Interaction Between Omeprazole and Gliclazide in CYP2C19 Normal/ Ultrarapid Metabolisers

NCT04198948 | Completed Phase 1 Results

• 2 other identifiers: 0101-3678/18209943/Z/17/Z
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

Brief Summary

Proton pump inhibitors (PPIs) are treatment of choice for different gastrointestinal disorders common in type 2 diabetes. Sulfonylureas (SUs) are anti-diabetes agents particularly widely used in developing countries. Gliclazide, a recommended SU drug, is metabolised in part by CYP2C19, the main enzyme responsible for the PPI metabolism. A randomised, placebo-controlled, two-sequence, two-period crossover study will be performed to explore whether gliclazide pharmacokinetics (PK) and pharmacodynamics (PD) are altered upon co-administration with omeprazole. Sixteen healthy volunteers, CYP2C19 extensive/ultrarapid metabolisers (EM/UM), will receive placebo or omeprazole alone for 4 days, and concomitantly with single dose of gliclazide on day 5. Plasma concentration of gliclazide will be measured for 24 hours, and plasma glucose and insulin levels up to 12 hours after gliclazide administration.

Conditions

Diabetes Mellitus, Type 2

Outcome Measures

Primary Outcomes (1)

• Gliclazide AUC

  Area under the concentration-time curve (AUC) up to the last concentration measured

  24 hours

Secondary Outcomes (2)

• Glucose

  12 hours

• Insulin

  12 hours

Study Arms (2)

Omeprazole, Then Placebo

EXPERIMENTAL

Healthy volunteers, CYP2C19 extensive/ultrarapid metabolisers, will receive 20 mg of omeprazole alone for 4 days, and concomitantly with single dose of gliclazide on day 5. After a wash-out period, they will receive placebo under same conditions in a cross-over manner.

Drug: Omeprazole; Drug: Placebo oral tablet; Drug: Gliclazide

Placebo, Then Omeprazole

EXPERIMENTAL

Healthy volunteers, CYP2C19 extensive/ultrarapid metabolisers, will receive placebo alone for 4 days, and concomitantly with single dose of gliclazide on day 5. After a wash-out period, they will receive omeprazole under same conditions in a cross-over manner.

Drug: Omeprazole; Drug: Placebo oral tablet; Drug: Gliclazide

Interventions

Omeprazole DRUG

Omeprazole (20 mg) will be administered orally once daily for 5 days in one of the two treatment periods.

Omeprazole, Then Placebo; Placebo, Then Omeprazole

Placebo oral tablet DRUG

Placebo will be administered orally once daily for 5 days in one of the two treatment periods.

Omeprazole, Then Placebo; Placebo, Then Omeprazole

Gliclazide DRUG

Gliclazide (40 mg) will be administered orally once, concomitantly with omeprazole or placebo on day 5.

Omeprazole, Then Placebo; Placebo, Then Omeprazole

Eligibility Criteria

• Age: 18 Years - 30 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Men
• Age 18-30 years
• Non-smokers
• CYP2C19 extensive/ultrarapid metabolisers

You may not qualify if:

• medical history of hepatic, renal, gastrointestinal and hematologic disease or any acute or chronic disease, or drug allergy to sulfonylureas or PPIs or history of drug abuse
• abnormalities in physical examination, ECG and routine clinical laboratory tests (including fasting blood glucose concentration)
• medication use during the 14 days prior and during the study period
• grapefruit, grapefruit juice, alcohol, beverages or food containing methylxanthines use during 72 h prior and during the study period

Sponsors & Collaborators

• University of Sarajevo: lead
• General Hospital Prim. Dr. Abdulah Nakas: collaborator
• University of Dundee: collaborator
• Wellcome Trust: collaborator

Study Sites (1)

General Hospital Prim. Dr. Abdulah Nakas

Sarajevo, 71000, Bosnia and Herzegovina

Location

Related Publications (9)

• Kalra S, Aamir AH, Raza A, Das AK, Azad Khan AK, Shrestha D, Qureshi MF, Md Fariduddin, Pathan MF, Jawad F, Bhattarai J, Tandon N, Somasundaram N, Katulanda P, Sahay R, Dhungel S, Bajaj S, Chowdhury S, Ghosh S, Madhu SV, Ahmed T, Bulughapitiya U. Place of sulfonylureas in the management of type 2 diabetes mellitus in South Asia: A consensus statement. Indian J Endocrinol Metab. 2015 Sep-Oct;19(5):577-96. doi: 10.4103/2230-8210.163171.

