Naproxen Pharmacogenetic Study (Project 1, Aim 2)

Project 1: Program on Genetic and Dietary Predictors of Drug Response in Rural and AI/AN Populations (Naproxen Study)

This is a mechanism-based study in healthy adults to determine the effect of the CYP2C9 M1L gene polymorphism on the functional activity of the encoded CYP2C9 enzyme towards the probe substrate naproxen. CYP2C9 activity will be evaluated by measurement of O-desmethyl naproxen and unchanged naproxen in 24-hour urine following administration of a single oral dose of naproxen (Aleve) in Yup'ik Alaska Native adult men and women who were previously determined in a separate observational study to be homozygous for the CYP2C9*1 allele or a carrier of the CYP2C9 M1L allele.

Study Overview

• Status: Unknown
• Conditions: Pharmacogenetics
• Intervention / Treatment: Drug: Naproxen tablet

Detailed Description

This pharmacogenetics study will test the hypothesis that inheritance of a M1L variant in the CYP2C9 gene, which was first discovered in Yup'ik Alaska Native people, causes complete loss of function in CYP-2C9-dependent catalytic activity.

Study participants will be selected from a cross-sectional population of >750 Yup'ik men and women, ≥18 years, for whom CYP2C9 genotype has already been determined as part of a SNP discovery study, and who consented to be contacted for future research. There will be 15 participants in each of two genotyped groups ((1) Met1/Met1 and (2) Met1/Leu1 or Leu1/Leu1), for a total of 30 participants. The two groups will be matched for sex of the participants; the proportion determined by the composition of the least frequent Leu1 carrier group. The investigators will attempt to recruit a similar range of ages in each genotyped group and the widest range possible. Recruitment will occur in one of 10 communities in the Yukon-Kuskokwim delta that participated in our original SNP discovery study.

Participants will be asked to fast overnight prior to the study and will be allowed to eat ad libitum 2 hours after naproxen is taken. A fasting 13 ml venous blood sample will be collected from each participant for isolation of DNA and plasma. Spot urine will be collected from each participant as an analytic control the morning of the blood draw. At approximately 9 am, each participant will be given a single 220-mg dose of Naproxen, by mouth, with a glass of water. The total urine output over the next 24-hour will be collected by the participant and returned to the clinic the next day. The urine volume will be measured and recorded and two 5 mL aliquots will be frozen at -80°C and stored for unchanged drug and metabolite analysis analyses.

Total (conjugated and unconjugated) 6-O-Desmethyl naproxen and unchanged naproxen concentrations in urine will be measured by LC-MS/MS. A ratio of the total 6-O-desmethyl naproxen/naproxen (M/P) excreted in urine over 24-hours will be computed. 6-O-desmethyl naproxen is formed selectively by CYP2C9.

Pairwise comparison of the mean M/P ratios, assuming unequal variance, will be evaluated using a t-test to determine if there are significant differences in activity for carriers of the Leu 1 variant. The sample size provides 80% power to detect a difference, at a significance level of 0.05.

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Kenneth E. Thummel, PhD; Phone Number: 205-543-0819; Email: thummel@uw.edu

Study Locations

• United States
  • Oregon
    • Portland, Oregon, United States, 97239-3098
      • Recruiting
      • Oregon Health & Science University
      • Contact: Bert B. Boyer, PhD; Phone Number: 503-494-3368; Email: boyerbe@ohsu.edu
      • Contact: Scarlett Hopkins, RN, MA; Phone Number: 503-494-3369; Email: hopkisca@ohsu.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. No history of significant medical conditions including cardiac, pulmonary, gastrointestinal, or renal disease, HIV, or history of asthma, urticaria, or allergic-type reactions with aspirin (ASA) or other NSAID (nonsteroidal anti-inflammatory drug).
2. Both males or females 18 years and older.
3. Self-identified as Yup'ik or Cup'ik
4. Able to read and understand English or Yup'ik.
5. Able to provide informed consent.
6. Women not currently pregnant or lactating.

Exclusion Criteria:

1. Individuals with any significant chronic medical condition, including cardiac, pulmonary, hepatic, gastrointestinal, or renal disease, HIV, or history of asthma, urticaria, or allergic-type reactions with aspirin (ASA) or other NSAID
2. Individuals less than 18 years of age.
3. Individuals unable to read and understand English or Yup'ik.
4. Individuals unable to provide informed consent.
5. Individuals taking drugs or natural products known to affect the metabolic activity of CYP2C9 (e.g., rifampin, carbamazepine, barbiturates, phenytoin, valproic acid, fluconazole, ketoconazole, miconazole, amiodarone, fluvastatin and milk thistle.
6. Women who are pregnant or lactating.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Naproxen Tablet; Subjects will received a single 220-mg dose of naproxen sodium (Aleve) by mouth.	Drug: Naproxen tablet; For this single intervention arm, each subject will receive a single 220-mg dose of naproxen sodium (Aleve), followed by urine collection for 24-hours.; Other Names: Aleve

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
6-O-desmethyl naproxen/naproxen ratio	A ratio of the total mount of 6-O-desmethyl naproxen/unchanged naproxen in 24-hour urine	24-hours

Collaborators and Investigators

• Sponsor: University of Washington
• Collaborators: Oregon Health and Science University; National Institute of General Medical Sciences (NIGMS)
• Investigators: Principal Investigator: Kenneth E. Thummel, PhD, University of Washington

Study record dates

Study Major Dates

• Study Start (Actual): January 12, 2016
• Primary Completion (Anticipated): July 31, 2021
• Study Completion (Anticipated): July 31, 2022

Study Registration Dates

• First Submitted: June 23, 2020
• First Submitted That Met QC Criteria: June 23, 2020
• First Posted (Actual): June 26, 2020

Study Record Updates

• Last Update Posted (Actual): June 29, 2020
• Last Update Submitted That Met QC Criteria: June 25, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: CYP2C9; naproxen; polymorphism
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Gout Suppressants; Naproxen
• Other Study ID Numbers: SITE00000671; 5P01GM116691 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No