The Effect of Thyroid Hormone on Drug Elimination in Cancer Patients

This study has been completed.
Sponsor:
Information provided by:
National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT00080574
First received: April 7, 2004
Last updated: March 3, 2008
Last verified: November 2005
  Purpose

This study will examine whether and how levothyroxine (Synthroid, a synthetic thyroid hormone) affects the way the body handles other drugs. If levothyroxine does affect the metabolism of other drugs, the dose of those medications may need to be increased to enhance their action or decreased to avoid adverse reactions.

Patients 18 years of age and older with thyroid cancer who are participating in NIH protocol #77-DK-0096 and are receiving long-term suppression therapy with levothyroxine may be eligible for this study. This is not a study of thyroid cancer or of potential new drugs to treat it. Thyroid cancer patients are being studied because their treatment regimen provides an opportunity to study drug metabolism while patients are both on and off levothyroxine therapy.

Participants come to the NIH Clinical Center on two occasions: once while they are regularly taking their levothyroxine, and once while they are off the medication in preparation for their radioactive iodide diagnostic scan for the procedures outlined below. The time interval between the two clinic visits depends on whether the first visit is while the patient is on or off medication. Participants are asked to fast overnight before each visit and to abstain from certain foods and beverages for 48 to 72 hours before the visit. At each visit, patients undergo the following procedures:

  • Medication history, limited physical examination, and blood draw for laboratory tests, including a test to look for genes important in eliminating medications from the body.
  • Insertion of a catheter (thin plastic tube) into an arm vein for collecting blood samples.
  • Shave skin biopsy (optional) to explore how proteins in the skin that metabolize and transport drugs are affected by thyroid hormone. For this procedure, the skin is cleaned, numbed with medicine, and a small sample of the top layer is removed with a razor blade. The wound heals in 2 to 3 days.
  • Medication dosing. Participants take all of the following substances by mouth at the same time: 1) 200 mg of caffeine, a compound commonly found in chocolate, soda/pop, coffee, tea and non-prescription products to prevent sleep; 2) 30 mg of dextromethorphan, a non-prescription cough suppressant; 3) 40 mg of omeprazole, a prescription drug for heartburn and stomach ulcers; 4) 8 mg of midazolam, a prescription drug used to cause relaxation and drowsiness; and 5) 120 mg of fexofenadine, a non-sedating prescription antihistamine used to treat allergies.
  • Blood and urine sampling. Fifteen blood samples of about 5 mL (1 teaspoon) each are collected through the catheter and urine is collected over the next 24 hours to determine what happens to the test drugs in the body.

Participants may resume their normal diet 4 hours after taking the study medications.


Condition Intervention Phase
Thyroid Cancer
Procedure: Skin Biopsy
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Primary Purpose: Treatment
Official Title: The Effects of Thyroid Hormone on Cytochrome P450 and P-Glycoprotein Activity in Thyroid Cancer Patients

Resource links provided by NLM:


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

Estimated Enrollment: 20
Study Start Date: April 2004
Estimated Study Completion Date: November 2005
Detailed Description:

Interaction between thyroid hormones and commonly prescribed drugs has been well documented, resulting in augmentation or attenuation of the action of either compound. Phase I drug metabolism is mediated mostly by enzymes belonging to the cytochrome p450 superfamily. Studies in animals and cell cultures have shown that thyroid hormones play an important role in the constitutive expression of the p450 enzymes, thus potentially altering the metabolism and the effects of a variety of drugs. P-glycoprotein is expressed in the major organs associated with drug absorption, distribution, and elimination from the body (e.g. intestine, kidney, liver, skin, and the blood-brain barrier). Expression of intestinal P-glycoprotein in humans also appears to be influenced by thyroid hormones. We intend to study the effect of thyroid hormones on the activity of CYP1A2, CYP2C19, CYP2D6, CYP3A4 and P-glycoprotein by using a five-drug cocktail (caffeine, omeprazole, dextromethorphan, midazolam, and fexofenadine) administered in patients with thyroid cancer, both on thyroid hormone suppression therapy (in conditions of subclinical hyperthyroidism) and off this treatment (in conditions of hypothyroidism) at the time of their routine radioactive iodine scan. Additionally we will perform two skin biopsies in order to assess the pattern of expression of metabolic enzymes and drug transport proteins on and off thyroid hormone suppression therapy.

  Eligibility

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

INCLUSION CRITERIA:

  1. Subject has signed the informed consent document;
  2. Subject is greater than or equal to 18 years of age;
  3. Subjects diagnosed with thyroid cancer participating in protocol 77DK0096;
  4. Subjects receiving THST with levothyroxine;
  5. Serum TSH less than 0.4 mIU/L while on THST, and more than 20 mIU/L while off THST.

EXCLUSION CRITERIA:

Subject is pregnant, currently breast-feeding, practicing birth control with hormonal contraceptives, or is on hormone replacement therapy (HRT).

Subject is a smoker.

Subject has a confounding medical illness (es) that in the judgement of the investigators would pose an added risk for the subject (e.g. severe respiratory disease).

Subject has a history of substance abuse within the past 5 years or drug or alcohol use, that may affect enzyme levels and function.

Caffeine or caffeine-containing beverages and chocolate bars consumption within 48 hours of scheduled caffeine administration for CYP1A2 phenotyping; scheduled omeprazole administration during or within 14 days of the study; scheduled dextromethorphan administration during or within 30 days of study; scheduled fexofenadine administration during or within 7 days of the study.

AST or ALT greater than or equal to 2 times the upper normal reference limit.

Concurrent administration of known CYP and/or P-gp inducers (barbiturates, phenytoin, carbamazepine, rifampicin) and inhibitors (amiodarone, atorvastatin, chloroquine, cimetidine, co-trimoxazole, cyclosporine, diltazem, erythromycin, fluoxetine fluvoxamine, isoniazid, itrakonazole, ketokonazole, metronidazole, mexiletine, nefazadone, norfloxacin, verapamil) or use of any alternative/complementary therapies for at least 30 days prior to study or during the study. Non-herbal vitamin and mineral preparations will be allowed.

Inability to obtain venous access for sample collection, or basal hemoglobin of equal or less than 10 g/dl.

Patients receiving scheduled therapy with alprazolam, triazolam, clonazepam, diazepam, lorazepam, oxazepam, temazepam or chlorodiazepoxide, during or within 30 days of study.

Patients consuming grapefruit products (juice or the fresh fruit), apple and orange juice during or within 72 hrs of study.

History of intolerance to caffiene, omeprazole, dextromethorphan, midazolam or fexofenadine.

The presence of persistent diarrhea or malabsorption syndromes that would interfere with the patient's ability to adequately absorb drugs; and/or

Patients receiving monoamine oxidase inhibitors (MAOIs) such as phenelzine, tranylcypromine, and isocarboxazid.

Patients with a history of cheloids formation.

  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: NCT00080574

Locations
United States, Maryland
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
  More Information

Publications:
ClinicalTrials.gov Identifier: NCT00080574     History of Changes
Other Study ID Numbers: 040140, 04-DK-0140
Study First Received: April 7, 2004
Last Updated: March 3, 2008
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Pharmacokinetics
Drug Metabolism
Levothyroxine
Hypothyroidism
Hyperthyroidism
Drug Interactions
Cytochrome P450
P-Glycoprotein
Drug Transport Proteins
Thyroid Hormone
Thyroid Cancer

Additional relevant MeSH terms:
Thyroid Neoplasms
Thyroid Diseases
Endocrine Gland Neoplasms
Neoplasms by Site
Neoplasms
Head and Neck Neoplasms
Endocrine System Diseases
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 24, 2014