Genotype Stratified Pharmacokinetic Study of Montelukast
| Status: | Completed |
|---|---|
| Conditions: | Asthma |
| Therapuetic Areas: | Pulmonary / Respiratory Diseases |
| Healthy: | No |
| Age Range: | 7 - 35 |
| Updated: | 4/2/2016 |
| Start Date: | March 2010 |
| End Date: | September 2014 |
| Contact: | Mary K Warde, RN |
| Email: | mwarde@nemours.org |
| Phone: | (904) 697-3176 |
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.
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.
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.
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.
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.
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