Effects of Genotype on CYP2C9 Drug Interactions

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
University of Minnesota - Clinical and Translational Science Institute
ClinicalTrials.gov Identifier:
NCT01061112
First received: January 29, 2010
Last updated: November 12, 2013
Last verified: November 2013
  Purpose

This research study will help determine how a person's genetic makeup affects their responses to drugs, the ability of the body to break down drugs, and their potential to experience an interaction between drugs. We are investigating the drug interactions between an antifungal drug called fluconazole and the commonly used drugs tolbutamide, flurbiprofen, and ketoprofen. Tolbutamide is used for management of Type 2 diabetes. Both flurbiprofen and ketoprofen are non-steroidal anti-inflammatory drugs (NSAIDs) often used for arthritis or pain. We are interested in studying whether individuals with certain genetic profiles have different drug interactions than normal. This research is being done to see if certain genetic profiles require us to adjust medication doses differently than is needed for the general population. Genetic profiles of subjects are determined from their previous participation in the Pharmacogenetics Registry (Investigator Richard Brundage, University of Minnesota).

The study hypothesis is: Fraction metabolized by CYP2C9 enzyme determines the extent of drug interactions in CYP2C9*1/*1 individuals but this factor (fraction metabolized) becomes less influential and drug interactions are attenuated in a gene-dose dependent manner in individuals with one or more defective alleles.


Condition Intervention
Healthy
Genetic: Pharmacogenetics

Study Type: Observational
Study Design: Observational Model: Case-Crossover
Time Perspective: Prospective
Official Title: Effects of Genotype on CYP2C9 Drug Interactions

Resource links provided by NLM:


Further study details as provided by University of Minnesota - Clinical and Translational Science Institute:

Primary Outcome Measures:
  • Blood sample measurements during each study visit during the study periods will quantify the extent to which the fraction metabolized and variant genotypes interact to determine the magnitude of drug interactions. [ Time Frame: Over six 3-day study periods. ] [ Designated as safety issue: No ]

Enrollment: 23
Study Start Date: December 2009
Estimated Study Completion Date: June 2014
Estimated Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)
Groups/Cohorts Assigned Interventions
Crossover
Three study periods for all subjects.
Genetic: Pharmacogenetics
Fluconazole, tolbutamide, ketoprofen, flurbiprofen
Other Name: Diflucan, Arudis, Ansaid, Orincea

Detailed Description:

The study hypothesis is: Fraction metabolized by CYP2C9 enzyme determines the extent of drug interactions in CYP2C9*1/*1 individuals but this factor (fraction metabolized) becomes less influential and drug interactions are attenuated in a gene-dose dependent manner in individuals with one or more defective alleles.

Objective: Examine the extent of fluconazole inhibition of drugs with varying degrees of fraction metabolized by CYP2C9 in individuals with the CYP2C9*1/*1, CYP2C9*1/*3 and CYP2C9*3/*3 genotypes.

People differ in their genetic makeup. This includes differences in genes involved in drug metabolism, transport, and effect in the body. People with certain genetic profiles produce altered enzymes, transporters, and receptors that may respond in different ways to drugs. Altered enzymes cause some drugs to be broken down at a different rate than normal. As a result, drug concentrations build up in the blood, and increase the risk of side effects. Furthermore, when two drugs are taken together, the possibility exists for the drugs to interact, with one drug causing a change in the metabolism of the other or both of the drugs. It is not known whether people with an altered genetic makeup also have an altered experience with drug interactions. Altered drug transporters can affect the absorption and elimination of drugs as compared to normal causing differences in how long the drug stays in the body. Finally, altered drug receptors can respond differently to drugs and, thus, produce altered desired or undesired effects.

In this study, we will be investigating the drug interactions between an antifungal drug called fluconazole and the commonly used drugs tolbutamide, flurbiprofen, and ketoprofen in subjects with three different alleles of the CYP2C9 genotype. Tolbutamide is used for management of Type 2 diabetes. Both flurbiprofen and ketoprofen are non-steroidal anti-inflammatory drugs (NSAIDs) often used for arthritis or pain. We are interested in studying whether individuals with certain genetic profiles have different drug interactions than normal. This research is being done to see if certain genetic profiles require us to adjust medication doses differently than is needed for the general population.

The cytochrome P450 (CYP) superfamily of enzymes plays an important role in the oxidative conversion of numerous xenobiotics into their more hydrophilic metabolites. CYP2C9, is an important member of the CYP superfamily, accounting for 10-20% of the CYP protein content in human liver and catalyzes approximately 20% of the CYP mediated drug oxidation reactions, including tolbutamide and the non-steroidal anti-inflammatory drugs (NSAIDs) such as ketoprofen and flurbiprofen. It is now well established that genetic factors play an important role in the control of CYP2C9 expression and activity. In particular, the *3 allele is expressed at an allele frequency of 15%. Homozygotic *3 individuals exhibit significantly reduced oral clearance for several CYP2C9 substrates. In most of these cases, the reduction in clearance approaches 80% and even in heterozygotic individuals, this reduction in clearance is 40-50% due to the co-dominant expression of CYP2C9. This reduction in clearance has been associated with an increased frequency of adverse events following warfarin or phenytoin administration, two clinically important drugs that exhibit a narrow therapeutic index. The therapeutic index is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxic effects.

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population

Subjects are selected from a pharmacogenetics registry in which their drug metabolism genotype has been determined.

Criteria

Inclusion Criteria:

  • Subjects will be 18-60 years old.
  • Women of child-bearing age must be willing to use measures to avoid conception during the study period.
  • Subjects must agree not to take any known substrates, inhibitors, inducers or activators of CYP2C9

Exclusion Criteria:

  • Current cigarette smoker
  • Abnormal renal, liver function tests, physical exam, or recent history of hepatic, renal, gastrointestinal or neoplastic disease.
  • Allergy to tolbutamide, flurbiprofen, ketoprofen, fluconazole or phenytoin and other chemically related drugs.
  • Recent ingestion (< 1 week) of any medication known to be metabolized by or alter CYP2C9 activity.
  • A positive pregnancy test during the time of the pharmacokinetic study
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01061112

Locations
United States, Minnesota
Clinical and Translational Science Institute
Minneapolis, Minnesota, United States, 55414
Sponsors and Collaborators
University of Minnesota - Clinical and Translational Science Institute
Investigators
Principal Investigator: Richard Brundage, PhD University of Minnesota - Clinical and Translational Science Institute
  More Information

No publications provided

Responsible Party: University of Minnesota - Clinical and Translational Science Institute
ClinicalTrials.gov Identifier: NCT01061112     History of Changes
Other Study ID Numbers: 0812M56082, R01GM069753
Study First Received: January 29, 2010
Last Updated: November 12, 2013
Health Authority: United States: Institutional Review Board
United States: Federal Government

Keywords provided by University of Minnesota - Clinical and Translational Science Institute:
drug interactions
genetics
healthy volunteers
normal controls
CYP2C9

ClinicalTrials.gov processed this record on September 18, 2014