Abstract 1128P
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.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.