PMID- 29524031
OWN - NLM
STAT- MEDLINE
DCOM- 20180828
LR  - 20181202
IS  - 1559-131X (Electronic)
IS  - 1357-0560 (Linking)
VI  - 35
IP  - 4
DP  - 2018 Mar 9
TI  - Contribution of UGT1A1 genetic polymorphisms related to axitinib pharmacokinetics 
      to safety and efficacy in patients with renal cell carcinoma.
PG  - 51
LID - 10.1007/s12032-018-1113-8 [doi]
AB  - Axitinib is a potent second-line molecular-targeted agent for metastatic renal 
      cell carcinoma (mRCC). Axitinib pharmacokinetics and its relation with genetic 
      polymorphisms were evaluated to predict the adverse events (AEs) and efficacy of 
      axitinib. We analyzed 46 patients with mRCC who were treated with axitinib. The 
      plasma axitinib level was measured at 0, 2, 4, 8, and 12 h after administration 
      (C(0), C(2), C(4), C(8), and C(12); ng/mL) on day 7 of the treatment. Genetic 
      polymorphisms related to axitinib pharmacokinetics, including SLCO1B1, SLCO1B3, 
      SLCO2B1, ABCB1, ABCG2, CYP2C19, CYP3A5, and UGT1A1, were analyzed. Axitinib C(0) 
      and AUC(0-12) in patients with UGT1A1 poor metabolisers (*6/*6, *6/*28, and 
      *28/*28; n = 10) were significantly higher than those in patients with UGT1A1 
      extensive metabolisers (*1/*1, *1/*6,*1/*28, and *27/*28; n = 36) (23.6 vs. 
      7.8 ng/mL, p = 0.030, and 441.3 vs. 217.1 ng h/mL, p = 0.007). The cutoff levels 
      of C(0) to predict >/= G2 hypothyroidism and >/= G2 anorexia were 6.6 and 7.1 ng/mL, 
      respectively (p = 0.005 and p = 0.035). The overall survival (OS) in patients 
      with C(0) > 5 ng/mL was significantly better than that in patients with 
      C(0) < 5 ng/mL (p = 0.022). Genetic polymorphisms in UGT1A1 were significantly 
      associated with the plasma axitinib level. The plasma axitinib level was 
      significantly associated with the frequency of AEs and OS in patients with mRCC. 
      No direct relationship was observed between UGT1A1 genotypes and the frequency of 
      AEs or OS.
FAU - Igarashi, Ryoma
AU  - Igarashi R
AD  - Department of Urology, Akita University Graduate School of Medicine, 1-1-1 Hondo, 
      Akita, 010-8543, Japan.
FAU - Inoue, Takamitsu
AU  - Inoue T
AD  - Department of Urology, Akita University Graduate School of Medicine, 1-1-1 Hondo, 
      Akita, 010-8543, Japan. takamitu@doc.med.akita-u.ac.jp.
AD  - AMED-CREST, Agency for Medical Research and Development (AMED), Tokyo, 102-0004, 
      Japan. takamitu@doc.med.akita-u.ac.jp.
FAU - Fujiyama, Nobuhiro
AU  - Fujiyama N
AD  - Center for Kidney Disease and Transplantation, Akita University Hospital, Akita, 
      Japan.
AD  - Department of Pharmacy, Akita University Hospital, Akita, Japan.
FAU - Tsuchiya, Norihiko
AU  - Tsuchiya N
AD  - Department of Urology, Faculty of Medicine, Yamagata University, Yamagata, Japan.
FAU - Numakura, Kazuyuki
AU  - Numakura K
AD  - Department of Urology, Akita University Graduate School of Medicine, 1-1-1 Hondo, 
      Akita, 010-8543, Japan.
FAU - Kagaya, Hideaki
AU  - Kagaya H
AD  - Department of Pharmacy, Akita University Hospital, Akita, Japan.
FAU - Saito, Mitsuru
AU  - Saito M
AD  - Department of Urology, Akita University Graduate School of Medicine, 1-1-1 Hondo, 
      Akita, 010-8543, Japan.
FAU - Narita, Shintaro
AU  - Narita S
AD  - Department of Urology, Akita University Graduate School of Medicine, 1-1-1 Hondo, 
      Akita, 010-8543, Japan.
AD  - AMED-CREST, Agency for Medical Research and Development (AMED), Tokyo, 102-0004, 
      Japan.
FAU - Satoh, Shigeru
AU  - Satoh S
AD  - Center for Kidney Disease and Transplantation, Akita University Hospital, Akita, 
      Japan.
FAU - Niioka, Takenori
AU  - Niioka T
AD  - Department of Pharmacy, Akita University Hospital, Akita, Japan.
AD  - Department of Pharmacy, Hirosaki University Hospital, Aomori, Japan.
FAU - Miura, Masatomo
AU  - Miura M
AD  - Department of Pharmacy, Akita University Hospital, Akita, Japan.
FAU - Habuchi, Tomonori
AU  - Habuchi T
AD  - Department of Urology, Akita University Graduate School of Medicine, 1-1-1 Hondo, 
      Akita, 010-8543, Japan.
AD  - AMED-CREST, Agency for Medical Research and Development (AMED), Tokyo, 102-0004, 
      Japan.
LA  - eng
GR  - 25293332/the Japanese Society for the Promotion of Science/
GR  - 16H02679/the Japanese Society for the Promotion of Science/
GR  - 23590168/the Japanese Society for the Promotion of Science/
PT  - Clinical Trial
PT  - Journal Article
DEP - 20180309
PL  - United States
TA  - Med Oncol
JT  - Medical oncology (Northwood, London, England)
JID - 9435512
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Imidazoles)
RN  - 0 (Indazoles)
RN  - 0 (Protein Kinase Inhibitors)
RN  - C9LVQ0YUXG (Axitinib)
RN  - EC 2.4.1.- (UGT1A1 enzyme)
RN  - EC 2.4.1.17 (Glucuronosyltransferase)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antineoplastic Agents/adverse effects/pharmacokinetics/therapeutic use
MH  - Axitinib
MH  - Carcinoma, Renal Cell/*drug therapy/genetics
MH  - Female
MH  - Genotype
MH  - Glucuronosyltransferase/*genetics/metabolism
MH  - Humans
MH  - Imidazoles/adverse effects/*pharmacokinetics/therapeutic use
MH  - Indazoles/adverse effects/*pharmacokinetics/therapeutic use
MH  - Kidney Neoplasms/*drug therapy/genetics
MH  - Male
MH  - Middle Aged
MH  - Polymorphism, Single Nucleotide
MH  - Protein Kinase Inhibitors/adverse effects/*pharmacokinetics/therapeutic use
OTO - NOTNLM
OT  - Genetic polymorphisms
OT  - Molecular-targeted agents
OT  - Renal cell carcinoma
OT  - Therapeutic drug monitoring
EDAT- 2018/03/11 06:00
MHDA- 2018/08/29 06:00
CRDT- 2018/03/11 06:00
PHST- 2018/02/19 00:00 [received]
PHST- 2018/03/04 00:00 [accepted]
PHST- 2018/03/11 06:00 [entrez]
PHST- 2018/03/11 06:00 [pubmed]
PHST- 2018/08/29 06:00 [medline]
AID - 10.1007/s12032-018-1113-8 [pii]
AID - 10.1007/s12032-018-1113-8 [doi]
PST - epublish
SO  - Med Oncol. 2018 Mar 9;35(4):51. doi: 10.1007/s12032-018-1113-8.