Abstract
AimTo determine the safety, feasibility, pharmacokinetics, and cost of UGT1A1 genotype-guided dosing of irinotecan. Patients and methodsIn this prospective, multicentre, non-randomised study, patients intended for treatment with irinotecan were pre-therapeutically genotyped for UGT1A1∗28 and UGT1A1∗93. Homozygous variant carriers (UGT1A1 poor metabolisers; PMs) received an initial 30% dose reduction. The primary endpoint was incidence of febrile neutropenia in the first two cycles of treatment. Toxicity in UGT1A1 PMs was compared to a historical cohort of UGT1A1 PMs treated with full dose therapy, and to UGT1A1 non-PMs treated with full dose therapy in the current study. Secondary endpoints were pharmacokinetics, feasibility, and costs. ResultsOf the 350 evaluable patients, 31 (8.9%) patients were UGT1A1 PM and received a median 30% dose reduction. The incidence of febrile neutropenia in this group was 6.5% compared to 24% in historical UGT1A1 PMs (P = 0.04) and was comparable to the incidence in UGT1A1 non-PMs treated with full dose therapy. Systemic exposure of SN-38 of reduced dosing in UGT1A1 PMs was still slightly higher compared to a standard-dosed irinotecan patient cohort (difference: +32%). Cost analysis showed that genotype-guided dosing was cost-saving with a cost reduction of €183 per patient. ConclusionUGT1A1 genotype-guided dosing significantly reduces the incidence of febrile neutropenia in UGT1A1 PM patients treated with irinotecan, results in a therapeutically effective systemic drug exposure, and is cost-saving. Therefore, UGT1A1 genotype-guided dosing of irinotecan should be considered standard of care in order to improve individual patient safety.
Highlights
Irinotecan is a commonly prescribed anticancer drug for the treatment of advanced colorectal and pancreatic cancer
The incidence of febrile neutropenia in this group was 6.5% compared to 24% in historical UDPeglucuronosyltransferase 1A1 (UGT1A1) PMs (P Z 0.04) and was comparable to the incidence in UGT1A1 non-PMs treated with full dose therapy
UGT1A1 genotype-guided dosing significantly reduces the incidence of febrile neutropenia in UGT1A1 PM patients treated with irinotecan, results in a therapeutically effective systemic drug exposure, and is cost-saving
Summary
Irinotecan is a commonly prescribed anticancer drug for the treatment of advanced colorectal and pancreatic cancer. Treatment with irinotecan is often complicated by severe adverse events (AEs) such as febrile neutropenia and diarrhea [1]. This may lead to hospitalisation, loss of quality of life, treatment delay, and even treatment discontinuation. Irinotecan is a prodrug that is activated via carboxylesterases in the liver and blood to SN-38 [1]. SN-38 in turn is inactivated in the liver and intestines into SN-38-glucuronide by UDPeglucuronosyltransferase 1A1 (UGT1A1). UGT1A1 is the main enzyme responsible for the inactivation of SN-38 [2]
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