Purpose: The relationship between the pharmacokinetics of irinotecan and outcomes of advanced colorectal cancer is unclear, and few studies have examined individualized irinotecan-based chemotherapy depending on plasma 7-ethyl-10-hydroxy camptothecin (SN-38) levels and dihydropyrimidine dehydrogenase (DPD) activity, particularly for the UGT1A1*6 or UGT1A1*28 heterozygous type.
Methods: This study retrospectively explored the relationship among plasma SN-38 level 1.5 hours after critical enzyme for irinotecan (CPT-11) administration (C_{SN-38 1.5h}), plasma SN-38 level 49 hours after CPT-11 administration (C_{SN-38 49h}), DPD activity, and clinical outcomes for the UGT1A1*6 and UGT1A1*28 heterozygous types.
Results: C_{SN-38 1.5h} and C_{SN-38 49h} of the UGT1A1*6 or UGT1A1*28 heterozygous type were close to those of UGT1A1*6 and UGT1A1*28 wild-types; some of those with relatively high C_{SN-38 1.5h} levels obtained better median progression-free survival (mPFS), whereas others with higher C_{SN-38 49h} concentrations showed a relatively high incidence of adverse reactions possibly because of the decreased activity of DPD.
Conclusion: Increasing the dosage of CPT-11 according to C_{SN-38 1.5h} may improve the efficacy in patients with lower C_{SN-38 1.5h} levels. For cases with comparably low DPD activity, advisable primary and subsequent dose adjustment of 5-fluorouracil based on plasma 5-fluorouracil levels may be a practical strategy for reducing the occurrence of adverse reactions for personalized treatment of the UGT1A1*6 or UGT1A1*28 heterozygous type.
Keywords: irinotecan, pharmacokinetics, enzyme activity, uridine diphosphate glucuronosyltransferase 1A1, colorectal cancer