Emma C Hulshof1, Mirjam de With2, Femke M de Man3, Geert-Jan Creemers4, Birgit A L M Deiman5, Jesse J Swen6, Saskia Houterman7, Stijn L W Koolen8, Sander Bins3, Anna M J Thijs4, Marjan M J Laven4, Anke M Hövels9, Saskia A C Luelmo10, Danny Houtsma11, Katerina Shulman12, Howard L McLeod13, Ron H N van Schaik14, Henk-Jan Guchelaar6, Ron H J Mathijssen3, Hans Gelderblom10, Maarten J Deenen15. 1. Department of Clinical Pharmacy, Catharina Hospital, Eindhoven, the Netherlands; Department of Clinical Pharmacy and Toxicology, Leiden University Medical Centre, Leiden, the Netherlands. 2. Department of Medical Oncology, Erasmus University Medical Centre, Rotterdam, the Netherlands; Department of Clinical Chemistry, Erasmus University Medical Centre, Rotterdam, the Netherlands. 3. Department of Medical Oncology, Erasmus University Medical Centre, Rotterdam, the Netherlands. 4. Department of Medical Oncology, Catharina Hospital, Eindhoven, the Netherlands. 5. Department of Molecular Biology, Catharina Hospital, Eindhoven, the Netherlands. 6. Department of Clinical Pharmacy and Toxicology, Leiden University Medical Centre, Leiden, the Netherlands. 7. Department of Education and Research, Catharina Hospital, Eindhoven, the Netherlands. 8. Department of Medical Oncology, Erasmus University Medical Centre, Rotterdam, the Netherlands; Department of Hospital Pharmacy, Erasmus University Medical Centre, Rotterdam, the Netherlands. 9. Hovels Consultancy HTA and Health Economics, Bilthoven, the Netherlands. 10. Department of Medical Oncology, Leiden University Medical Centre, Leiden, the Netherlands. 11. Department of Medical Oncology, Haga Hospital, The Hague, the Netherlands. 12. Department of Medical Oncology, Carmel Medical Centre and Clalit Haifa District Regional Oncology Clinics, Haifa, Israel. 13. University of South Florida Taneja College of Pharmacy, Tampa, FL, USA. 14. Department of Clinical Chemistry, Erasmus University Medical Centre, Rotterdam, the Netherlands. 15. Department of Clinical Pharmacy, Catharina Hospital, Eindhoven, the Netherlands; Department of Clinical Pharmacy and Toxicology, Leiden University Medical Centre, Leiden, the Netherlands. Electronic address: maarten.deenen@catharinaziekenhuis.nl.
Abstract
AIM: To determine the safety, feasibility, pharmacokinetics, and cost of UGT1A1 genotype-guided dosing of irinotecan. PATIENTS AND METHODS: In 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. RESULTS: Of 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. CONCLUSION: 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. Therefore, UGT1A1 genotype-guided dosing of irinotecan should be considered standard of care in order to improve individual patient safety.
AIM: To determine the safety, feasibility, pharmacokinetics, and cost of UGT1A1 genotype-guided dosing of irinotecan. PATIENTS AND METHODS: In 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. RESULTS: Of 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. CONCLUSION: 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. Therefore, UGT1A1 genotype-guided dosing of irinotecan should be considered standard of care in order to improve individual patient safety.