Clinical trial NCT01223339: Evaluation of Pharmacokinetics, Safety, And Tolerability Of Ertugliflozin (PF-04971729, MK-8835) In Japanese And Western Healthy Participants (MK-8835-041)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Diabetes Mellitus, Type 2
Keywords: Ertugliflozin
Japanese and Western population
pharmacokinetics
pharmacodynamics
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
Collaborators: name: Pfizer
First posted: 2010-10-19
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Maximum plasma concentration (Cmax) of ertugliflozin for the Single Dose Cohort
timeFrame: Up to Day 4 of each treatment period
measure: Time taken to reach the maximum observed plasma concentration (Tmax) of ertugliflozin for the Single Dose Cohort
timeFrame: Up to Day 4 of each treatment period
measure: 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
timeFrame: Up to Day 4 of each treatment period
measure: AUC from Hour 0 to infinity (AUCinf) for ertugliflozin for the Single Dose Cohort
timeFrame: Up to Day 4 of each treatment period
measure: Ertugliflozin half life (t1/2) for the Single Dose Cohort
timeFrame: Up to Day 4 of each treatment period
measure: Apparent clearance (CL/F) of ertugliflozin for the Single Dose Cohort
timeFrame: Up to Day 4 of each treatment period
measure: Apparent volume of distribution (Vz/F) for the Single Dose Cohort
timeFrame: Up to Day 4 of each treatment period
measure: Accumulation Ratio of Area Under the Curve for the dosing interval of ertugliflozin (Rac) for the Single Dose Cohort
timeFrame: Up to Day 4 of each treatment period
measure: Number of participants who experienced an adverse event (AE) for the Single Dose Cohort
timeFrame: Up to 10 days after the final dose of study drug (Up to Day 11)
measure: Number of participants who discontinued study drug due to an AE for the Single Dose Cohort
timeFrame: Up to Day 1 of each treatment period
measure: Urinary Glucose Excretion over 24 hours for the Single Dose Cohort
timeFrame: Up to 24 hours postdose (Up to Day 2)
measure: Cmax of ertugliflozin for the Multiple Dose Cohort
timeFrame: Up to Day 10
measure: Tmax of ertugliflozin for the Multiple Dose Cohort
timeFrame: Up to Day 10
measure: AUClast for ertugliflozin for the Multiple Dose Cohort
timeFrame: Up to Day 10
measure: AUCinf for ertugliflozin for the Multiple Dose Cohort
timeFrame: Up to Day 10
measure: t1/2 for the Multiple Dose Cohort
timeFrame: Up to Day 10
measure: CL/F of ertugliflozin for the Multiple Dose Cohort
timeFrame: Up to Day 10
measure: Vz/F for the Multiple Dose Cohort
timeFrame: Up to Day 10
measure: Rac for the Single Dose Cohort
timeFrame: Up to Day 10
measure: Number of participants who experienced an AE for the Multiple Dose Cohort
timeFrame: Up to 10 days after the final dose of study drug (Up to Day 17)
measure: Number of participants who discontinued study drug due to an AE for the Multiple Dose Cohort
timeFrame: Up to Day 7
measure: Urinary Glucose Excretion over 24 hours for the Multiple Dose Cohort
timeFrame: Up to 24 hours postdose (Up to Day 8)
Secondary outcomes:
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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.
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: 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.