Role of sunitinib and SU12662 on dermatological toxicities in metastatic renal cell carcinoma patients: in vitro, in vivo, and outcomes investigation

Sunitinib commonly exhibits dose-limiting dermatological toxicities (DTs) that adversely affect health-related quality of life (HRQoL). Pharmacological activity of sunitinib is attributed to sunitinib and an equipotent, active metabolite, SU12662. The objective of this study is to compare the dermatotoxic potential of sunitinib and SU12662, and changes in HRQoL due to DTs. A prospective cohort study was conducted on metastatic renal cell carcinoma patients. Plasma drug concentrations were determined by high-performance liquid chromatography. DTs were graded by Common Terminology Criteria for Adverse Events. HRQoL of patients with hand-foot skin reaction (HFSR) was assessed by the hand-foot syndrome-specific quality-of-life questionnaire (HFS-14). In addition, the IC(50)s of both compounds were determined with HaCaT keratinocytes. Sunitinib was more dermatotoxic in vitro, with a lower IC50 than SU12662 (23.33 vs. 35.32 mu M, p = 0.02). Similar results were observed in vivo, with higher sunitinib-to-SU12662 ratio in patients with pruritus, than patients without pruritus (p = 0.04). Higher HFS-14 scores were observed in patients with higher HFSR grade and in those with both hands and feet affected, indicating poorer HRQoL. Sunitinib may be more dermatotoxic than SU12662 from both in vivo and in vitro evidences. Therefore, appropriate management of DTs may be essential, especially in patients with a reduced sunitinib metabolising ability.