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https://hdl.handle.net/2440/134207
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Type: | Journal article |
Title: | Evaluation of pharmacogenomics and hepatic nuclear imaging–related covariates by population pharmacokinetic models of irinotecan and its metabolites |
Author: | Liu, Z. Martin, J.H. Liauw, W. McLachlan, S.A. Link, E. Matera, A. Thompson, M. Jefford, M. Hicks, R.J. Cullinane, C. Hatzimihalis, A. Campbell, I. Crowley, S. Beale, P.J. Karapetis, C.S. Price, T. Burge, M.E. Michael, M. |
Citation: | European Journal of Clinical Pharmacology, 2022; 78(1):53-64 |
Publisher: | Springer-Verlag |
Issue Date: | 2022 |
ISSN: | 0031-6970 1432-1041 |
Statement of Responsibility: | Zheng Liu ... Timothy Price ... et al. |
Abstract: | Background Body surface area (BSA)–based dosing of irinotecan (IR) does not account for its pharmacokinetic (PK) and pharmacodynamic (PD) variabilities. Functional hepatic nuclear imaging (HNI) and excretory/metabolic/PD pharmacogenomics have shown correlations with IR disposition and toxicity/efficacy. This study reports the development of a nonlinear mixed-effect population model to identify pharmacogenomic and HNI-related covariates that impact on IR disposition to support dosage optimization. Methods Patients had advanced colorectal cancer treated with IR combination therapy. Baseline blood was analysed by Affymetrix DMET™ Plus Array and, for PD, single nucleotide polymorphisms (SNPs) by Sanger sequencing. For HNI, patients underwent 99mTc-IDA hepatic imaging, and data was analysed for hepatic extraction/excretion parameters. Blood was taken for IR and metabolite (SN38, SN38G) analysis on day 1 cycle 1. Population modelling utilised NONMEM version 7.2.0, with structural PK models developed for each moiety. Covariates include patient demographics, HNI parameters and pharmacogenomic variants. Results Analysis included (i) PK data: 32 patients; (ii) pharmacogenomic data: 31 patients: 750 DMET and 22 PD variants; and (iii) HNI data: 32 patients. On initial analysis, overall five SNPs were identified as significant covariates for CLSN38. Only UGT1A3_c.31 T > C and ABCB1_c.3435C > T were included in the final model, whereby CLSN38 reduced from 76.8 to 55.1%. Conclusion The identified UGT1A3_c.31 T > C and ABCB1_c.3435C > T variants, from wild type to homozygous, were included in the final model for SN38 clearance. |
Keywords: | Liver Humans Colorectal Neoplasms Neoplasm Metastasis Glucuronosyltransferase Antineoplastic Combined Chemotherapy Protocols Prospective Studies Pharmacogenetics Genotype Polymorphism, Single Nucleotide Models, Biological Australia Topoisomerase I Inhibitors Pharmacogenomic Variants Irinotecan ATP Binding Cassette Transporter, Subfamily B |
Description: | Published online: 4 September 2021 |
Rights: | © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021 |
DOI: | 10.1007/s00228-021-03206-w |
Grant ID: | http://purl.org/au-research/grants/nhmrc/628564 |
Published version: | http://dx.doi.org/10.1007/s00228-021-03206-w |
Appears in Collections: | Medicine publications |
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