Contribution of UGT2B17 to the Pharmacokinetics of Diclofenac

NCT06053411 | Recruiting Early Phase 1 FDA Drug

• 1 other identifier: 20104
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this pilot study is to gather preliminary data on the (1) contribution of the understudied drug metabolizing enzyme, UDP-glucuronosyltransferase (UGT) 2B17, to the metabolism of a widely used medication, diclofenac, and (2) impact of the UGT2B17 inhibitor and natural product, curcumin, on diclofenac pharmacokinetics. Results will inform future studies aimed to assess the effects of UGT2B17 genetic polymorphisms and co-consumed xenobiotics on the pharmacokinetics and toxicity risk of diclofenac and other UGT2B17 drug substrates.

Conditions

Interaction

Keywords

Pharmacokinetic

Outcome Measures

Primary Outcomes (12)

• Diclofenac area under the concentration vs. time curve (AUC) in UGT2B17 extensive metabolizers (EMs)

  Diclofenac AUC in UGT2B17 EMs

  0-12 hours

• Diclofenac AUC in poor metabolizers (PMs)

  Diclofenac AUC in UGT2B17 PMs

  0-12 hours

• Diclofenac AUC in EMs in the presence of curcumin

  Diclofenac AUC in UGT2B17 EMs in the presence of curcumin

  0-12 hours

• Diclofenac maximum concentration (Cmax) in EMs

  Diclofenac Cmax in UGT2B17 EMs

  0-12 hours

• Diclofenac Cmax in PMs

  Diclofenac Cmax in UGT2B17 PMs

  0-12 hours

• Diclofenac Cmax in EMs in the presence of curcumin

  Diclofenac Cmax in UGT2B17 EMs in the presence of curcumin

  0-12 hours

• Diclofenac renal clearance (CLr) in EMs

  Diclofenac CLr in UGT2B17 EMs

  0-12 hours

• Diclofenac CLr in PMs

  Diclofenac CLr in UGT2B17 PMs

  0-12 hours

• Diclofenac CLr in EMs in the presence of curcumin

  Diclofenac CLr in UGT2B17 EMs in the presence of curcumin

  0-12 hours

• Diclofenac half-life (t1/2) in EMs

  Diclofenac t1/2 in UGT2B17 EMs

  0-12 hours

• Diclofenac half-life (t1/2) in PMs

  Diclofenac t1/2 in UGT2B17 PMs

  0-12 hours

• Diclofenac half-life (t1/2) in EMs in the presence of curcumin

  Diclofenac t1/2 in UGT2B17 EMs in the presence of curcumin

  0-12 hours

Study Arms (2)

Arm 1: diclofenac alone (baseline)

EXPERIMENTAL

A single dose of diclofenac (25 mg capsule) will be administered by mouth to 5 participants (minimum 2 females) genotyped as extensive metabolizers (Arm 1A) and 5 participants (minimum 2 females) genotyped as poor metabolizers (Arm 1B). Plasma and urine will be collected from 0-12 hours. A washout of at least 3 days will elapse between Arm 1 and Arm 2.

Drug: Diclofenac

Arm 2: diclofenac + curcumin

EXPERIMENTAL

A single oral dose of diclofenac (25 mg capsule) and a single oral dose of curcumin (2,000 mg tablet) will be administered by mouth to the 5 participants genotyped as extensive metabolizers. Plasma and urine will be collected from 0-12 hours.

Drug: Diclofenac; Dietary Supplement: curcumin

Interventions

Diclofenac DRUG

25 mg capsule

Also known as: Voltaren

Arm 1: diclofenac alone (baseline); Arm 2: diclofenac + curcumin

curcumin DIETARY_SUPPLEMENT

2,000 mg tablet

Arm 2: diclofenac + curcumin

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Aged from 18-64 years and healthy
• Not taking any medications (prescription and non-prescription) or dietary/herbal supplements known to alter the pharmacokinetics of diclofenac or curcumin
• Willing to abstain from consuming caffeinated beverages or other caffeine-containing products the evening before and morning of the first day of each study arm
• Willing to abstain from consuming any alcoholic beverages for one day prior to any study day, during the 14-hour inpatient days, and for the outpatient visit(s) following the 14-hour days
• Willing to use a secondary method of birth control that does not include the introduction or discontinuance of hormonal-based birth control (such as abstinence, copper IUD, or condoms)
• Have the time to participate
• Written informed consent (and assent when applicable) obtained from subject or subject's legal representative and ability for the subject to comply with the requirements of the study

