title: Role of sunitinib and SU12662 on dermatological toxicities in metastatic renal cell carcinoma patients: in vitro, in vivo, and outcomes investigation.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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 IC50s of both compounds were determined with HaCaT keratinocytes.
  
  
  RESULTS
  Sunitinib was more dermatotoxic in vitro, with a lower IC50 than SU12662 (23.33 vs. 35.32 μM, 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore, 117543, Singapore.
authors.forename: Yi Ling
authors.initials: YL
authors.lastname: Teo
authors.forename: Xue Jing
authors.initials: XJ
authors.lastname: Chong
authors.forename: Xiu Ping
authors.initials: XP
authors.lastname: Chue
authors.forename: Noan Minh
authors.initials: NM
authors.lastname: Chau
authors.forename: Min-Han
authors.initials: MH
authors.lastname: Tan
authors.forename: Ravindran
authors.initials: R
authors.lastname: Kanesvaran
authors.forename: Hwee Lin
authors.initials: HL
authors.lastname: Wee
authors.forename: Han Kiat
authors.initials: HK
authors.lastname: Ho
authors.forename: Alexandre
authors.initials: A
authors.lastname: Chan
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D015331:Cohort Studies; D005260:Female; D060831:Hand-Foot Syndrome / Q000209:etiology*; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects*; D011788:Quality of Life; D012867:Skin / Q000187:drug effects* / Q000473:pathology; D000077210:Sunitinib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; C544393:SU 12662; D000077210:Sunitinib