5. Quaranta,
S. and F.
Thomas,
Pharmacogenetics of anti-cancer drugs: State of the
art and implementation - recommendations of the French National
Network of Pharmacogenetics.
Therapie, 2017.
72(2): p.
205-215.
4. Irinotecan – UGT1A1,
Netherlands, [Cited May 2017]. Available from:
http://kennisbank.knmp.nl [Access is restricted to KNMP
membership.]
This section contains excerpted
2
information on gene-based dosing recommendations. Neither this section nor
other parts of this review contain the complete recommendations from the
sources.
2017 Statement from the US Food and Drug Administration (FDA)
Individuals who are homozygous for the UGT1A1*28 allele (UGT1A1 7/7
genotype) are at increased risk for neutropenia following initiation of
Irinotecan Hydrochloride Injection, USP treatment.
In a study of 66 patients who received single-agent Irinotecan Hydrochloride
Injection, USP (350 mg/m2
once-every-3-weeks), the incidence of
grade 4 neutropenia in patients homozygous for the UGT1A1*28 allele was 50%, and in patients heterozygous for
this allele (UGT1A1 6/7 genotype) the
incidence was 12.5%. No grade 4 neutropenia was observed in patients
homozygous for the wild-type allele (UGT1A1
6/6 genotype).
When administered as a single-agent, a reduction in the starting dose by at
least one level of Irinotecan Hydrochloride Injection, USP should be
considered for patients known to be homozygous for the UGT1A1*28 allele. However, the precise dose reduction in this
patient population is not known and subsequent dose modifications should be
considered based on individual patient tolerance to treatment.
UGT1A1 Testing
A laboratory test is available to determine the UGT1A1 status of patients. Testing can detect the UGT1A1 6/6, 6/7 and
7/7 genotypes.
Please review the complete therapeutic recommendations that are located
here:
(1).
2017 Recommendations from the French National Network of Pharmacogenetics (RNPGx)
Interpreting Results
The RNPGx has proposed a decision tree for guiding irinotecan prescription
based on the UGT1A1 genotype and the
protocol’s theoretical dose:
- for low doses (< 180 mg/m2
/week), presence of the
UGT1A1*28 allele is not a major
risk factor (little difference in risk of hematological or digestive
toxicity irrespective of the genotype);
- for doses in the 180—230mg/m2
spaced by
2—3-week intervals, patients who are homozygous for the
UGT1A1*28 allele have a higher
risk of hematological and/or digestive toxicity than patients who
are heterozygous or non-carriers. For these *28/*28 patients, a 25% to 30% dose reduction is
recommended, especially if the patient presents other risk factors
for toxicity. Dose can be adjusted for subsequent cycles depending
on the tolerance;
- for doses of 240mg/m2
or higher spaced by 2—3
weeks intervals, homozygous UGT1A1*28
patients have a greatly increased risk of hematological toxicity
(neutropenia) compared with other genotypes, contraindicating
administration at this higher dose and leading to discussion of a
standard dose depending on the associated risk factors.
Administration of an intensive dose (240 mg/m2
) is
recommended only for *1/*1 patients, or for *1/*28 patients who have
no other risk factors and who benefit from intensive
surveillance.
[...]
The first-intention of this strategy for analysis of UGT1A1 status is to detect the *28 variant, the most common
deficiency variant observed in the Caucasian population, to be performed
before initiating treatment. Referring to the level of evidence
classification for RNPGx recommendations detailed in the article by Picard
et al. in this issue, UGT1A1 genotyping is
advisable for a standard dose (180—230mg/m2
) and
essential for intensified dose (> 240 mg/m2
).
Thus, individualized treatment can be proposed based on the UGT1A1 genotype, with either a dose reduction for
*28/*28 homozygous patients, or possibly
dose intensification for non-carriers of the *28 allele.
For the other UGT1A1 alleles, genotyping is
performed by a limited number of laboratories and is considered a second-
intention test.
Moreover, the RNPGx suggests that this analysis could be performed
concomitantly with other genetic explorations for colorectal cancer patients
(search for KRAS, BRAF mutations. . .) and constitutional (search for DYPD variants) in order to guarantee optimal
irinotecan therapy within adequate delay for optimal hospital practices.
Please review the complete therapeutic recommendations that are located
here:
(5).
2014 Recommendations from the Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP)
UGT1A1 Intermediate Metabolizers (IM)
NO action is
needed for this gene-drug interaction.This genetic variation (IM)
is more common in Western populations than the wild-type (*1/*1). This means
that treatment is largely geared to patients with this genetic variation.
Adjustment of the treatment is therefore not useful.
UGT1A1 Poor Metabolizers (PM)
Genetic variation reduces
conversion of irinotecan to inactive metabolites. This increases the risk of
serious, life-threatening adverse events.Recommendation:1.
Start with 70% of the standard doseIf the patient tolerates this
initial dose, the dose can be increased, guided by the neutrophil count.
UGT1A1 *1/*28
NO action is needed for this gene-drug
interaction.This genetic variation (*1/*28) is more common in
Western populations than the wild-type (*1/*1). This means that treatment is
largely geared to patients with this genetic variation. Adjustment of the
treatment is therefore not useful.
UGT1A1 *28/*28
Genetic variation reduces conversion of
irinotecan to inactive metabolites. This increases the risk of serious,
life-threatening adverse events.Recommendation:1. Start
with 70% of the standard doseIf the patient tolerates this initial
dose, the dose can be increased, guided by the neutrophil count.
Please review the complete therapeutic recommendations that are located
here:
(4).
2
The FDA labels specific drug formulations. We have substituted the generic
names for any drug labels in this excerpt. The FDA may not have labeled all
formulations containing the generic drug.