You may not qualify if:

• Under the age of 18 or over the age of 65 years
• Smoke/vape/chew tobacco products
• Use cannabis products, including marijuana, hemp, and other THC- or CBD-containing products
• Have any current major illness or chronic illness such as (but not limited to) kidney disease, hepatic disease, diabetes mellitus, hypertension, coronary artery disease, chronic obstructive pulmonary disease, cancer, or HIV/AIDS
• History of anemia or any other significant hematologic disorder
• History of drug or alcohol addiction or major psychiatric illness
• Pregnant or nursing or plan to become pregnant within 3 weeks after participation
• History of allergy intolerance to diclofenac or curcumin
• Taking concomitant medications, both prescription and non-prescription (including dietary supplements/herbal products), known to alter the pharmacokinetics of diclofenac or curcumin
• Taking any turmeric spice or curcumin supplement
• Presence of a condition or abnormality that, in the opinion of the Investigator, would compromise participant safety or quality of the data
• Out-of-range clinical laboratory value that the study physician considers participation in the study a health risk

Sponsors & Collaborators

• Washington State University: lead

Study Sites (1)

Washington State University College of Pharmacy and Pharmaceutical Sciences

Spokane, Washington, 99202, United States

RECRUITING

Related Publications (5)

• Schjerning AM, McGettigan P, Gislason G. Cardiovascular effects and safety of (non-aspirin) NSAIDs. Nat Rev Cardiol. 2020 Sep;17(9):574-584. doi: 10.1038/s41569-020-0366-z. Epub 2020 Apr 22.

  PMID: 32322101 BACKGROUND

• Whirl-Carrillo M, Huddart R, Gong L, Sangkuhl K, Thorn CF, Whaley R, Klein TE. An Evidence-Based Framework for Evaluating Pharmacogenomics Knowledge for Personalized Medicine. Clin Pharmacol Ther. 2021 Sep;110(3):563-572. doi: 10.1002/cpt.2350. Epub 2021 Jul 22.

  PMID: 34216021 BACKGROUND

• Ahire D, Heyward S, Prasad B. Intestinal Metabolism of Diclofenac by Polymorphic UGT2B17 Correlates with its Highly Variable Pharmacokinetics and Safety across Populations. Clin Pharmacol Ther. 2023 Jul;114(1):161-172. doi: 10.1002/cpt.2907. Epub 2023 Apr 29.

  PMID: 37042794 BACKGROUND

• Xue Y, Sun D, Daly A, Yang F, Zhou X, Zhao M, Huang N, Zerjal T, Lee C, Carter NP, Hurles ME, Tyler-Smith C. Adaptive evolution of UGT2B17 copy-number variation. Am J Hum Genet. 2008 Sep;83(3):337-46. doi: 10.1016/j.ajhg.2008.08.004. Epub 2008 Aug 28.

  PMID: 18760392 BACKGROUND

• Wang YH, Trucksis M, McElwee JJ, Wong PH, Maciolek C, Thompson CD, Prueksaritanont T, Garrett GC, Declercq R, Vets E, Willson KJ, Smith RC, Klappenbach JA, Opiteck GJ, Tsou JA, Gibson C, Laethem T, Panorchan P, Iwamoto M, Shaw PM, Wagner JA, Harrelson JC. UGT2B17 genetic polymorphisms dramatically affect the pharmacokinetics of MK-7246 in healthy subjects in a first-in-human study. Clin Pharmacol Ther. 2012 Jul;92(1):96-102. doi: 10.1038/clpt.2012.20. Epub 2012 Jun 6.

  PMID: 22669291 BACKGROUND

MeSH Terms

Interventions

Diclofenac; Curcumin

Intervention Hierarchy (Ancestors)

Phenylacetates; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Diarylheptanoids; Heptanes; Alkanes; Hydrocarbons, Acyclic; Hydrocarbons; Catechols; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic

Central Study Contacts

Mary F Paine, RPh, PhD

CONTACT

509-358-7759; mary.paine@wsu.edu

Siavosh Naji-Talakar, PharmD, MS

CONTACT

509-358-7739; s.naji-talakar@wsu.edu

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: September 15, 2023
• First Posted: September 25, 2023
• Study Start: March 1, 2024
• Primary Completion: December 18, 2025
• Study Completion (Estimated): August 18, 2026
• Last Updated: November 18, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)