Pharmacogenomics and functional imaging to predict irinotecan pharmacokinetics and pharmacodynamics: the predict IR study

Michael Michael, Winston Liauw, Sue Anne McLachlan, Emma Link, Annetta Matera, Michael Thompson, Michael Jefford, Rod J. Hicks, Carleen Cullinane, Athena Hatzimihalis, Ian G. Campbell, Simone Rowley, Phillip J. Beale, Christos S. Karapetis, Timothy Price, Mathew E. Burge

    Research output: Contribution to journalArticlepeer-review


    Purpose: Irinotecan (IR) displays significant PK/PD variability. This study evaluated functional hepatic imaging (HNI) and extensive pharmacogenomics (PGs) to explore associations with IR PK and PD (toxicity and response). Methods: Eligible patients (pts) suitable for Irinotecan-based therapy. At baseline: (i) PGs: blood analyzed by the Affymetrix-DMET™-Plus-Array (1936 variants: 1931 single nucleotide polymorphisms [SNPs] and 5 copy number variants in 225 genes, including 47 phase I, 80 phase II enzymes, and membrane transporters) and Sanger sequencing (variants in HNF1A, Topo-1, XRCC1, PARP1, TDP, CDC45L, NKFB1, and MTHFR), (ii) HNI: pts given IV 250 MBq-99mTc-IDA, data derived for hepatic extraction/excretion parameters (CLHNI, T1/2-HNI, 1hRET, HEF, Td1/2). In cycle 1, blood was taken for IR analysis and PK parameters were derived by non-compartmental methods. Associations were evaluated between HNI and PGs, with IR PK, toxicity, objective response rate (ORR) and progression-free survival (PFS). Results: N = 31 pts. The two most significant associations between PK and PD with gene variants or HNI parameters (P < 0.05) included: (1) PK: SN38-Metabolic Ratio with CLHNI, 1hRET, (2) Grade 3+ diarrhea with SLC22A2 (rs 316019), GSTM5 (rs 1296954), (3) Grade 3+ neutropenia with CLHNI, 1hRET, SLC22A2 (rs 316019), CYP4F2 (rs2074900) (4) ORR with ALDH2 (rs 886205), MTHFR (rs 1801133). (5) PFS with T1/2-HNI, XDH (rs 207440), and ABCB11 (rs 4148777). Conclusions: Exploratory associations were observed between Irinotecan PK/PD with hepatic functional imaging and extensive pharmacogenomics. Further work is required to confirm and validate these findings in a larger cohort of patients. Australian New Zealand Clinical Trials Registry (ANZCTR) Number: ACTRN12610000897066, Date registered: 21/10/2010.

    Original languageEnglish
    Pages (from-to)39-52
    Number of pages14
    JournalCancer Chemotherapy and Pharmacology
    Issue number1
    Publication statusPublished - Jul 2021

    Bibliographical note



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


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