Dose-Finding and Pharmacokinetic Study to Optimize the Dosing of Irinotecan According to the UGT1A1 Genotype of Patients With Cancer

Abstract

Purpose The risk of severe neutropenia from treatment with irinotecan is related in part to UGT1A1*28, a variant that reduces the elimination of SN-38, the active metabolite of irinotecan. We aimed to identify the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of irinotecan in patients with advanced solid tumors stratified by the *1/*1, *1/*28, and *28/*28 genotypes. Patients and Methods Sixty-eight patients received an intravenous flat dose of irinotecan every 3 weeks. Forty-six percent of the patients had the *1/*1 genotype, 41% had the *1/*28 genotype, and 13% had the *28/*28 genotype. The starting dose of irinotecan was 700 mg in patients with the *1/*1 and *1/*28 genotypes and 500 mg in patients with the *28/*28 genotype. Pharmacokinetic evaluation was performed at cycle 1. Results In patients with the *1/*1 genotype, the MTD was 850 mg (four DLTs per 16 patients), and 1,000 mg was not tolerated (two DLTs per six patients). In patients with the *1/*28 genotype, the MTD was 700 mg (five DLTs per 22 patients), and 850 mg was not tolerated (four DLTs per six patients). In patients with the *28/*28 genotype, the MTD was 400 mg (one DLT per six patients), and 500 mg was not tolerated (three DLTs per three patients). The DLTs were mainly myelosuppression and diarrhea. Irinotecan clearance followed linear kinetics. At the MTD for each genotype, dosing by genotype resulted in similar SN-38 areas under the curve (AUCs; r2 = 0.0003; P = .97), but the irinotecan AUC was correlated with the actual dose (r2 = 0.39; P < .001). Four of 48 patients with disease known to be responsive to irinotecan achieved partial response. Conclusion The UGT1A1*28 genotype can be used to individualize dosing of irinotecan. Additional studies should evaluate the effect of genotype-guided dosing on efficacy in patients receiving irinotecan.

DPD and UGT1A1 deficiency in colorectal cancer patients receiving triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan

“…The same methodological issue may have influenced the results for patients with UGT1A1*28/*28. In fact, it is well described that UGT1A1*28 genotype may help clinicians to individualize better the adequate dosing of irinotecan when a standard schedule is planned [12]. In general, our results suggest that 21 (33%) patients harbouring at least one DPYD variant among DPYD c.496A > G, DPYD c.1896 T > C and UGT1A1*28/*28 had an increased risk of toxicity following triplet chemotherapy.…”

“…The UGT1A1*28 allele affects gene expression and leading to decreased glucuronidation of the metabolite SN-38 and increased risk of severe irinotecan-induced neutropenia [11]. The UGT1A1*28 genotype can be used to individualize the dosing of irinotecan [12].…”

Personalizing chemotherapy dosing using pharmacological methods

“…More recently, a similar trial of patients receiving irinotecan monotherapy demonstrated fixed MTDs of 850, 700, and 400 mg in *1/*1, *1/*28, and *28/*28 patients. Interestingly, at the MTD for each genotype, dosing by genotype resulted in similar SN-38 areas under the curve (AUCs; r 2 = 0.0003; P = 0.97), while the irinotecan AUC was correlated with the actual dose (r 2 = 0.39; P < 0.001) [52].…”

Combination Chemotherapy Regimens in Pancreatic Cancer

“…Полиморфизм данного гена UGT1A1*28 и UGT1A1*6, наблюдаемый при синдроме Жильбера и Криглера -Найяра, ассоциирован со снижением актив-ности фермента и, как следствие, повышением риска раз-вития глубокой нейтропении на фоне терапии ириноте-каном [66]. Наличие полиморфизма данного гена означа-ет необходимость редукции дозы иринотекана, если она превышает 180 мг/м 2 .…”