Official Title: “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 Type: Interventional

Study Design: Basic Science, Randomized, Open Label, Active Control, Crossover Assignment, Pharmacokinetics Study

Study Primary Completion Date: December 2008

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.

Intervention(s) in this Clinical Trial

• Dietary Supplement: Grapefruit juice
  • Coingestion of 240 ml of grapefruit juice with 10 mg of montelukast.
• Dietary Supplement: Orange Juice
  • Coingestion of 240 ml of orange juice with 10 mg of montelukast.
• Dietary Supplement: Gatorade
  • Coingestion of 240 ml of Gatorade with 10 mg of montelukast.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
  • Coingestion of 240 ml of grapefruit juice with 10 mg of montelukast.
• Active Comparator: 2
  • Coingestion of 240 ml of orange juice with 10 mg of montelukast.
• Placebo Comparator: 3
  • Coingestion of 240 ml of Gatorade with 10 mg of montelukast.

Primary 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.
    Safety Issue?: No

Secondary 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.
    Safety Issue?: No

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

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 15 Years

Maximum Age for this Clinical Trial: 18 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Nemours Children's Clinic

Overall Clinical Trial Officials and Contacts

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

Overall Contact: Laurie J Duckworth, ARNP (904) 390-3465 lduckworth@nemours.org

Information obtained from ClinicalTrials.gov on September 05, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00513760

Study ID Number: 32711

ClinicalTrials.gov Identifier: NCT00513760

Health Authority: United States: Institutional Review Board

Merck's Singulair site