The Utility of Genomics and Functional Imaging to Predict Sunitinib Pharmacokinetics and Pharmacodynamics: The Predict Su Study

Abstract

Purpose: Sunitinib has marked pharmacokinetic (PK) & pharmacodynamic (PD) interpatient variability. This study evaluated the utility of extensive excretory/metabolic/PD pharmacogenomics (PGx) with hepatic functional imaging (HNI) to explore associations with Sunitinib PK/PD (toxicity/response) and progression-free survival (PFS). Methods: Eligible patients (pts) suitable for Sunitinb therapy. At baseline: (i) PGx: blood analyzed 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 800MBq 99mTc-MIBI, imaging data analysed for hepatic extraction/excretion parameters (CLHNI, T1/2-HNI, 1hRET, HEF, Td1/2). 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 <0.05) for: (i) PK included: (a) SU logAUC0-14days with HEF, ATP7B-(rs1801246), UGT8-(rs4148254), (b) SU logAUC0-28days, with Td1/2, SLC15A1-(rs8187832), SLC10A2-(rs188096), (c) SU Css, with Td1/2, SLC15A1-(rs8187832) (d) SU Ctrough with TNFα-(rs1799724), ATP7B-(rs1801246), (e) Total SU logAUC0-14days with Td1/2, TNFα-(rs1799724), (f) Total SU logAUC0-28days with Td1/2 and SLCO3A1-(rs2283458), (g) Total SU Css and Td1/2, UGT8-(rs4148254) and (h) Total SU Ctrough with SLC16A1-(rs11585690). (ii) Toxicity (a) Diarrhea Gr1+ with HEF, VEFGR3-(rs307826), AKAP9-(rs7785971) (b) ≥Grade 3 AEs with CBR1-(rs998383) (iii) Overall response rate with SULT1E1-(rs1881668), GSTA2-(rs2180314) (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