Pharmacogenetic and Pharmacokinetics of Naproxen and Associated Naproxen-esomeprazole

Poor Metabolizer Due to Cytochrome p450 CYP2C19 Variant Clinical Trial

Official title:

Clinical Pharmacokinetics of Cytochrome P450: Influence on the Pharmacokinetics of Naproxen (CYP2C8 and CYP2C9) and Associated Naproxen-esomeprazole (CYP2C19)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03092193
• Other study ID #: 49806115.0.0000.5417
• Status: Completed
• Phase: Phase 4
• Start date: March 1, 2017
• Est. completion date: October 1, 2017

Study information

• Verified date: November 2020
• Source: University of Sao Paulo
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The family of cytochrome P450 (CYP) is the most important drug metabolizing enzymes which contributes to the metabolism of a large proportion of drugs in humans. Some CYP450 enzymes reduce or alter the pharmacodynamic activity of many drugs and are involved in oxidative metabolism and elimination of many drugs commonly used by the population. Polymorphisms in CYP2C8 and CYP2C9 are common in different populations around the world and genetic variations in these alleles can cause decreased enzyme activity to nonsteroidal anti-inflammatory drugs (NSAIDs) such as celecoxib, diclofenac, ibuprofen, indomethacin, lornoxicam, meloxicam, valdecoxib, piroxicam, tenoxicam and naproxen. This compromise the bioavailability of the drug can alter the pharmacokinetics of these drugs and patients with mutations in these genes can exhibit increased plasma concentrations of values and areas under the curve (AUC), in addition to decreased clearance of drugs. Associations between NSAIDs and gastric protectors or proton pump inhibitors (PPIs) have become common nowadays, especially in patients who make chronic use of these drugs. Naproxen associated to esomeprazole, a proton pump inhibitor (PPI), was launched in the market recently and its application in acute pain is not yet elucidated. Esomeprazole suffers strong influence of CYP2C19 (hepatic drug-metabolizing enzyme that degrades PPIs). In patients with high enzyme activity of the CYP2C19, the drug can suffer high enzymatic degradation, and its diminished effect. Moreover, in patients with low enzyme CYP2C19 activity, the effect of acid inhibition by PPIs can be very strong.

Description:

The genotype presented by the patient in relation to CYP2C8, 2C9 and 2C19 could influence the absorption and metabolism of these NSAIDs with or without the gastric protectors, and may differ from anti-inflammatory action and side effects. In this proposal, 20 volunteers will be genotyped and phenotyped for these haplotypes of cytochrome P450. For analysis of the proposed genes, saliva will be collected as a source of genomic DNA. For molecular analysis will be performed polymerase chain reaction (PCR) assays are used produced and validated by Applied Biosystems®. For pharmacokinetics will be collected saliva samples at various times after ingestion of a tablet of naproxen (500 mg) or naproxen associated to esomeprazole (500 + 20 mg), using mass spectrometry for analysis of drug concentrations in the samples. The results will be described with a 0.05 significance level.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 8
• Est. completion date: October 1, 2017
• Est. primary completion date: October 1, 2017
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

Inclusion Criteria:

• Good general health

• Absence of infection and inflammation

• Absence of systemic diseases

Exclusion Criteria:

• patients with systemic diseases;

• patients with inflammation or infection;

• patients with a history of gastrointestinal bleeding or ulcerations;

• patients with cardiovascular, renal or hepatic diseases;

• patients who use antidepressant drugs, diuretics or anticoagulants;

• patients with a history of allergy to naproxen (500 mg);

• patients with a history of allergy to naproxen and ezomeprazole (500 mg and 20 mg);

• patients with a history of allergy to any other NSAID;

• pregnant and lactating women.

Related Conditions & MeSH terms

• Poor Metabolizer Due to Cytochrome p450 CYP2C19 Variant
• Poor Metabolizer Due to Cytochrome P450 CYP2C9 Variant

Intervention

Drug:
• Naproxen
20 phenotyped for CYP2C9 and CYP2C19 (by PCR) and for the pharmacokinetics of naproxen, saliva samples will be collected of these patients at different times after ingestion of a tablet of naproxen (500mg) (before, 0,25; 0,5; 0,75; 1; 1,5; 2; 3; 4; 5; 6; 8; 11; 24; 48; 72 e 96 hours after ingestion).
• Naproxen-esomeprazole
20 phenotyped for CYP2C9 and CYP2C19 (by PCR) and for the pharmacokinetics of naproxen-esomeprazole, saliva samples will be collected of these patients at different times after ingestion of a tablet of naproxen-esomeprazole (500mg+20mg) (after one month of the first collection) (before, 0,25; 0,5; 0,75; 1; 1,5; 2; 3; 4; 5; 6; 8; 11; 24; 48; 72 e 96 hours after ingestion).

Locations

Country	Name	City	State
Brazil	Bauru School of Dentistry/USP	Bauru	São Paulo

Sponsors (2)

Lead Sponsor	Collaborator
University of Sao Paulo	Fundação de Amparo à Pesquisa do Estado de São Paulo

Country where clinical trial is conducted

Brazil, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Saliva concentration of naproxen	20 phenotyped for CYP2C9 (by PCR) and for the pharmacokinetics of naproxen and naproxen-ezomeprazole saliva samples will be collected of these patients at different times after ingestion of a tablet of naproxen (500mg) (before, 0,25; 0,5; 0,75; 1; 1,5; 2; 3; 4; 5; 6; 8; 11; 24; 48; 72 e 96 hours after ingestion).	one week after the ingestion
Primary	Saliva concentration of naproxen-esomeprazole	20 phenotyped for CYP2C9 and CYP2C19 (by PCR) and for the pharmacokinetics of naproxen and naproxen-ezomeprazole saliva samples will be collected of these patients at different times after ingestion of a tablet of naproxen-esomeprazole (500mg+20mg) (before, 0,25; 0,5; 0,75; 1; 1,5; 2; 3; 4; 5; 6; 8; 11; 24; 48; 72 e 96 hours after ingestion).	one week after ingestion