Transporter Mediated Uptake of Montelukast (TPORT)

January 21, 2020 updated by: Ed Mougey, Nemours Children's Clinic

Characterization of Transporter Mediated Uptake of Montelukast in Humans

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

27

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Florida
      • Jacksonville, Florida, United States, 32207
        • Nemours Children's Clinic

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

15 years to 18 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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 Names:
  • 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 Names:
  • 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 Names:
  • Brand: Gatorade Rain.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
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.
Within 12 hours after administration of a single 10 mg dose.

Secondary Outcome Measures

Outcome Measure
Time Frame
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.
Within 12 hours after administration of a single 10 mg dose.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Nemours Children's Clinic

Collaborators

Merck Sharp & Dohme LLC

Investigators

  • Principal Investigator: Edward B Mougey, Ph.D., Nemours Children's Clinic

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2007

Primary Completion (Actual)

September 1, 2014

Study Completion (Actual)

December 1, 2014

Study Registration Dates

First Submitted

August 7, 2007

First Submitted That Met QC Criteria

August 8, 2007

First Posted (Estimate)

August 9, 2007

Study Record Updates

Last Update Posted (Actual)

January 22, 2020

Last Update Submitted That Met QC Criteria

January 21, 2020

Last Verified

January 1, 2020

More Information

Terms related to this study

Keywords

Other Study ID Numbers

  • 32711
  • 32-03215-003 (Other Grant/Funding Number: Nemours internal activity number)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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