Background: IRI is a prodrug converted to SN-38 through the action of liver carboxylesterases. SN-38 is the main responsible for the antitumor response of IRI, and also for the dose-limiting toxicities. UGT1A1*28 polymorphism is associated with severe neutropenia and/or diarrhea. CYP3A also plays a role in the inactivation of IRI. We aim to characterize the biotransformation of IRI and SN-38 in the studied group, establishing its relationship with the genetic, biochemical and demographic variables evaluated, as well as with the occurrence of toxic effects associated with chemotherapy.Methods: Patients with oncologic indication tof IRI were included. Blood sample 15 min after the infusion was collected . IRI, SN-38 and SN-38G concentrations in plasma were measured by high-performance liquid chromatography. The polymorphisms of UGT1A1, CYP3A and DYPD were assessed. Pharmacokinetics ratios were compared between toxicity groups and genotypes by Mann-Whitney test. Quantitative variables were associated with Spearman correlation analysis. The evaluation of [SN38]/IRI dose ratio cut-offs for identifying any severe adverse event and diarrhea was set using area under the ROC curve. A P-value of 0.05 was considered statistically significant.Results: Forty-three patients were included from 2019 to 2020. The frequency of grade 3 or 4 (G3/4) adverse events (AE) was 39.5%. UGT1A1*28/*28 was detected in 9,3%. UGT1A1 activity showed 34.9% as extensive, 51.2% intermediate and 9.3% reduced. CYP3A activity showed: 4,7% as slow, 58,1% were intermediate and 34,9% were extensive metabolizers. SN 38/IRI dose ratio was higher in patients with G3/4 AE with a median of 0.1 versus 0.049 p <0.00001. [SN38]/IRI dose ratio had area under the ROC curve of 0.823 to detect any G3/4 AE and 0.833 to detect severe diarrhea. In patients with reduced UGT1A1 activity 75% had severe diarrhea.
Conclusions:A brazilian population with pharmacogenetic, and pharmacokinetic data was characterized. The measuremet of the SN38/IRI dose showed a significant correlation with serious adverse events and showed good results as a diagnostic tool, with high sensitivity and specificity. Reduced UGT1A1 activity was related to severe diarrhea.Legal entity responsible for the study: The authors.
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