FDA Highlights Risks Associated With DPD Deficiency, Advises Testing Before Treatment

In this interview, Houda Hachad, PharmD, vice president, Aranscia, provides a brief overview of the US Food and Drug Administration’s (FDA) safety announcement regarding the importance of dihydropyrimidine dehydrogenase (DPD) deficiency testing and discussions with patients prior to capecitabine or fluoropyrimidine therapy.

Please introduce yourself by stating your name, title, organization, and relevant professional experience. 

Hi, I'm Houda Hachad. I'm the vice president of clinical operations here at Aranscia. I'm trained as a pharmacist and a clinical pharmacologist. I spent 20 years in academia and in the industry building drug information technologies around drug interactions and pharmacogenomics (PGx). My goal has always been to advance the safe use of therapeutics for health care providers, but also to empower researchers in the industry to put safer medications on the market. I serve on multiple pharmacogenomic working groups and committees, aiming to standardize and facilitate the adoption of PGx testing.

How do the recent FDA labeling updates for capecitabine and fluorouracil regarding DPD deficiency influence current DPYD testing guidelines?

The FDA has issued updated warnings regarding the cancer drugs capecitabine and fluorouracil, highlighting the risks associated with dihydropyrimidine dehydrogenase (DPD) deficiency. People with genetic variants that result in low or absent DPD activity may not metabolize these drugs properly, putting them at a higher risk for severe, potentially fatal side effects.

The FDA's recent update stresses the importance of oncology care teams being aware of the risks of DPD deficiency, informing patients about these risks—including serious or life-threatening toxicities—before treatment, and discussing testing for the deficiency with their patients.

The safety announcement states, "Providers should consider testing for DPD deficiency before starting capecitabine or fluorouracil to reduce the risk of serious adverse reactions."

What strategies can be implemented to ensure health care providers effectively communicate the risks of DPD deficiency and the availability of DPYD testing to patients before initiating fluoropyrimidine therapy?

The following key actions should be considered before initiating fluoropyrimidine therapy:

• Establish a policy: Create hospital-wide protocols for preemptive DPYD testing before starting fluoropyrimidine therapies in oncology settings.
• Integrate into workflows: Ensure DPYD testing is part of pre-treatment protocols, with easy access to test orders and results.
• Educate care teams: Provide training on the significance, interpretation, and dose adjustments based on test results.
• Follow Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines: Implement dosing optimizations in patients with DPD deficiency to reduce toxicities.
• Inform patients: Develop materials to educate patients and families about DPD deficiency and testing.
• Ensure timely access to uridine triacetate: This will be needed for severe toxicity cases.
• Address barriers: Minimize challenges like cost and test turnaround time.
• Monitor and update: Continuously evaluate the program and update policies based on new data.

How do you foresee the FDA’s safety announcement influencing future policy decisions, insurance coverage, or guideline updates regarding pre-treatment DPYD testing for fluoropyrimidine-based therapies?

The FDA’s safety announcement is expected to drive changes in the following areas:

• Increased awareness and testing: The FDA highlights the risks of DPD deficiency, encouraging pre-treatment DPYD testing. Product label updates may further promote testing.
• Guideline revisions: The recognition of life-threatening toxicities in product labeling may prompt updates to professional guidelines from American Society of Clinical Oncology and National Comprehensive Cancer Network.
• Global support: The European Medicines Agency, the UK’s National Health Service, and the Canadian province of Quebec endorse pre-treatment genotyping for DPD deficiency.
• Insurance coverage: MolDX covers actionable PGx tests in 28 US states; Cigna also covers DPYD testing. More insurance providers are likely to follow as testing becomes more widespread.
• Cost-effectiveness: Real-world studies support the cost-effectiveness of DPYD testing.
• Growing evidence: As genomic datasets expand, new findings will bolster CPIC recommendations and Association for Molecular Pathology standards for DPYD testing.