title: Severe toxicity induced by accumulation of active sunitinib metabolite in a Japanese patient with renal cell carcinoma: a case report.
abstract: BACKGROUND
  Sunitinib is a multi-targeted tyrosine kinase inhibitor that is approved for treatment of renal cell carcinoma as an oral anticancer drug. Therapeutic drug monitoring of total sunitinib (sunitinib and N-desethyl sunitinib) is used in our hospital to improve therapeutic efficacy, while preventing adverse effects. Here, we report the first case of a patient with metastatic renal cell carcinoma undergoing hemodialysis and presenting severe adverse events induced by the accumulation of N-desethyl sunitinib.
  
  
  METHODS
  A 60-year-old Japanese man was diagnosed with metastatic renal cell carcinoma requiring hemodialysis. On day 26 of the first cycle of sunitinib therapy, our patient presented grade 3 thrombocytopenia and leukopenia, which required interruption of therapy although the plasma levels of total sunitinib in the patient were less than the effective concentration of 50 ng/mL. The elimination half-life of sunitinib was normal at 50.8 hours, but that of N-desethyl sunitinib was an extended 211.4 hours. Moreover, the N-desethyl sunitinib/sunitinib trough level ratio was higher than 1.0. We attribute our patient's severe adverse events to the excessive accumulation of N-desethyl sunitinib owing to its delayed excretion. Although the reason for the delayed excretion of N-desethyl sunitinib in this patient was unknown, it may have been caused by genetic polymorphisms related to the pharmacokinetics of sunitinib rather than the hemodialysis. In this case, the patient was homozygous for the ABCG2 421C allele, but was capable of potentially harboring polymorphisms in other genes, such as ABCB1, an efflux pump of sunitinib. In addition, even though there is no clear evidence, urinary excretion of the metabolic products of N-desethyl sunitinib could be inhibited by the interaction of transporters such as the organic ion transporter.
  
  
  CONCLUSIONS
  The monitoring of not only total sunitinib concentration but also N-desethyl sunitinib concentration and their elimination half-lives during sunitinib therapy is recommended to avoid critical adverse events.
authors.affiliation: Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aobaku, Sendai, Miyagi, 980-8574, Japan. takasaki_shinya@hosp.tohoku.ac.jp.
authors.forename: Shinya
authors.identifier: http://orcid.org/0000-0003-1438-7800
authors.initials: S
authors.lastname: Takasaki
authors.affiliation: Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aobaku, Sendai, Miyagi, 980-8574, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kikuchi
authors.affiliation: Department of Urology, Tohoku University Hospital, 1-1 Seiryo-machi, Aobaku, Sendai, Miyagi, 980-8574, Japan.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Kawasaki
authors.affiliation: Department of Urology, Tohoku University Hospital, 1-1 Seiryo-machi, Aobaku, Sendai, Miyagi, 980-8574, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ito
authors.affiliation: Department of Urology, Tohoku University Hospital, 1-1 Seiryo-machi, Aobaku, Sendai, Miyagi, 980-8574, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Arai
authors.affiliation: Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aobaku, Sendai, Miyagi, 980-8574, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Yamaguchi
authors.affiliation: Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aobaku, Sendai, Miyagi, 980-8574, Japan.
authors.forename: Nariyasu
authors.initials: N
authors.lastname: Mano
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism*; D044466:Asian People; D002292:Carcinoma, Renal Cell / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D004334:Drug Administration Schedule; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism*; D000077210:Sunitinib; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib
keywords: Hemodialysis; N-desethyl sunitinib; Sunitinib; Therapeutic drug monitoring; Tyrosine kinase inhibitor