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Page 60 Olivera et al. Cancer Drug Resist 2019;2:53-68 I http://dx.doi.org/10.20517/cdr.2018.25

Tegafur is another fluorpyrimidine that does not present a CPIC recommendation. However, the DPWG
guide has a recommendation to poor metabolizers to select an alternative drug, avoiding capecitabine and
[6]
fluorouracils since they are also metabolized by DPD .

Irinotecan and UGT1A1
Irinotecan is a hemisynthetic camptothecin mainly used for the treatment of metastatic colorectal cancer,
multiform glioblastoma, lung cancer, upper gastrointestinal cancer and pancreas cancer. It is metabolized
by the liver to be converted in its active metabolite called SN-38. The SN-38 targets DNA topoisomerase I,
stabilizing the cleavable complexes that break the DNA strands and producing the cancerous cells death [30,31] .

The UGT1A1 (UDP Glucuronosyltransferase family 1 member A1) enzyme is the responsible of SN-38
inactivation and detoxification. Variants of this gene, such as *28, related with reduced activity of this
[32]
enzyme, increase the blood levels of SN-38 metabolite and its toxicity .
2
The DPWG guide recommends in patients with a programmed dose of more than 250 mg/m , to reduce
the initial dose of irinotecan by 30% in homozygous (*28/*28) poor metabolizer patients, and increase it
[6]
as response to neutrophils count . UGT1A1*28 has an rs code, rs8175347, but it is not a SNP, instead is a
variable number tandem repeat of a dinucleotide TA. There is a surrogate marker, according to the CPIC
[33]
Atazanavir guideline , rs887829 that could be an alternative to analyze this variant.
The French National Network of Pharmacogenetics (RNPGx) and the Group of Clinical Oncopharmacology
[34]
(GPCO-Unicancer) also presented a guide for *28 allele . When initial doses of irinotecan are between
2
180 and 230 mg/m every 2-3 weeks homozygous *28/*28 patients present greater risk of hematologic and
digestive toxicity than other genotypes. This guide recommends in this case to reduce the initial doses by
25%-30%, especially in those patients with associated risk factors.

When the initial dose is ≥ 240 mg/m every 2-3 weeks, the neutropenia risk is greater. This dose is
2
contraindicated for *28/*28 homozygous patients. It would be possible only in patients homozygous for wild
type allele or heterozygous *1/*28 without other associated risk factors and under rigorous surveillance (the
2
same in 180-230 mg/m ).
FDA and HCSC agencies include recommendations within the drug label, considered actionable. They
indicate that the initial dose in *28 homozygous patients should be considered to be reduced because of
the hematologic toxicity risk. It is also recommended not to use neither CYP3A4 inducers during two
weeks before initiating irinotecan treatment nor strong CYP3A4 inhibitors one week before and during
the irinotecan treatment period. PMDA agency indicates the requirement of genetic test prior to drug
administration.

Ondansetron and CYP2D6
Ondansetron is a serotonin receptor antagonist (5-hydroxitriptamine, subtype 3), employed as antiemetic
after chemotherapeutic or surgical treatment. It is metabolized within the liver by cytochrome P450
enzymes, specifically CYP2D6. This gene presents large amount of variants that can mediate higher or lower
efficacy and toxicity [35-37] .

The CPIC guide presents recommendations for this drug. It assigns an activity value from 0 to 1 to
each functional group. In this sense, this activity value is 0 for poor metabolizers, 0.5 for intermediate
metabolizers and 1 for NM. When the allele has more than 1 copy of the functional gene, the activity value
is multiplied by the copy number present. Thus, the global activity value is obtained by adding the values of
each allele. The patients with an activity value over 2 will be considered UM .
[38]