This DGI pertains to the interaction between the CYP2D6 gene and codeine. Codeine is used to treat mild to moderate pain. It belongs to a class of drugs known as opioids. It works by activating the brain to produce a response of pain relief. Extensive literature and FDA warning labels indicate patients with genetically reduced CYP2D6 function demonstrate lower systemic exposure to the active metabolite of codeine than do patients with normal CYP2D6 function.
The CYP2D6 gene encodes an enzyme that is involved in the metabolism of codeine. There are different CYP2D6 gene versions, or variants, and each has a different effect on how well codeine works in the body. The version termed ‘poor metabolizer’ does not produce a functional CYP2D6 enzyme to metabolize codeine, due to an individual carrying no functional alleles. The version termed ‘normal metabolizer’ results in a functional CYP2D6 enzyme. Patients who carry at least ONE reduced function and ONE nonfunctional allele are termed ‘intermediate metabolizer’. Studies have shown patients carrying more than TWO copies of functional alleles are termed ‘ultrarapid metabolizer’ and may be at increased risk for toxicity and adverse drug events while taking a standard dose of codeine.
Genotyping for CYP2D6 was performed within a high complexity, certified DNA laboratory at Vanderbilt University Medical Center that is in full compliance with all guidelines established by the government as regulated by the Centers for Medicare & Medicaid Services under the Clinical Laboratory Improvement act of 1988. This validated clinical Laboratory Developed Test is carried out with strict adherence to protocols outlined by the College of American Pathology. The performance of the assay is closely monitored and the accuracy of the results is determined to be >99%.
CYP2D6 phenotype-specific codeine population pharmacokinetics.
Linares Oscar A, Fudin Jeffrey, Schiesser William E, Daly Linares Annemarie L, Boston Raymond C in Journal of pain & palliative care pharmacotherapy (2015)
METHODS: A codeine pharmacokinetic pathway model accurately fit the time courses of plasma codeine and its metabolites. We used this model to build a population pharmacokinetic codeine pathway model.
RESULTS: The population model indicated that about 10% of a codeine dose was converted to morphine in poor-metabolizer phenotype subjects. The model also showed that about 40% of a codeine dose was converted to morphine in EM subjects, and about 51% was converted to morphine in ultrarapid-metabolizers. The population model further indicated that only about 4% of MO formed from codeine was converted to morphine-6-glucoronide in poor-metabolizer phenotype subjects. The model also showed that about 39% of the MO formed from codeine was converted to morphine-6-glucoronide in extensive-metabolizer phenotypes, and about 58% was converted in ultrarapid-metabolizers.
CONCLUSION: A population pharmacokinetic codeine pathway model can be useful because beyond helping to achieve a quantitative understanding the codeine and MO pathways, the model can be used for simulation to answer questions about codeine’s pharmacogenetic-based disposition in the body. Our study suggests that pharmacogenetics for personalized dosing might be most effectively advanced by studying the interplay between pharmacogenetics, population pharmacokinetics, and clinical pharmacokinetics.