title: The effect of CYP2C19 polymorphism on the safety, tolerability, and pharmacokinetics of tivantinib (ARQ 197): results from a phase I trial in advanced solid tumors.
abstract: BACKGROUND
  Tivantinib (formerly ARQ 197) is a selective inhibitor of c-Met mainly metabolized by CYP2C19. CYP2C19 is known for genetic polymorphisms, and ~20% of Asians are poor metabolizers (PMs), while others are extensive metabolizers (EMs). In this study, we examined the safety, pharmacokinetics (PK), and preliminary efficacy of tivantinib as a single agent to determine recommended phase II doses (RPIIDs).
  
  
  METHODS
  Forty-seven patients (EMs, 33; PMs, 14) with solid tumors were orally treated with tivantinib, from 70 to 360 mg bid in a 3 + 3 dose-escalation scheme. EMs and PMs were separately enrolled at the doses >120 mg bid.
  
  
  RESULTS
  Tivantinib was well tolerated up to 360 mg bid for EMs and 240 mg bid for PMs. Neutropenia, leukopenia, anemia, fatigue, and anorexia were the frequent adverse events related to tivantinib and were commonly observed in both EMs and PMs. PMs had 1.9-fold higher AUC(0-12) compared with EMs at 240 mg bid. Regardless of CYP2C19 phenotype, Gr.4 neutropenia occurred in patients with relatively high exposure to tivantinib. A confirmed partial response was achieved in two non-small-cell lung cancer (NSCLC) patients.
  
  
  CONCLUSIONS
  Two different settings of RPIIDs, 360 mg bid for EMs and 240 mg bid for PMs, were determined.
authors: Division of Thoracic Oncology, Shizuoka Cancer Center, Naga-izumi, Japan. n.yamamoto@scchr.jp
authors: N
authors: N
authors: Yamamoto
authors: H
authors: H
authors: Murakami
authors: T
authors: T
authors: Nishina
authors: T
authors: T
authors: Hirashima
authors: K
authors: K
authors: Sugio
authors: K
authors: K
authors: Muro
authors: T
authors: T
authors: Takahashi
authors: T
authors: T
authors: Naito
authors: H
authors: H
authors: Yasui
authors: S
authors: S
authors: Akinaga
authors: Y
authors: Y
authors: Koh
authors: N
authors: N
authors: Boku
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D015331:Cohort Studies; D065731:Cytochrome P-450 CYP2C19; D004305:Dose-Response Relationship, Drug; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D011760:Pyrrolidinones / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011804:Quinolines / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: C551661:ARQ 197; D011760:Pyrrolidinones; D011804:Quinolines; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19
keywords: CYP2C19 polymorphism; c-Met inhibitor; pharmacokinetics; phase I study; tivantinib