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

Zheng Liu, Jennifer H Martin, Winston Liauw, Sue-Anne McLachlan, Emma Link, Anetta Matera, Michael Thompson, Michael Jefford, Rod J Hicks, Carleen Cullinane, Athena Hatzimihalis, Ian Campbell, Simone Crowley, Phillip J Beale, Christos S Karapetis, Timothy Price, Mathew E Burge, Michael Michael

    Research output: Contribution to journalArticlepeer-review

    1 Citation (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)53-64
    Number of pages12
    JournalEuropean Journal of Clinical Pharmacology
    Volume78
    Issue number1
    Early online date4 Sept 2021
    DOIs
    Publication statusPublished - Jan 2022

    Keywords

    • DMET
    • Hepatic functional imaging
    • Irinotecan
    • Pharmacodynamics
    • Pharmacokinetics
    • Population model

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