Published: 2 March 2023

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Role of dihydropyrimidine dehydrogenase deficiency in systemic fluoropyrimidine-related toxicity

Published: 2 March 2023
Prescriber Update 44(1): 19–21
March 2023

Background

The Centre for Adverse Reactions Monitoring (CARM) recently received 2 fatal case reports involving systemic fluoropyrimidines (fluorouracil and capecitabine; CARM IDs 140395 and 143421, respectively). Suspected dihydropyrimidine dehydrogenase (DPD) deficiency was thought to contribute to severe fluoropyrimidine toxicity in both cases.

This article highlights the role of DPD in fluoropyrimidine metabolism, the genetic basis of DPD deficiency and treatment considerations for DPD-deficient patients receiving fluoropyrimidines.

What are fluoropyrimidines?

Fluorouracil and capecitabine are fluoropyrimidines used to treat a wide variety of cancers. Fluorouracil is a pyrimidine analogue antimetabolite that interferes with DNA and RNA synthesis¹, while capecitabine is a prodrug of fluorouracil.²

The DPYD gene encodes DPD and is highly polymorphic

DPD is the rate-limiting enzyme responsible for inactivating fluorouracil in the body. The activity of this enzyme can vary from a partial to a complete loss of activity among DPD-deficient individuals.³

DPD deficiency is most often the result of genetic polymorphism in the DPYD gene that encodes DPD. DPYD is highly polymorphic, with more than 160 genetic variants identified to date, some resulting in altered or near-complete loss of enzyme activity.⁴ DPYD*2A is the most well-known DPYD variant associated with DPD deficiency.⁵ Variants DPYD*13, c.2846A>T and HapB3 have also been associated with altered DPD activity.⁵

In the European population, the prevalence of partial and complete DPD deficiency is approximately 3–9% and 0.01–0.5%, respectively.⁴ There is limited data on the prevalence of DPD deficiency in other ethnic groups. However, it has been suggested that Asian and African populations are at greater risk of DPD deficiency.⁴

Treatment considerations in DPD-deficient patients

Patients with partial or complete DPD deficiency treated with a standard dose of a fluoropyrimidine will have increased levels of active metabolites. These individuals have an increased risk of severe or even fatal fluoropyrimidine-related toxicities such as diarrhoea, mucositis, myelosuppression and neurotoxicity.⁵

Toxicity in DPD-deficient patients usually occurs during the first treatment cycle or after a dose increase.^2,6 These reactions tend to occur earlier and be more severe and prolonged compared to typical fluoropyrimidine toxicity.⁵

Consider the following if the patient’s DPD status is known.

• In patients with a known complete loss of DPD activity: there is no safe dose of fluorouracil and capecitabine. Treatment is contraindicated in these patients.^2,6
• In patients with a known partial DPD deficiency: initiate treatment with fluoropyrimidines with extreme caution. A reduced starting dose, frequent monitoring, and subsequent dose adjustments may be required – consult local guidelines. The clinical efficacy of fluoropyrimidines with reduced doses remains uncertain.^2,6

Other risk factors for developing fluoropyrimidine-related toxicity

The following factors may increase an individual’s risk of fluoropyrimidine-related toxicity:

• renal impairment – the incidence of severe to life-threatening toxicity is higher in patients with renal impairment⁷
• drug-drug interactions – through pharmacokinetic interactions or the additive effects of other myelosuppressive medicines⁶
• female sex⁶
• patients aged 70 years or older.⁶

Investigating individual DPD status

In some countries, DPD status may be investigated by DPYD genotyping and measuring the DPD phenotype (uracil levels).^4,7 Currently, there are uncertainties regarding the optimal method for determining an individual’s risk of fluoropyrimidine-related toxicity.⁴

The fluorouracil and capecitabine data sheets recommend that DPD status of the patient is determined before therapy through laboratory testing for the detection of complete or partial DPD deficiency, where testing is available.^2,6 Determining DPD status can also be useful when evaluating patients experiencing fluoropyrimidine-related toxicities.^2,6

At present, DPD testing (either genotype or phenotype testing) is not routinely available in New Zealand. However, there is ongoing clinical and translational research in this area, including which tests would be clinically relevant for the New Zealand population.

References

1. Access Lexicomp Online. 2022. Fluorouracil (systemic): Drug information. In: UpToDate v349.0. URL: uptodate.com/contents/fluorouracil-systemic-drug-information (accessed 19 September 2022).
2. Rex Medical Ltd. 2022. Brinov New Zealand Data Sheet. 27 July 2022. URL: medsafe.govt.nz/profs/datasheet/b/brinovtab.pdf (accessed 17 January 2023).
3. Henricks LM, Opdam FL, Beijnen JH, et al. 2017. DPYD genotype-guided dose individualization to improve patient safety of fluoropyrimidine therapy: call for a drug label update. Annals of Oncology 28(12): 2915-22. DOI: doi.org/10.1093/annonc/mdx411 (accessed 13 October 2022).
4. European Medicines Agency. 2020. Fluorouracil and fluorouracil related substances (capecitabine, tegafur and flucytosine) containing medicinal products Article 31 referral - Assessment report 27 March 2020. URL: ema.europa.eu/en/documents/referral/fluorouracil-fluorouracil-related-substances-article-31-referral-assessment-report_en.pdf (accessed 13 June 2022).
5. Cancer Institude NSW eviQ. 2020. Dihydropyrimidine dehydrogenase (DPD) enzyme deficiency 28 September 2020. URL: eviq.org.au/clinical-resources/side-effect-and-toxicity-management/prophylaxis-and-treatment/1744-dihydropyrimidine-dehydrogenase-dpd-enzyme (accessed 14 October 2020).
6. Pharmacy Retailing (NZ) Limited t/a Healthcare Logistics. 2022. Fluorouracil Accord Injection New Zealand Data Sheet. 21 July 2022. URL: medsafe.govt.nz/profs/datasheet/f/fluorouracilAccordinj.pdf (accessed 14 October 2022).
7. Helsby N, Burns K, Findlay M, et al. 2021. Testing for dihydropyrimidine dehydrogenase deficiency in New Zealand to improve the safe use of 5-fluorouracil and capecitabine in cancer patients. New Zealand Medical Journal 134(1545): 120-8. URL: journal.nzma.org.nz/journal-articles/testing-for-dihydropyrimidine-dehydrogenase-deficiency-in-new-zealand-to-improve-the-safe-use-of-5-fluorouracil-and-capecitabine-in-cancer-patients (accessed 14 October 2022).