitted: April 3, 2015
• First Submitted That Met QC Criteria: April 3, 2015
• First Posted (Estimate): April 8, 2015

Study Record Updates

• Last Update Posted (Actual): September 18, 2018
• Last Update Submitted That Met QC Criteria: August 20, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• 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: 8835-020; B1521043 (Other Identifier: Pfizer Protocol Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf