The utility of genomics and functional imaging to predict sunitinib pharmacokinetics and pharmacodynamics: The predict SU study.

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 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 < .05) for: (i) PK included: (a) SU logAUC0-14days with HEF, ATP7B (rs1801246) and UGT8 (rs4148254); (b) SU logAUC0-28days, with Td1/2, SLC15A1 (rs8187832) and SLC10A2 (rs188096); (c) SU12662 logAUC0-14days with HEF, ABCC3 (rs11568591), PPARD (rs1003973) and SLC15A1 (rs8187840); and (d) SU12662 logAUC0-28days 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.