While numerous factors may influence patient responses to medications, treatment response likely depends on the relationship between the pharmacokinetics, pharmacodynamics, and pharmacogenetics for each individual patient.
Jeffrey Fudin, PharmD, FCCP, FASHP, clinical pharmacy specialist and director of the PGY-2 Pharmacy Pain Residency Program at the Stratton Veterans Administration Medical Center in Albany, New York, discussed pharmacogenetic testing as part of a presentation on dosage thresholds during a session here.
Pharmacogenetic testing can serve as a tool that provides information in terms of how genetic variability affects individual responses to medications, specifically, Dr. Fudin explained, by helping clinicians determine how medications may be metabolized.
Traditionally 4 common phenotypes designate how an individual will metabolize medications: normal or extensive metabolizers, poor metabolizers, intermediate metabolizers, and ultrarapid metabolizers.
Practitioners need to understand the clinical effect of genetic polymorphisms in metabolizing enzymes , Dr. Fudin said, which can vary depending on the phenotype and the specific medication.
In discussing poor metabolizers, Dr. Fudin said, “for a medication that has an active parent compound, the potential clinical consequences in general include increased efficacy and the potential for lower doses to provide efficacy, or increased toxicity as a result of buildup of the active parent compound.”
For a medication for which the parent drug has little or no activity, he said, the clinical consequences in general may include decreased toxicity, little or no efficacy, and the potential need for higher doses if the drug is even a useful option.
Pharmacogenetic testing may also be helpful, Dr. Fudin explained, to identify the potential benefits and risks of certain medications, such as methadone, prior to prescribing or continuing treatment.
Due to its make-up, “methadone has unique pharmacokinetic characteristics and for this reason has been associated with distinctive and serious toxicity compared with other opioids,” he cautioned.
Methadone is a racemic mixture of the (R) and (S) isomers.
The (R)-enantiomer is primarily responsible for analgesic effects while the (S)-enantiomer is associated with cardiotoxic adverse effects, specifically prolongation of the heart-rate corrected QT (QTc) interval, Dr. Fudin explained. Both isomers are metabolized to the inactive metabolite, EDDP, but through different pathways.
(R)-methadone is metabolized primarily by CYP3A4 (but other CYP enzymes have a lesser role, including 2C19 and 2D6). (S)-methadone is primarily metabolized by CYP2B6; thus, he said, a poor metabolizer of CYP2B6 would be at increased risk for buildup of the cardiotoxic S-enantiomer and at higher risk for QTc prolongation and arrhythmia associated with sudden death.
Knowing this information through testing, prior to prescribing, may be helpful to minimize the risk of a potentially serious or fatal toxicity, according to Dr. Fudin.
Dr. Fudin reports he is a member of the speakers’ bureau for Millennium Health, LLC; he is also a consultant for AstraZeneca, Millennium Health LLC, Kaléo Pharma, Zogenix, and Depomed.