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Genotype Stratified Pharmacokinetic Study of Montelukast (GSPOM)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01086527
Recruitment Status : Completed
First Posted : March 15, 2010
Last Update Posted : January 23, 2020
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Ed Mougey, Nemours Children's Clinic

Brief Summary:

Leukotriene receptor antagonists (LTRAs) are frequently prescribed to reduce the symptoms associated with asthma. Singulair (montelukast), 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 revolving doors to allow drugs to move from the intestine to the bloodstream. The activity of a transporter can be influenced by individual genetic variability.

We think that adsorption of Singulair requires help from a transport protein called OATP2B1. We have found that a single common genetic change in this protein is associated with low plasma concentration of montelukast. In this proposal we will determine plasma levels of montelukast in individuals with two copies of this genetic change. We predict that these individuals will have roughly half the plasma level of montelukast as individuals with no copies of this genetic change.

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 or disease Intervention/treatment Phase
Asthma Drug: 10 mg tablet of montelukast (Singulair) Phase 1

Detailed Description:

We have previously reported that montelukast is a substrate for transport by OATP2B1 and that a common variant of SLCO2B1 (the gene coding for OATP2B1), c.[935G>A], which results in the substitution of Arg→Glu at amino acid position 312, was associated with steady-state plasma concentrations of montelukast and response(1). Compared to G/G homozygotes, A/G heterozygotes had lower plasma concentrations at both 1 and 6 months of therapy. Additionally, scores on the Asthma Symptom Utility Index were higher (better asthma control) in G/G homozygotes compared to A/G heterozygotes at both sampling intervals, but not prior to treatment. We concluded that genotype at c.935 may contribute to the variability in response to montelukast.

We recently completed a study of the influence of genotype at c.935 and the co-ingestion of citrus juice on the pharmacokinetics of a single 10-mg dose of montelukast in 26 adolescent subjects with physician-diagnosed asthma (NCT00513760). Twenty-one participants were genotyped as G/G homozygotes and five as A/G heterozygotes. The area under the montelukast plasma concentration vs. time curve (AUC) in A/G heterozygotes was 46% lower than the AUC in G/G homozygotes, replicating our earlier findings that genotype at c.935 influences the pharmacokinetics of montelukast.

Assuming an additive genetic model, our data predict that the AUC of montelukast in individuals carrying the A/A genotype would be even lower than in heterozygotes. The prevalence of the homozygous mutant allele (A/A) is low among African and European Americans (0 - 3%; However the prevalence of the A/A genotype is 18% in both Asian Americans and Hispanics, and thus these racial / ethnic groups represent an ideal model to test the hypothesis that genotype at c.935 influences the pharmacokinetics and pharmacodynamics of montelukast. In this study, we will generate preliminary data showing that the AUC of montelukast is lowest in A/A, intermediate in A/G and highest in G/G and confirm the suitability of this model to replicate our earlier findings that genotype at c.935 is associated with response to montelukast.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 2 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Genotype Stratified Pharmacokinetic Study of Montelukast
Study Start Date : March 2010
Actual Primary Completion Date : September 2014
Actual Study Completion Date : December 2014

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: SLCO2B1{NM_007256.2}:c.[935G>A] + [=]
Individuals in this group will be homozygous for SLCO2B1{NM_007256.2}:c.[935G>A].
Drug: 10 mg tablet of montelukast (Singulair)
Fasting patients will take a single 10 mg tablet of montelukast with 240 ml of Gatorade. Eight blood samples will be drawn to assess the plasma concentration of montelukast over the subsequent 12 hours.
Other Name: Singulair

Primary Outcome Measures :
  1. AUC of montelukast [ Time Frame: 0-12 hours ]
    Area under the concentration vs. time curve for the plasma concentration of montelukast.

Secondary Outcome Measures :
  1. Ke of montelukast [ Time Frame: 0-12 hours ]
    Elimination rate constant of montelukast.

Information from the National Library of Medicine

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Ages Eligible for Study:   7 Years to 35 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

Inclusion Criteria:

  • Individuals will be 7-35 years old.
  • Individuals will be healthy or have doctor diagnosed asthma.
  • Individuals 7-18 years old will have doctor diagnosed asthma.
  • Individuals will have the (A/A) genotype at c.935.

Exclusion Criteria:

  • Individuals must not be taking any oral medications except for ICS/or albuterol.
  • Women must not be pregnant.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01086527

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United States, Florida
Nemours Children's Clinic
Jacksonville, Florida, United States, 32207
Sponsors and Collaborators
Nemours Children's Clinic
Merck Sharp & Dohme Corp.
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Principal Investigator: Edward B Mougey, Ph.D. Nemours Children's Clinic
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Responsible Party: Ed Mougey, Research Scientist, Nemours Children's Clinic Identifier: NCT01086527    
Other Study ID Numbers: 37885
32-03215-005 ( Other Identifier: Nemours Children's Clinic )
First Posted: March 15, 2010    Key Record Dates
Last Update Posted: January 23, 2020
Last Verified: January 2020
Keywords provided by Ed Mougey, Nemours Children's Clinic:
Leukotriene Antagonists
Anti-Asthmatic Agents
Intestinal Absorption
biochemical transport
Membrane Transport Proteins
Additional relevant MeSH terms:
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Anti-Asthmatic Agents
Respiratory System Agents
Leukotriene Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Cytochrome P-450 CYP1A2 Inducers
Cytochrome P-450 Enzyme Inducers
Molecular Mechanisms of Pharmacological Action