Pharmacogenetic and Pharmacokinetics of Naproxen and Associated Naproxen-esomeprazole

NCT03092193 | Completed Phase 4 DMC

• 1 other identifier: 49806115.0.0000.5417
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Keywords

Naproxen; Association of naproxen-esomeprazole; High pressure liquid chromatography; Cytochrome P450

Outcome Measures

Primary Outcomes (2)

• 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

• 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

Study Arms (2)

Naproxen

EXPERIMENTAL

20 patients will receive naproxen (one tablet 500 mg) to collected saliva samples for pharmacokinetic and pharmacogenetic studies

Drug: Naproxen

Naproxen-esomeprazole

EXPERIMENTAL

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

Drug: Naproxen-esomeprazole

Interventions

Naproxen DRUG

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).

Also known as: CYP2C9

Naproxen

Naproxen-esomeprazole DRUG

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).

Also known as: CYP2C9, CYP2C19

Naproxen-esomeprazole

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

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

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Sao Paulo: lead
• Fundação de Amparo à Pesquisa do Estado de São Paulo: collaborator

Study Sites (1)

Bauru School of Dentistry/USP

Bauru, São Paulo, 17012-901, Brazil

Location

MeSH Terms

Interventions

Naproxen; Cytochrome P-450 CYP2C9; Cytochrome P-450 CYP2C19

Intervention Hierarchy (Ancestors)

Naphthaleneacetic Acids; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Limonene Hydroxylases; Cytochrome P450 Family 2; Cytochrome P-450 Enzyme System; Cytochromes; Enzymes and Coenzymes; Mixed Function Oxygenases; Oxygenases; Oxidoreductases; Enzymes; Hemeproteins; Proteins; Amino Acids, Peptides, and Proteins

Study Officials

• Adriana M Calvo, PhD

  Bauru School of Dentistry/USP

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: March 15, 2017
• First Posted: March 27, 2017
• Study Start: March 1, 2017
• Primary Completion: October 1, 2017
• Study Completion: October 1, 2017
• Last Updated: November 3, 2020

Record last verified: 2020-11

Data Sharing

• IPD Sharing: Will not share

Locations

BR (1)