Evaluation of pharmacogenomics and hepatic nuclear imaging-related covariates by population pharmacokinetic models of irinotecan and its metabolites

Liu, Z; Martin, JH; Liauw, W; McLachlan, SA; Link, E; Matera, A; Thompson, M; Jefford, M; Hicks, RJ; Cullinane, C; Hatzimihalis, A; Campbell, I; Crowley, S; Beale, PJ; Karapetis, CS; Price, T; Burge, ME; Michael, M

Author(s): Liu, Z; Martin, JH; Liauw, W; McLachlan, SA; Link, E; Matera, A; Thompson, M; Jefford, M; Hicks, RJ; Cullinane, C; Hatzimihalis, A; Campbell, I; Crowley, S; Beale, PJ; Karapetis, CS; Price, T; Burge, ME; Michael, M;
Details: Publication Year 2022-01,Volume 78,Issue #1,Page 53-64
Journal Title: European Journal of Clinical Pharmacology
Publication Type: Research article
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 (99m)Tc-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 CL(SN38). Only UGT1A3_c.31 T > C and ABCB1_c.3435C > T were included in the final model, whereby CL(SN38) 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.
Publisher: Springer Nature
Keywords: ATP Binding Cassette Transporter, Subfamily B/genetics; Antineoplastic Combined Chemotherapy Protocols/therapeutic use; Australia; Colorectal Neoplasms/*drug therapy/pathology; Genotype; Glucuronosyltransferase/*genetics; Humans; Irinotecan/*pharmacokinetics/therapeutic use; Liver/diagnostic imaging/*metabolism; Models, Biological; Neoplasm Metastasis; Pharmacogenetics; Pharmacogenomic Variants; Polymorphism, Single Nucleotide; Prospective Studies; Topoisomerase I Inhibitors/*pharmacokinetics/therapeutic use; Dmet; Hepatic functional imaging; Irinotecan; Pharmacodynamics; Pharmacokinetics; Population model
Department(s): Biostatistics and Clinical Trials; Cancer Imaging; Medical Oncology; Australian Cancer Survivorship Centre; Health Services Research; Laboratory Research
PubMed ID: 34480602
Publisher's Version: https://doi.org/10.1007/s00228-021-03206-w
Terms of Use/Rights Notice: Refer to copyright notice on published article.

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