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Irinotecan-Induced Toxicity: A Pharmacogenetic Study Beyond UGT1A1
Background and objective Side effects of irinotecan treatment can be dose limiting and may impair quality of life. In this study, we investigated the correlation between single nucleotide polymorphisms (SNPs) in genes encoding enzymes involved in the irinotecan metabolism and transport, outside UGT1...
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Published in: | Clinical pharmacokinetics 2023-11, Vol.62 (11), p.1589-1597 |
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Main Authors: | , , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | Background and objective
Side effects of irinotecan treatment can be dose limiting and may impair quality of life. In this study, we investigated the correlation between single nucleotide polymorphisms (SNPs) in genes encoding enzymes involved in the irinotecan metabolism and transport, outside
UGT1A1
, and irinotecan-related toxicity. We focused on carboxylesterases, which are involved in formation of the active metabolite SN-38 and on drug transporters.
Methods
Patients who provided written informed consent at the Erasmus Medical Center Cancer Institute to the Code Geno study (local protocol: MEC02-1002) or the IRI28-study (NTR-6612) were enrolled in the study and were genotyped for 15 SNPs in the genes
CES1
,
CES2, SLCO1B1
,
ABCB1
,
ABCC2
, and
ABCG2
.
Results
From 299 evaluable patients, 86 patients (28.8%) developed severe irinotecan-related toxicity. A significantly higher risk of toxicity was seen in
ABCG2
c.421C>A variant allele carriers (
P
= 0.030, OR 1.88, 95% CI 1.06–3.34). Higher age was associated with all grade diarrhea (
P
= 0.041, OR 1.03, 95% CI 1.00–1.06). In addition,
CES1
c.1165-41C>T and
CES1
n.95346T>C variant allele carriers had a lower risk of all-grade thrombocytopenia (
P
= 0.024, OR 0.42, 95% CI 0.20–0.90 and
P
= 0.018, OR 0.23, 95% CI 0.08–0.79, respectively).
Conclusion
Our study indicates that
ABCG2
and
CES1
SNPs might be used as predictive markers for irinotecan-induced toxicity. |
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ISSN: | 0312-5963 1179-1926 |
DOI: | 10.1007/s40262-023-01279-7 |