Pharmacokinetics of Mycophenolate Mofetil in Healthy Volunteers

This study has been completed.
Sponsor:
Information provided by:
National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT00128947
First received: August 9, 2005
Last updated: March 3, 2008
Last verified: May 2006
  Purpose

This study will examine how people differ in the way their bodies process and eliminate mycophenolate mofetil (MMF), a drug that is used to treat problems affecting the eye and immune system and to prevent organ rejection in transplant patients. MMF is metabolized by a group of enzymes called UGTs, each of which is made by a different gene. This study will investigate whether people with different UGT genes differ in how well their bodies use and remove MMF. The results may help scientists learn the best way to give MMF to patients.

Normal healthy volunteers between 18 and 55 years of age may be eligible for this study. Candidates are screened with a medical history, physical examination, and blood and urine tests, including a blood test for analysis of genes that control and regulate UGTs. Pregnant women and nursing mothers are excluded from the study. Women who are able to have a child and men who can father a child must either abstain from sex or use two reliable forms of birth control during the study and for 3 months after its completion.

Participants come to the NIH Clinical Center at 6:30 a.m. on the first day of the study and stay in the outpatient clinic for 12 hours. The next 4 mornings, they return to the Clinical Center for a single blood collection. The procedures for the 5 days are as follows:

Day 1

Upon arrival at the Clinical Center a catheter is inserted into the subject's arm vein. At 7:00 AM, the subject takes one dose of MMF by mouth with a glass of water. Small blood samples are collected through the catheter before the MMF dose and again at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours after taking the drug. Heart rate and blood pressure are measured before the blood collection and then every 4 hours. After the last blood sample is collected, the volunteer can return home.

Days 2-5

Volunteers come to the Clinical Center at 7:00 AM on study days 2, 3, 4, and 5 for a single blood draw, collected using a needle.

Volunteers are contacted by telephone 1, 2, and 3 months after completing the study to see how they are doing and to check on their pregnancy status and use of appropriate birth control.


Condition Intervention Phase
Healthy
Drug: Mycophenolic Acid
Drug: Mycophenolate 7-O-Phenolic Glucuronide
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Primary Purpose: Treatment
Official Title: Pharmacokinetics of Mycophenolic Acid and Mycophenolate 7-O-Phenolic Glucuronide in Healthy Subjects With or Without Two Common Genetic Polymorphisms in the Promoter Region of Uridine Diphosphate Glucuronosyltransferase 1A9

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Estimated Enrollment: 130
Study Start Date: July 2005
Estimated Study Completion Date: May 2006
Detailed Description:

The immunosuppressant mycophenolate mofetil (MMF) is metabolized by several uridine diphosphate glucuronosyltransferases (UGTs), among which UGT1A9 is the most important enzyme. Two commonly occurring single nucleotide polymorphisms (SNPs) in the promoter region of the UGT1A9 gene have been shown to enhance UGT1A9 protein level and activity in vitro. This study is to investigate the potential in vivo effects of these two SNPs on the metabolism and hence the pharmacokinetics of MMF metabolites. One hundred and thirty healthy volunteers will be screened for the presence of UGT1A9 C-2152T and T-275A polymorphisms. Seventeen subjects who carry the variant alleles, along with 17 others who do not have the polymorphisms, will be selected to participate in the pharmacokinetic study. Pharmacokinetics of the metabolites mycophenolic acid (active) and mycophenolate 7-O-phenolic glucuronide (inactive) will be determined, and parameter values will be compared between the two groups. It is hypothesized that the metabolism of MMF is enhanced in subjects with the two SNPs, resulting in an increase in clearance and a decrease in the exposure of mycophenolic acid.

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

INCLUSION CRITERIA:

  • Normal healthy volunteers who are in good health as determined by medical history, physical examination, and baseline laboratory tests
  • Age 18 - 55
  • Both males and females
  • Willingness to practice effective contraception during the study and for three months after the administration of MMF for women who are sexually active and have child bearing potential, and for sexually active males who have the potential to father a child. Barrier or non-hormonal methods will be allowed during the study, whereas the use of oral, injectable, or implantable hormones will be prohibited since drug interaction is known to occur between oral contraceptives and mycophenolate mofetil.
  • Subjects who are able to understand and sign the informed consent form.

EXCLUSION CRITERIA:

  • Children and adolescents less than 18 years of age
  • Individuals who smoke or have excessive alcohol (greater than 1 beer or an equivalent alcoholic beverage per day)
  • Pregnant women and nursing mothers
  • Subjects with certain underlying diseases which include diabetes, cardiovascular diseases, liver diseases, cancer, and human immunodeficiency virus infection
  • Individuals with compromised immune systems
  • Subjects who have an active infection
  • Individuals with history of biliary tract disease, and biliary or gastrointestinal surgery
  • Subjects with persistent diarrhea or other gastrointestinal problems that could impede drug absorption
  • Subjects with abnormal liver and kidney functions as determined by medication history and laboratory evaluation (AST and ALT less than or equal to 2 x upper normal limit, total bilirubin less than or equal to 1 mg/dL, serum creatinine less than or equal to 1.2 mg/dL, hemoglobin greater than or equal to 11 g/dL, WBC greater than or equal to 3.5 x 10(9)/L)
  • Volunteers on chronic prescribed and over-the-counter medications, and dietary and herbal supplements within 4 weeks of study participation
  • Subjects who are taking any medications that could potentially interact with MMF pharmacokinetically and pharmacodynamically such as eccinacea, iron preparations, antacids, bile-resin cholesterol lowering agents, and steroids.
  • Volunteers with documented allergy to MMF
  • Prior enrollment into a similar study within the past two months and enrollment in another study at the same time
  • Subjects who are felt to be unwilling or unable to practice effective contraception methods or comply with protocol specifications
  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: NCT00128947

Locations
United States, Maryland
National Institutes of Health Clinical Center (CC)
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
  More Information

Publications:
ClinicalTrials.gov Identifier: NCT00128947     History of Changes
Other Study ID Numbers: 050209, 05-CC-0209
Study First Received: August 9, 2005
Last Updated: March 3, 2008
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Immunosuppresant
Pharmacogenetics
Glucuronidation
Metabolism
UGT

Additional relevant MeSH terms:
Mycophenolate mofetil
Mycophenolic Acid
Antibiotics, Antineoplastic
Antineoplastic Agents
Enzyme Inhibitors
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on October 23, 2014