Likely DPD phenotype based upon genotype and recommended dosing of fluoropyrimidines by DPD phenotype^[1]

Recommended dosing of fluoropyrimidines^¶ by DPD phenotype, from CPIC
Phenotype	Implications for phenotypic measures	Dosing recommendations		Classification of recommendations
DPYD normal metabolizer	Normal DPD activity and "normal" risk for fluoropyrimidine toxicity	Based upon genotype, there is no indication to change dose or therapy. Use label-recommended dosing and administration.		Strong
DPYD intermediate metabolizer	Decreased DPD activity (leukocyte DPD activity at 30 to 70% that of the normal population) and increased risk for severe or even fatal drug toxicity when treated with fluoropyrimidine drugs	Reduce starting dose based upon activity score, followed by titration of dose based upon toxicity^Δ or therapeutic drug monitoring (if available). Activity score 1 or 1.5: Reduce dose by 50%.		Activity score 1: Strong Activity score 1.5: Moderate
DPYD poor metabolizer	Complete DPD deficiency and increased risk for severe or even fatal drug toxicity when treated with fluoropyrimidine drugs	Activity score 0.5: Avoid use of fluorouracil or fluorouracil prodrug-based regimens. In the event, based upon clinical advice, alternative agents are not considered a suitable therapeutic option, fluorouracil should be administered at a strongly reduced dose^◊ with early therapeutic drug monitoring.^§ Activity score 0: Avoid use of fluorouracil or fluorouracil prodrug-based regimens.		Strong
Assignment of likely DPD phenotypes based on DPYD genotypes, from CPIC
Likely phenotype	Activity score^¥	Genotypes^‡	Examples of genotypes^†	Alternative designation: The high-risk genotype
DPYD normal metabolizer	2	An individual carrying two normal-function alleles	[ = ];[ = ]
DPYD intermediate metabolizer	1 or 1.5	An individual carrying one normal-function allele plus one no-function allele or one decreased-function allele, or an individual carrying two decreased-function alleles
	1		c.[1905+1G>A];[ = ]	*2A/normal
	1		c.[1679T>G];[ = ]	*13/normal
	1.5		c.[2846A>T];[ = ]	*9B/normal
	1		c.[2846A>T];[2846A>T]	9B/9B
	1		c.[2846A>T];[1129-5923C>G, c.1236G>A (HapB3)]^¶¶	*9B/HapB3 with 1129-5923C>G
	1.5		c.[1129-5923C>G, c.1236G>A (HapB3)];[ = ]^¶¶	HapB3 with 1129-5923C>G/normal
	1		c.[1129-5923C>G, c.1236G>A (HapB3)]/[1129-5923C>G, c.1236G>A (HapB3)]^¶¶	HapB3 with 1129-5923C>G/HapB3 with 1129-5923C>G
DPYD poor metabolizer	0 or 0.5	An individual carrying two no-function alleles or an individual carrying one no-function plus one decreased-function allele
	0.5		c.[1679T>G];[2846A>T]	13/9B
	0.5		c.[1679T>G];[1129-5923C>G, c.1236G>A (HapB3)]^¶¶	*13/[1129-5923C>G, c.1236G>A (HapB3)]
	0.5		c.[1905+1G>A];[2846A>T]	2A/9B
	0.5		c.[1905+1G>A];[1129-5923C>G, c.1236G>A (HapB3)]^¶¶	*2A/[1129-5923C>G, c.1236G>A (HapB3)]
	0		c.[1679T>G];[1679T>G]	13/13
	0		c.[1905+1G>A];[1679T>G]	2A/13
	0		c.[1905+1G>A];[1905+1G>A]	2A/2A

DPD: dihydropyrimidine dehydrogenase; fluoropyrimidines: fluorouracil, capecitabine, and tegafur; CPIC: Clinical Pharmacogenetics Implementation Consortium; c.[=]: sequence variant that does not confer heightened risk, refer to the Human Genome Variation Society (HVGS) website (http://varnomen.hgvs.org).
¶ Fluorouracil or capecitabine.
Δ Increase the dose in patients experiencing no or clinically tolerable toxicity in the first two cycles to maintain efficacy; decrease the dose in patients who do not tolerate the starting dose to minimize toxicities.
◊ If available, a phenotyping test (refer to UpToDate topic for further details) should be considered to estimate the starting dose. In the absence of phenotyping data, a dose of <25% of the normal starting dose is estimated assuming additive effects of alleles on fluorouracil clearance.
§ Therapeutic drug monitoring should be done at the earliest timepoint possible (eg, minimum timepoint in steady state) in order to immediately discontinue therapy if the drug level is too high.
¥ Calculated as the sum of the two lowest individual variant activity scores. Refer to CPIC website for further information.
‡ Allele definitions, assignment of allele function, and references can be found on the CPIC website.
† HGVS nomenclature using the reference sequence NM_000110.3.
¶¶ Likely HapB3 causal variant.

From: Amstutz U, Henricks LM, Offer SM, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update. Clin Pharmacol Ther 2018; 103(2):210-216. https://ascpt.onlinelibrary.wiley.com/doi/abs/10.1002/cpt.911. Copyright © 2018 American Society for Clinical Pharmacology and Therapeutics. Modified with permission of John Wiley & Sons Inc. This image has been provided by or is owned by Wiley. Further permission is needed before it can be downloaded to PowerPoint, printed, shared or emailed. Please contact Wiley's permissions department either via email: [email protected] or use the RightsLink service by clicking on the 'Request Permission' link accompanying this article on Wiley Online Library (http://onlinelibrary.wiley.com).
Updated with information from:

CPIC® Guideline for Fluoropyrimidines and DPYD. Clinical Pharmacogenetics Implementation Consortium. Original CPIC Guidelines published by Amstutz U et al. further updated in 2018 and 2020. Updated Guidelines available at: https://cpicpgx.org/guidelines/guideline-for-fluoropyrimidines-and-dpyd/ (Accessed on August 11, 2020).

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Likely DPD phenotype based upon genotype and recommended dosing of fluoropyrimidines by DPD phenotype[1]

Likely DPD phenotype based upon genotype and recommended dosing of fluoropyrimidines by DPD phenotype^[1]