The Clinical Pharmacogenetics Implementation Consortium (CPIC) is committed to translating pharmacogenomics (PGx) research into actionable prescribing guidelines. In so doing, CPIC aims to standardize PGx testing and improve patient outcomes. Drawing upon expert insight and emerging research, CPIC continually publishes updated guidelines. So far, 2019 has seen several significant updates.
Atomoxetine CYP2D6 (February 2019)
In February, CPIC issued new guidelines for atomoxetine, a stimulant that is used by adults and children with ADHD, and sold as Strattera. Current Food and Drug Administration prescribing guidelines acknowledge the potential for CYP2D6 drug-gene interactions, but only include dosing recommendations for poor metabolizers.
New CPIC guidelines address this gap by adding recommendations for non-poor-metabolizer phenotypes. Post-marketing studies suggest more favorable treatment responses, but also a higher risk of side effects among poor metabolizers. Ultrarapid metabolizers, by contrast, are unlikely to achieve serum concentrations that are high enough to result in significant benefits. The new guidelines address this phenomenon by advising ongoing monitoring and dosing adjustments based on genotype.
Siponimod CYP2C9 (March 2019)
Siponimod (also known as Mayzent) is a selective sphingosine-1-phosphate receptor modulator used in the treatment of multiple sclerosis. The FDA’s label indicates that the drug is contraindicated for patients with a CYP2C9*3/*3 genotype. Because patients with severely reduced CYP2C9 activity may experience toxically high exposure to the drug, individualized dose titration and diligent monitoring for bradycardia are critical. Dose titration should occur over a five-day period, culminating in a dosage of 1 milligram per day.
This marks the first instance of a drug that is specifically contraindicated for a CYP2C9 genotype. However, more testing is necessary. The FDA label lists only the CYP2C9 alleles commonly found in Asians and Caucasians, but does not discuss the impact of other decreased or no-function CYP2C9 alleles that affect Africans or African-Americans.
Efavirenz CYP2B6 (April 2019)
In April, CPIC issued a CYP2B6 genotype recommendation for users of efavirenz (Sustiva), an anti-retroviral drug used to prevent and treat HIV/AIDS. The World Health Organization (WHO) lists the drug among its Essential Medications, although its use is currently limited in the U.S. The drug plays a key role in fighting the HIV/AIDS epidemic in developing and resource-limited nations. Yet drug discontinuation remains common, presenting a significant barrier to efforts to slow down the epidemic.
Certain CYP2B6 genotypes may increase the risk of neuropsychiatric toxicities and treatment discontinuation. CPIC recommends lower starting doses for intermediate and poor metabolizers. The guideline also added CYP2B6 to the list of actionable pharmacogenes for which clinical implementation is appropriate.
Erdafitinib CYP2C9 (April 2019)
Erdafitinib (Balversa) gained FDA approval in April for use by adult patients with locally advanced or metastatic urothelial carcinomas in patients with susceptible FGR3 or FGR2 genetic alterations, and a history of failed platinum-containing chemotherapy. The FDA label indicates that models and simulations predicted a 50 percent higher exposure to this drug in patients with the CYP2C9*3/*3 genotype. These poor metabolizers have significantly reduced CYP2C9 activity. This variant has an estimated prevalence of 0.4 percent to 3 percent of the population.
As with siponimod, the label is limited by the listing of only the most prominent decreased-function CYP2C9 alleles found in Asians and Caucasians, and does not discuss other decreased or no-function alleles that may decrease function in African-Americans or Africans.
Translational Software relies on CPIC guidelines to update its own prescribing recommendations. This empowers our clients to offer robust recommendations based on the latest research. Laboratories, healthcare systems, and other organizations can rest easy knowing that our database is continually updated based on new guidelines. We rely only on compelling data, reducing alert fatigue and ensuring that patients gain real value and improved outcomes from PGx testing.