The utility of genomics and functional imaging to predict sunitinib pharmacokinetics and pharmacodynamics: The predict SU study
- Author(s)
- Michael, M; Toner, GC; Ganju, V; Link, E; Thompson, M; Matera, A; Hicks, RJ; Campbell, I; Rowley, S; Karapetis, CS; Burge, M; Pook, DW;
- Journal Title
- British Journal of Clinical Pharmacology
- Publication Type
- Online publication before print
- Abstract
- AIM: Sunitinib has marked pharmacokinetic (PK) and pharmacodynamic (PD) interpatient variability. This study evaluated the utility of extensive excretory/metabolic/PD pharmacogenomics (PGx) with hepatic functional imaging (HNI) to explore their associations with sunitinib PK/PD (toxicity/response) and progression-free survival (PFS), respectively. METHODS: Eligible patients (pts) suitable for sunitinib therapy. At baseline: (i) PGx: blood analysed by the Affymetrix DMET™ Plus Array (1936 variants/225 genes) and Sanger sequencing (HNF1A, FLT3, VEGFR2, VEGFR3, RET, PDGFRα, TNFα). (ii) HNI: pts given IV 800 MBq (99m)Tc-MIBI, imaging data analysed for hepatic extraction/excretion parameters (CL(HNI), T(1/2-HNI), 1hRET, HEF, T(d1/2)). In cycles 1 and 2, bloods taken for sunitinib parent (SU), metabolite (SU12662) and total SU (metabolite + parent) PK. Associations evaluated between (i) HNI parameters and (2) PGx, with sunitinib PK, toxicity/response and PFS. RESULTS: N = 15 pts. The two most significant associations in either direction between PGx variants or HNI parameters (p < .05) for: (i) PK included: (a) SU logAUC(0-14days) with HEF, ATP7B (rs1801246) and UGT8 (rs4148254); (b) SU logAUC(0-28days), with T(d1/2), SLC15A1 (rs8187832) and SLC10A2 (rs188096); (c) SU12662 logAUC(0-14days) with HEF, ABCC3 (rs11568591), PPARD (rs1003973) and SLC15A1 (rs8187840); and (d) SU12662 logAUC(0-28days) with SULT1A2 (rs1059491) and SLC10A2 (rs188096). (ii) Toxicity: (a) Diarrhoea grade 1+ with HEF, VEFGR3 (rs307826) and AKAP9 (rs7785971); (b) ≥grade 3 AEs with CBR1 (rs998383); (iii) overall response rate with SULT1E1 (rs1881668) and GSTA2 (rs2180314); and (iv) PFS with CYP4Z1 (rs4926802) and CYP2A6 (rs28399442). CONCLUSIONS: Exploratory associations were observed between sunitinib PK/PD with hepatic functional imaging with extensive pharmacogenomics. Further validation is required.
- Keywords
- Dmet; hepatic functional imaging; pharmacodynamics; pharmacokinetics; sunitinib
- Department(s)
- Medical Oncology; Biostatistics and Clinical Trials; Cancer Imaging; Laboratory Research
- Publisher's Version
- https://doi.org/10.1002/bcp.70431
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2026-01-23 11:58:22
Last Modified: 2026-01-23 12:00:54