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Effect of Genetic Polymorphisms of UGT on the PKs of Indapamide in Egyptians (UGT/PKs)

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ClinicalTrials.gov Identifier: NCT05294484
Recruitment Status : Unknown
Verified December 2021 by Ain Shams University.
Recruitment status was:  Not yet recruiting
First Posted : March 24, 2022
Last Update Posted : March 24, 2022
Sponsor:
Information provided by (Responsible Party):
Ain Shams University

Brief Summary:
The aim of this works is to investigate the effect of genetic variation of UGT2B7 on human response to treatment with indapamide and its correlation with pharmacokinetic parameters in Egyptian subjects.

Condition or disease Intervention/treatment Phase
Pharmacogenomics Drug: Indapamide 1.5 MG SR Phase 4

Detailed Description:

Indapamide is a thiazide-type diuretic commonly prescribed to treat mild to moderate hypertension. As it has fewer side effects in inducing metabolic derangements than other thiazide diuretics, indapamide is well accepted to be used as initial therapy to treat hypertension in patients with previous stroke or older people (over 80) or as an add-on treatment. However, severe hyponatremia and hypokalemia have been reported. Therefore, limiting the dose to that necessary to achieve maximal blood pressure reduction and improved cardiovascular outcomes is relevant. Although the major metabolites of indapamide have been identified, the pathways of cytochrome P450 (CYP450)-catalyzed indapamide biotransformation have not been fully elucidated. One recent report suggested that CYP2C19, CYP2C8, and CYP3A4 are involved in the metabolism. Recent advancement in the field of glucuronidation has identified a high degree of allelic diversity for human uridine diphosphate glucuronosyl transferases (UGTs).

As indapamide is glucuronidated by UGT enzymes, poly-morphisms in the genes encoding these drug-metabolizing enzymes could potentially influence its PK. Large inter-individual variability in the rate of glucuronidation of various drugs has been reported. The UGT2B7 enzyme is expressed in the liver and many extrahepatic tissues. Mutations in the UGT2B7 gene may therefore have pharmacological, toxicological, and physiological significance.

the investigators have little information on pharmacogenetics (PG) studies of indapamide. The effect of genetic variation on DMEs activity and the clinical impact on indapamide in particular are not fully understood.

The ultimate goal of personalized medicine is to identify specific genetic features with the differential risk of human diseases or the efficacy of certain therapeutic interventions . Mounting evidence has linked the genetic make-up to a significant portion of drug-induced toxicity. The primary focus of PG is DMEs activity.

The pharmacology of drugs subject to inherited variability in metabolism is often complex. Few have simple or single pathway of elimination. In addition, ethnicity may account for the observed differences in both pharmacokinetics (PK) and pharmacodynamics of drugs, thus resulting in variability in response to drug therapy. Furthermore, genetic polymorphism is one of the most important factors that may contribute to the ethnic sensitivity of a drug in its metabolic pathways.

Single nucleotide polymorphism (SNP) is the most frequently observed mutation in all organisms. The cost for mapping of the genetic variance among thousands of SNPs could be extremely high. Recent advances in whole-genome sequencing (WGS) have led to burst of bioinformation and a significant knowledge base for investigating the genetic architecture of drug metabolisms and treatment efficacies.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 38 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: A comparative randomized, single-dose, two-treatment (fed vs. fasting), parallel design of indapamide in healthy adult Egyptions
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Study on the Effect of Genetic Polymorphisms of Uridine Diphosphate Glucuronosyl Transferase (UGT) on the Pharmacokinetics of Indapamide in Egyptians
Estimated Study Start Date : March 15, 2022
Estimated Primary Completion Date : July 1, 2022
Estimated Study Completion Date : October 1, 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Indapamide

Arm Intervention/treatment
Active Comparator: Fasting group
Following an overnight fast of at least 10 hours, subjects should be administered single dose of indapamide 1.5 mg SR with 240 mL (8 fluid ounces) of water. No food should be allowed for at least 4 hours post-dose. Water can be allowed as desired except for one hour before and after drug administration. Subjects should receive standardized meals scheduled at the same time in each period of the study.
Drug: Indapamide 1.5 MG SR
the effect of genetic variation of UGT2B7 on human response to treatment with indapamide and its correlation with pharmacokinetic parameters in Egyptian subjects

Active Comparator: Fed group

Following an overnight fast of at least 10 hours, subjects should start the recommended meal 30 minutes prior to administration of the drug. Study subjects should eat this meal in 30 minutes or less; however, indapamide 1.5 mg SR should be administered 30 minutes after start of the meal. The drug should be administered with 240 mL (8 fluid ounces) of water. No food should be allowed for at least 4 hours post-dose. Water can be allowed as desired except for one hour before and after drug administration. Subjects should receive standardized meals scheduled at the same time in each period of the study.

