Effect of Glucuronosyltransferase (UGT) Genetic Variation on Pharmacokinetics of Empagliflozin

Effect of UGT Genetic Variation on Pharmacokinetics of Empagliflozin

The aim of this works is to investigate the effect of genetic polymorphism of snps on human response to treatment with empagliflozin and its correlation with with pharmacokinetic parameters in Egyptian subjects

Study Overview

• Status: Completed
• Conditions: Pharmacokinetics; Pharmacogenomic
• Intervention / Treatment: Drug: Empagliflozin 10 milligram

Detailed Description

Empagliflozin is a sodium glucose co-transporter-2 (SGLT-2) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes. SGLT2 co-transporters are responsible for reabsorption of glucose from the glomerular filtrate in the kidney. The glucuretic effect resulting from SGLT2 inhibition reduces renal absorption and lowers the renal threshold for glucose, therefore resulting in increased glucose excretion. Additionally, it contributes to reduced hyperglycaemia and also assists weight loss and blood pressure reduction.

ABSORPTION Following oral administration, peak plasma concentrations were reached at 1.5 hours post-dose and then declined in a biphasic manner with a rapid distribution phase and a relatively slow terminal phase. Administration following a high-fat and high-calorie meal results in a slightly lower exposure with area under the curve (AUC) decreasing by approximately 16% and Cmax decreasing by approximately 37% compared to fasted condition.

METABOLISM In vitro studies suggest that empagliflozin is primarily metabolized by glucuronidation by 5'-diphospho-glucuronosyltransferases UG2B7, UGT1A3, UGT1A8, and UGT1A9. The most abundant metabolites are three glucuronide metabolites: 2-O-, 3-O-, and 6-O-glucuronide. Empagliflozin does not inhibit, inactivate, or induce CYP450 isoforms. It is a substrate for p-glycoprotein (p-gp), however in vitro studies suggest that it is unlikely to cause interactions with drugs that are p-gp substrates.

After oral administration, empagliflozin was 41.2% eliminated in feces and 54.4% eliminated in urine.

Terminal elimination half life was found to be 12.4 h based on population pharmacokinetic analysis.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 3

Contacts and Locations

Study Locations

• Egypt
  • Cairo, Egypt
    • Faculty of Pharmacy

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Healthy adult volunteers
• Age between (18-45 years)
• Normal BMI.
• Understand the procedures and are willing to participate and gave their final written consent prior to the commencement of the study procedures.
• The volunteers will be asked to provide a complete medical history, and complete a physical examination, laboratory tests [hematology, clinical chemistry, urinalysis, serology (including hepatitis B surface antigen, anti-hepatitis C virus and antihuman immunodeficiency virus antibody).

Exclusion Criteria:

• Treatment with any known enzyme-inducing/inhibiting agents within 30 days prior to the start of the study and throughout the study.
• Subjects who have taken any medication less than two weeks of the trials starting date.
• Susceptibility to allergic reactions to study drugs.
• Any prior surgery of the gastrointestinal tract that may interfere with drug absorption.
• Gastrointestinal diseases.
• Renal diseases.
• Cardiovascular diseases.
• Pancreatic disease including diabetes.
• Hepatic diseases.
• Hematological disease or pulmonary disease
• Abnormal laboratory values.
• Subjects who have donated blood or who have been involved in multiple dosing study requiring a large volume of blood (more than 500 ml) to be drawn within 6 weeks preceding the start of the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: OTHER
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Study Group; Empagliflozin	Drug: Empagliflozin 10 milligram; antihyperglycemic medication; Other Names: Jardiance

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic parameters	AUC0→∞	48 hours
Bioavailability parameters	Cmax	24 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Secondary outcome	Tmax	48 hours

Collaborators and Investigators

• Sponsor: Ain Shams University
• Investigators: Principal Investigator: Sara M Shaheen, Assiss. Prof, ain shams University

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 15, 2022
• Primary Completion (ACTUAL): May 20, 2022
• Study Completion (ACTUAL): May 20, 2022

Study Registration Dates

• First Submitted: August 31, 2021
• First Submitted That Met QC Criteria: August 31, 2021
• First Posted (ACTUAL): September 5, 2021

Study Record Updates

• Last Update Posted (ESTIMATE): February 14, 2023
• Last Update Submitted That Met QC Criteria: February 12, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Empagliflozin; UGT polymorphism
• Additional Relevant MeSH Terms: Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Empagliflozin
• Other Study ID Numbers: PHCL277

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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