  PMID: 26425465 BACKGROUND

• Schopman JE, Simon AC, Hoefnagel SJ, Hoekstra JB, Scholten RJ, Holleman F. The incidence of mild and severe hypoglycaemia in patients with type 2 diabetes mellitus treated with sulfonylureas: a systematic review and meta-analysis. Diabetes Metab Res Rev. 2014 Jan;30(1):11-22. doi: 10.1002/dmrr.2470.

  PMID: 24030920 BACKGROUND

• Zhang Y, Si D, Chen X, Lin N, Guo Y, Zhou H, Zhong D. Influence of CYP2C9 and CYP2C19 genetic polymorphisms on pharmacokinetics of gliclazide MR in Chinese subjects. Br J Clin Pharmacol. 2007 Jul;64(1):67-74. doi: 10.1111/j.1365-2125.2007.02846.x. Epub 2007 Feb 12.

  PMID: 17298483 BACKGROUND

• Shao H, Ren XM, Liu NF, Chen GM, Li WL, Zhai ZH, Wang DW. Influence of CYP2C9 and CYP2C19 genetic polymorphisms on pharmacokinetics and pharmacodynamics of gliclazide in healthy Chinese Han volunteers. J Clin Pharm Ther. 2010 Jun;35(3):351-60. doi: 10.1111/j.1365-2710.2009.01134.x.

  PMID: 20831536 BACKGROUND

• Sun XM, Tan JC, Zhu Y, Lin L. Association between diabetes mellitus and gastroesophageal reflux disease: A meta-analysis. World J Gastroenterol. 2015 Mar 14;21(10):3085-92. doi: 10.3748/wjg.v21.i10.3085.

  PMID: 25780309 BACKGROUND

• Furuta T, Iwaki T, Umemura K. Influences of different proton pump inhibitors on the anti-platelet function of clopidogrel in relation to CYP2C19 genotypes. Br J Clin Pharmacol. 2010 Sep;70(3):383-92. doi: 10.1111/j.1365-2125.2010.03717.x.

  PMID: 20716239 BACKGROUND

• Dujic T, Zhou K, Donnelly LA, Leese G, Palmer CNA, Pearson ER. Interaction between variants in the CYP2C9 and POR genes and the risk of sulfonylurea-induced hypoglycaemia: A GoDARTS Study. Diabetes Obes Metab. 2018 Jan;20(1):211-214. doi: 10.1111/dom.13046. Epub 2017 Aug 25.

  PMID: 28656666 BACKGROUND

• Wedemeyer RS, Blume H. Pharmacokinetic drug interaction profiles of proton pump inhibitors: an update. Drug Saf. 2014 Apr;37(4):201-11. doi: 10.1007/s40264-014-0144-0.

  PMID: 24550106 BACKGROUND

• Semiz S, Dujic T, Ostanek B, Prnjavorac B, Bego T, Malenica M, Marc J, Causevic A. Analysis of CYP2C9*2, CYP2C19*2, and CYP2D6*4 polymorphisms in patients with type 2 diabetes mellitus. Bosn J Basic Med Sci. 2010 Nov;10(4):287-91. doi: 10.17305/bjbms.2010.2662.

  PMID: 21108610 BACKGROUND

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

Omeprazole; Gliclazide

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

2-Pyridinylmethylsulfinylbenzimidazoles; Sulfoxides; Sulfur Compounds; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Benzenesulfonamides; Sulfonamides; Amides; Sulfonylurea Compounds; Urea; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfones

Limitations and Caveats

Participants received half of the 80 mg gliclazide tablet registered as an immediate-release formulation in Bosnia and Herzegovina (Diprian®, Hemofarm d.o.o. Banja Luka, B\&H). However, the concentration-time profiles showed modified-release pattern and incomplete elimination within 24h; thus Cmax, tmax, t1/2, and AUC0-∞ could not be determined. The obtained PK profiles were used at the end for validation of physiologically based pharmacokinetic simulation of omeprazole-gliclazide interaction.

Results Point of Contact

• Title: Associate Professor Tanja Dujic, PhD
• Organization: University of Sarajevo

tanja.dujic@ffsa.unsa.ba

+38733586194

Study Officials

• Tanja Dujic, PhD

  University of Sarajevo

  PRINCIPAL INVESTIGATOR

• Aida Kulo Cesic, PhD

  University of Sarajevo

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: December 11, 2019
• First Posted: December 13, 2019
• Study Start: March 4, 2019
• Primary Completion: August 5, 2019
• Study Completion: August 5, 2019
• Last Updated: August 18, 2021
• Results First Posted: July 15, 2021

Record last verified: 2021-07

Data Sharing

• IPD Sharing: Will share

Locations

BO (1)