All subjects should abstain from the consumption of fruit juices during the study period. All the subjects are to be under complete medical supervision.

Drug: Indapamide 1.5 MG SR
the effect of genetic variation of UGT2B7 on human response to treatment with indapamide and its correlation with pharmacokinetic parameters in Egyptian subjects




Primary Outcome Measures :
  1. the PK parameters of Indapamide following single oral dose include: [ Time Frame: at Day 0: prior to drug administration (blank), then samples (5ml each) will be obtained at 0.5 hour, 1 hour, 1.5 hour, 2 hour, 2.5 hour, 3 hour, 4 hour, 5 hour, 6 hour, 8 hour, 10 hour, 12 hour, and 24 hour after drug administration ]
    area under the concentration-time curve over the dosing interval (AUC[0-tau])

  2. maximum concentration (Cmax) [ Time Frame: at Day 0: prior to drug administration (blank), then samples (5ml each) will be obtained at 0.5 hour, 1 hour, 1.5 hour, 2 hour, 2.5 hour, 3 hour, 4 hour, 5 hour, 6 hour, 8 hour, 10 hour, 12 hour, and 24 hour after drug administration ]
    maximum concentration (Cmax)

  3. time of occurrence of Cmax (Tmax) [ Time Frame: at Day 0: prior to drug administration (blank), then samples (5ml each) will be obtained at 0.5 hour, 1 hour, 1.5 hour, 2 hour, 2.5 hour, 3 hour, 4 hour, 5 hour, 6 hour, 8 hour, 10 hour, 12 hour, and 24 hour after drug administration ]
    time of occurrence of Cmax (Tmax)

  4. terminal phase half-life (T1/2) [ Time Frame: at Day 0: prior to drug administration (blank), then samples (5ml each) will be obtained at 0.5 hour, 1 hour, 1.5 hour, 2 hour, 2.5 hour, 3 hour, 4 hour, 5 hour, 6 hour, 8 hour, 10 hour, 12 hour, and 24 hour after drug administration ]
    terminal phase half-life (T1/2)

  5. clearance [ Time Frame: at Day 0: prior to drug administration (blank), then samples (5ml each) will be obtained at 0.5 hour, 1 hour, 1.5 hour, 2 hour, 2.5 hour, 3 hour, 4 hour, 5 hour, 6 hour, 8 hour, 10 hour, 12 hour, and 24 hour after drug administration ]
    clearance

  6. volume of distribution [ Time Frame: at Day 0: prior to drug administration (blank), then samples (5ml each) will be obtained at 0.5 hour, 1 hour, 1.5 hour, 2 hour, 2.5 hour, 3 hour, 4 hour, 5 hour, 6 hour, 8 hour, 10 hour, 12 hour, and 24 hour after drug administration ]
    volume of distribution

  7. Detection of UGT2B7 SNPs (rs 7438135, rs 11740316) (genetic variation in Egyptian population) [ Time Frame: 6 months ]
    Samples will be collected from each subject into tubes and stored at -80°C, Genomics DNA will be isolated according to manufactures instructions. Polymorphisms will be assessed using suitable recommended assay.


Secondary Outcome Measures :
  1. Vital sign measurement following single dose administration as a measure of safety and tolerability [ Time Frame: every month up to 6 months ]
    Vital sign measurements will include systolic and diastolic blood pressure

  2. pulse rate [ Time Frame: up to 6 months ]
    pulse rate

  3. body temperature [ Time Frame: up to 6-7 months ]
    body temperature measurement



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Subjects should be healthy adult volunteers with age between (18-45) with normal body weight.
  • 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 agent 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 reaction to study drugs
  • Any prior surgery of the gastrointestinal tract that may interfere with drug absorption
  • Gastrointestinal diseases
  • Renal diseases
  • Pancreatic disease including diabetes
  • Hepatic diseases
  • Hematological diseases or pulmonary diseases
  • Abnormal laboratory values
  • Subject 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05294484


Contacts
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Contact: Amal A Elkholy, PhD +201060355448 amalanas9@gmail.com
Contact: Banaz D Abbas, Master 01206053991 Banazdara2017@yahoo.com

Sponsors and Collaborators
Ain Shams University
Investigators
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Study Chair: Nagwa A. Sabri, professor Department of Clinical Pharmacy, Faculty of Pharmacy, Assiut University
Publications:
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Responsible Party: Ain Shams University
ClinicalTrials.gov Identifier: NCT05294484    
Other Study ID Numbers: PG/PK Study on Indapamide
First Posted: March 24, 2022    Key Record Dates
Last Update Posted: March 24, 2022
Last Verified: December 2021

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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
Additional relevant MeSH terms:
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Indapamide
Antihypertensive Agents
Diuretics
Natriuretic Agents
Physiological Effects of Drugs
Sodium Chloride Symporter Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action