Genotype Stratified Pharmacokinetic Study of Montelukast
Condition: Asthma
Study type: Interventional
Phase: Phase 1

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.
    

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%; http://www.ncbi.nlm.nih.gov/projects/SNP/). 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.
    

Intervention name(s): 10 mg tablet of montelukast (Singulair)
Intervention type(s): Drug
Intervention description(s): 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 intervention name(s): Singulair
Intervention MeSH terms: Montelukast
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Pharmacogenetics; Singulair; montelukast; Leukotriene Antagonists; Anti-Asthmatic Agents; Intestinal Absorption; pharmacokinetics; absorption; biochemical transport; Membrane Transport Proteins