Integration of DNA sequencing with population pharmacokinetics to improve the prediction of irinotecan exposure in cancer patients.

Autor: Karas S; Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Etheridge AS; Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Nickerson DA; Department of Genome Sciences, University of Washington, Seattle, WA, USA., Cox NJ; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA., Mohlke KL; Department of Genetics, University of North Carolina, Chapel Hill, NC, USA., Cecchin E; Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy., Toffoli G; Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy., Mathijssen RHJ; Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, Netherlands., Forrest A; Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Bies RR; Department of Pharmaceutical Sciences, University at Buffalo School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, USA.; Computational and Data Enabled Sciences and Engineering Program, University at Buffalo, State University of New York at Buffalo, Buffalo, NY, USA., Innocenti F; Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. innocent@email.unc.edu.
Jazyk: angličtina
Zdroj: British journal of cancer [Br J Cancer] 2022 Mar; Vol. 126 (4), pp. 640-651. Date of Electronic Publication: 2021 Oct 26.
DOI: 10.1038/s41416-021-01589-2
Abstrakt: Background: Irinotecan (CPT-11) is an anticancer agent widely used to treat adult solid tumours. Large interindividual variability in the clearance of irinotecan and SN-38, its active and toxic metabolite, results in highly unpredictable toxicity.
Methods: In 217 cancer patients treated with intravenous irinotecan single agent or in combination, germline DNA was used to interrogate the variation in 84 genes by next-generation sequencing. A stepwise analytical framework including a population pharmacokinetic model with SNP- and gene-based testing was used to identify demographic/clinical/genetic factors that influence the clearance of irinotecan and SN-38.
Results: Irinotecan clearance was influenced by rs4149057 in SLCO1B1, body surface area, and co-administration of 5-fluorouracil/leucovorin/bevacizumab. SN-38 clearance was influenced by rs887829 in UGT1A1, pre-treatment total bilirubin, and EGFR rare variant burden. Within each UGT1A1 genotype group, elevated pre-treatment total bilirubin and/or presence of at least one rare variant in EGFR resulted in significantly lower SN-38 clearance. The model reduced the interindividual variability in irinotecan clearance from 38 to 34% and SN-38 clearance from 49 to 32%.
Conclusions: This new model significantly reduced the interindividual variability in the clearance of irinotecan and SN-38. New genetic factors of variability in clearance have been identified.
(© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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