Table 2.

Recommended Dosing of fluoropyrimidines^a by DPD phenotype

Phenotype	Implications for Phenotypic Measures	Dosing Recommendations	Classification of Recommendationsb
DPYD Normal Metabolizer	Normal DPD activity and “normal” risk for fluoropyrimidine toxicity	Based on genotype, there is no indication to change dose or therapy. Use label-recommended dosage 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 on activity score followed by titration of dose based on toxicityc or therapeutic drug monitoring (if available). Activity score 1: Reduce dose by 50% Activity score 1.5: Reduce dose by 25% to 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 5-fluorouracil or 5-fluorouracil prodrug-based regimens In the event, based on clinical advice, alternative agents are not considered a suitable therapeutic option, 5-fluorouracil should be administered at a strongly reduced dosed with early therapeutic drug monitoring.e Activity score 0: Avoid use of 5-fluorouracil or 5-fluorouracil prodrug-based regimens.	Strong

^a5-fluorouracil or capecitabine

^bRating scheme described in Supplement.

^cIncrease 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.

^dIf available, a phenotyping test (see main text for further details) should be considered to estimate the starting dose. In absence of phenotyping data, a dose of <25% of the normal starting dose is estimated assuming additive effects of alleles on 5-FU clearance.

^eTherapeutic drug monitoring should be done at the earliest time point possible (e.g., minimum time point in steady state) in order to immediately discontinue the infusion if the drug level is too high.