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

Autor: Ian G. Campbell, Sue-Anne McLachlan, Timothy J. Price, Rod Hicks, M. Burge, Annetta Matera, Simone M Rowley, Michael Michael, Michael Jefford, Phillip Beale, Michael Thompson, Winston Liauw, Emma Link, Carleen Cullinane, Christos S. Karapetis, Athena Hatzimihalis
Rok vydání: 2021
Předmět:
Zdroj: Cancer Chemotherapy and Pharmacology. 88:39-52
ISSN: 1432-0843
0344-5704
Popis: 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). 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). N = 31 pts. The two most significant associations between PK and PD with gene variants or HNI parameters (P
Databáze: OpenAIRE
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