Pharmacogenetic and Pharmacokinetics of Naproxen and Associated Naproxen-esomeprazole

Phase 4

Completed

• Conditions: Poor Metabolizer Due to Cytochrome p450 CYP2C19 Variant; Poor Metabolizer Due to Cytochrome P450 CYP2C9 Variant
• Interventions: Drug: Naproxen-esomeprazole; Drug: Naproxen

• Registration Number: NCT03092193
• Lead Sponsor: University of Sao Paulo

Brief 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.

Detailed 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.

Study Timeline

• Study Start: 2017-03-01
• Study First Submitted: 2017-03-15
• Study First Submitted QC: 2017-03-24
• Study First Posted: 2017-03-27
• Primary Completion: 2017-10-01
• Study Completion: 2017-10-01
• Status Verified: 2020-11
• Last Update Submitted: 2020-11-02
• Last Update Posted: 2020-11-03

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 8

Inclusion Criteria

• Good general health
• Absence of infection and inflammation
• Absence of systemic diseases

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Naproxen-esomeprazole	Naproxen-esomeprazole	20 patients will receive after one month of first collection (with naproxen 500 mg), naproxen-esomeprazole (one tablet 500mg+20mg) to collected saliva samples for pharmacokinetic and pharmacogenetic studies
Naproxen	Naproxen	20 patients will receive naproxen (one tablet 500 mg) to collected saliva samples for pharmacokinetic and pharmacogenetic studies

Primary Outcome Measures

Name	Time	Method
Saliva concentration of naproxen	one week after the ingestion	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).
Saliva concentration of naproxen-esomeprazole	one week after ingestion	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).

Trial Locations

Locations (1)

Bauru School of Dentistry/USP; 🇧🇷 Bauru, São Paulo, Brazil