Dataset Information

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.

SUBMITTER: Karas S

PROVIDER: S-EPMC8854585 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Publications

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

Karas Spinel S Etheridge Amy S AS Nickerson Deborah A DA Cox Nancy J NJ Mohlke Karen L KL Cecchin Erika E Toffoli Giuseppe G Mathijssen Ron H J RHJ Forrest Alan A Bies Robert R RR Innocenti Federico F

British journal of cancer 20211026 4

<h4>Background</h4>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.<h4>Methods</h4>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 p ...[more]

PMID: 34703007

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Project description:WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT * Association of UDP-glucuronosyltransferase 1A1 (UGT1A1) genetic polymorphisms *6 and *28 with reduced clearance of SN-38 and severe neutropenia in irinotecan therapy was demonstrated in Japanese cancer patients. * The detailed gene structure of CES1 has been characterized. * Possible functional SNPs in the promoter region have been reported. WHAT THIS STUDY ADDS * Association of functional CES1 gene number with AUC ratio [(SN-38 + SN-38G)/irinotecan], an in vivo index of CES activity, was observed in patients with irinotecan monotherapy. * No significant effects of major CES1 SNPs on irinotecan PK were detected. AIMS Human carboxylesterase 1 (CES1) hydrolyzes irinotecan to produce an active metabolite SN-38 in the liver. The human CES1 gene family consists of two functional genes, CES1A1 (1A1) and CES1A2 (1A2), which are located tail-to-tail on chromosome 16q13-q22.1 (CES1A2-1A1). The pseudogene CES1A3 (1A3) and a chimeric CES1A1 variant (var1A1) are also found as polymorphic isoforms of 1A2 and 1A1, respectively. In this study, roles of CES1 genotypes and major SNPs in irinotecan pharmacokinetics were investigated in Japanese cancer patients. METHODS CES1A diplotypes [combinations of haplotypes A (1A3-1A1), B (1A2-1A1), C (1A3-var1A1) and D (1A2-var1A1)] and the major SNPs (-75T>G and -30G>A in 1A1, and -816A>C in 1A2 and 1A3) were determined in 177 Japanese cancer patients. Associations of CES1 genotypes, number of functional CES1 genes (1A1, 1A2 and var1A1) and major SNPs, with the AUC ratio of (SN-38 + SN-38G)/irinotecan, a parameter of in vivo CES activity, were analyzed for 58 patients treated with irinotecan monotherapy. RESULTS The median AUC ratio of patients having three or four functional CES1 genes (diplotypes A/B, A/D or B/C, C/D, B/B and B/D; n= 35) was 1.24-fold of that in patients with two functional CES1 genes (diplotypes A/A, A/C and C/C; n= 23) [median (25th-75th percentiles): 0.31 (0.25-0.38) vs. 0.25 (0.20-0.32), P= 0.0134]. No significant effects of var1A1 and the major SNPs examined were observed. CONCLUSION This study suggests a gene-dose effect of functional CES1A genes on SN-38 formation in irinotecan-treated Japanese cancer patients.

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Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

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