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

Abstract

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.

• Authors: Spinel Karas, Amy S Etheridge, Deborah A Nickerson, Nancy J Cox, Karen L Mohlke, Erika Cecchin, Giuseppe Toffoli, Ron H J Mathijssen, Alan Forrest, Robert R Bies, Federico Innocenti
• Journal: British journal of cancer (Br J Cancer) Vol. 126 Issue 4 Pg. 640-651 (03 2022) ISSN: 1532-1827 [Electronic] England
• PMID: 34703007 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s), under exclusive licence to Springer Nature Limited.

Chemical References

• Liver-Specific Organic Anion Transporter 1
• SLCO1B1 protein, human
• Irinotecan
• UGT1A1 enzyme
• Glucuronosyltransferase
• EGFR protein, human
• ErbB Receptors

Topics

• Administration, Intravenous
• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, pharmacokinetics)
• Clinical Trials as Topic
• ErbB Receptors (genetics)
• Female
• Glucuronosyltransferase (genetics)
• High-Throughput Nucleotide Sequencing
• Humans
• Irinotecan (adverse effects, pharmacokinetics)
• Liver-Specific Organic Anion Transporter 1
• Male
• Middle Aged
• Neoplasms (drug therapy, genetics)
• Pharmacogenomic Variants
• Polymorphism, Single Nucleotide
• Sequence Analysis, DNA (methods)