Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

Transporter Mediated Uptake of Montelukast (TPORT)

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2014 by Nemours Children's Clinic
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Ed Mougey, Nemours Children's Clinic
ClinicalTrials.gov Identifier:
NCT00513760
First received: August 7, 2007
Last updated: January 23, 2014
Last verified: January 2014
  Purpose

Leukotriene receptor antagonists (LTRAs) are frequently prescribed to reduce the symptoms associated with asthma. Singulair, manufactured by Merck, is a popular LTRA, however its effectiveness varies greatly between individuals. We are interested in understanding why the effectiveness of Singulair varies so greatly.

For an oral drug such as Singulair to be effective, the body must efficiently absorb it. We have found that blood levels of Singulair vary greatly between individuals, and we think that this variability is responsible for variability in response.

Drug absorption occurs primarily in the intestine. Due to differences in the chemical properties of drugs, some drugs can be absorbed easily while other drugs require help from special proteins produced by the cells that line the intestine. These proteins, or transporters act like turnstiles to allow drugs to move from the intestine to the bloodstream and are known to be inhibited by components of citrus juice. The activity of a transporter can be influenced by individual genetic variability.

We think that Singulair requires help from a transport protein to be absorbed and that genetic variability in this transporter leads to variability in the blood level of Singulair. In this proposal we will use citrus juice (grapefruit and orange) to inhibit intestinal membrane transport proteins and show that Singulair requires these transporters to be efficiently absorbed. Eventually, what we learn from this work will allow doctors to quickly test individuals with asthma to determine how well they will absorb Singulair and possibly other LTRAs. Knowing this will allow the doctor to adjust the drug treatment on an individual basis to maximize benefit in the treatment of asthma.


Condition Intervention
Asthma
Dietary Supplement: Grapefruit juice
Dietary Supplement: Orange Juice
Dietary Supplement: Gatorade

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Basic Science
Official Title: Characterization of Transporter Mediated Uptake of Montelukast in Humans

Resource links provided by NLM:


Further study details as provided by Nemours Children's Clinic:

Primary Outcome Measures:
  • Area under the concentration vs. time curve for the serum concentration of montelukast when coingested with grapefruit juice, orange juice, or Gatorade. [ Time Frame: Within 12 hours after administration of a single 10 mg dose. ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Improvement in respiratory function as assessed by spirometry, and impulse oscillometry vs. serum concentration of montelukast. [ Time Frame: Within 12 hours after administration of a single 10 mg dose. ] [ Designated as safety issue: No ]

Estimated Enrollment: 27
Study Start Date: June 2007
Estimated Study Completion Date: September 2014
Estimated Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
Coingestion of 240 ml of grapefruit juice with 10 mg of montelukast.
Dietary Supplement: Grapefruit juice
Coingestion of 240 ml of grapefruit juice with 10 mg of montelukast.
Other Name: Brand: Great Value frozen concentrated grapefruit juice(Walmart).
Active Comparator: 2
Coingestion of 240 ml of orange juice with 10 mg of montelukast.
Dietary Supplement: Orange Juice
Coingestion of 240 ml of orange juice with 10 mg of montelukast.
Other Name: Brand: Winn Dixie orange juice (Winn Dixie).
Placebo Comparator: 3
Coingestion of 240 ml of Gatorade with 10 mg of montelukast.
Dietary Supplement: Gatorade
Coingestion of 240 ml of Gatorade with 10 mg of montelukast.
Other Name: Brand: Gatorade Rain.

Detailed Description:

Montelukast (Merck brand name Singulair) is a selective Cys-LT1 receptor antagonist that is used to control asthma symptoms in children and adults. Although safe and effective, the inter-patient variability in response is substantial (25-60% response rate), which is due in part to genetic variability. For example, we recently reported that polymorphisms in candidate genes that encode proteins in the LT pathway influence responsiveness to the drug.

The long-range goal of our studies is to determine the contribution of genetic variability to the inter-patient variability in montelukast blood levels and responsiveness. In preliminary studies, we found that the plasma concentration vs. time data in single and multiple dose-studies vary more than 10-fold, which could contribute to inter-patient variability in response.

Montelukast is about 64% bioavailable, is cleared by CYP2C9 and CYP3A4 in the liver, and is nearly completely excreted into the bile. The physical properties of montelukast suggest that the drug undergoes transport by solute carrier transporters (SLC family transporters) and/or ATP-binding cassette transporters (ABC family transporters). Recent studies support the idea that genetic variation in genes encoding SLC and ABC transporters can influence the pharmacokinetics of drugs that are substrates for these transporters.

In the present submission, we propose to determine if montelukast is a substrate for SLC and/or ABC transporters. To accomplish this we will coadminister Singulair with citrus juice which contains known inhibitors of membrane transport proteins. If transporters are involved in the absorption of montelukast, then citrus juice should decrease the absorption of montelukast relative to Gatorade. Our working hypothesis for this study is that montelukast is a substrate for SLC (OATP1B3, OATP1B1, OATP2B1, OATP1A2) and ABC (MRP1, MRP2, and MRP3, BCRP) transporters. If true, then the pharmacokinetics of montelukast will be determined by the genetics of the membrane transporters. This highly significant observation will have important implications for understanding the disposition of montelukast in patients, and ultimately will lead to individualization of montelukast therapy in asthma.

  Eligibility

Ages Eligible for Study:   15 Years to 18 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Doctor diagnosed asthma.
  • Must not be taking any medications except for inhaled steroids.

Exclusion Criteria:

  • Clinical conditions other than asthma.
  • Upper respiratory tract infection within the past 30 days.
  • Gastrointestinal conditions.
  • Unable to stop taking or are required to begin taking any type of oral medication for the duration of the trial
  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: NCT00513760

Contacts
Contact: Stacey L Gray (904) 697-3683 slgray@nemours.org
Contact: Jenny M Batalla (904) 697-3506 jbatalla@nemours.org

Locations
United States, Florida
Nemours Children's Clinic Recruiting
Jacksonville, Florida, United States, 32207
Contact: Stacey L Gray    904-697-3683    slgray@nemours.org   
Contact: Jenny M Batalla    (904) 697-3506    jbatalla@nemours.org   
Principal Investigator: Edward B Mougey, Ph.D.         
Sub-Investigator: John J Lima, PharmD         
Sub-Investigator: Jason E Lang, MD         
Sponsors and Collaborators
Nemours Children's Clinic
Merck Sharp & Dohme Corp.
Investigators
Principal Investigator: Edward B Mougey, Ph.D. Nemours Children's Clinic
  More Information

Additional Information:
Publications:
Responsible Party: Ed Mougey, Reserach Scientist, Nemours Children's Clinic
ClinicalTrials.gov Identifier: NCT00513760     History of Changes
Other Study ID Numbers: 32711, 32-03215-003
Study First Received: August 7, 2007
Last Updated: January 23, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Nemours Children's Clinic:
Pharmacogenetics
Singulair
montelukast
Leukotriene Antagonists
Anti-Asthmatic Agents
Intestinal Absorption
pharmacokinetics
absorption
biochemical transport
Membrane Transport Proteins
Drug Interactions

Additional relevant MeSH terms:
Montelukast
Anti-Asthmatic Agents
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Leukotriene Antagonists
Pharmacologic Actions
Physiological Effects of Drugs
Respiratory System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on November 20, 2014