title: A phase 1 study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-063, a selective PDE10A inhibitor.
abstract: Schizophrenia is a complex neuropsychiatric disorder characterized, in part, by impaired dopamine signaling. TAK-063 is a selective inhibitor of phosphodiesterase 10A, a key regulator of intracellular signaling pathways that is highly expressed in the striatum.
  
  
  
  Safety, tolerability, and pharmacokinetics of TAK-063 were evaluated in a phase 1 study.
  
  
  
  Healthy Japanese and non-Japanese volunteers were randomized into dose cohorts of 3, 10, 30, 100, 300, and 1000 mg. Each fasting volunteer randomly received a single dose of TAK-063 or placebo. Individuals from the 100-mg cohort also received a post-washout, 100-mg dose under fed conditions. A total of 84 volunteers enrolled (14 per cohort).
  
  
  
  The most common drug-related adverse events (AEs) were somnolence (33.3 %), orthostatic tachycardia (19.7 %), and orthostatic hypotension (9.1 %). The three severe AEs recorded occurred at the highest doses: orthostatic hypotension (n = 1; 300 mg) and somnolence (n = 2; 1000 mg). There were no deaths, serious AEs, or discontinuations due to AEs. TAK-063 exposure increased in a dose-dependent manner. Median Tmaxwas reached 3 to 4 h postdose. Fed conditions slowed absorption (Tmax =6 h) and increased oral bioavailability. Renal elimination was negligible. Safety and pharmacokinetic parameters were similar between Japanese and non-Japanese subjects. Impairments in cognitive function consistent with the effects of other sedative or hypnotic agents were detected using a validated, computerized cognition battery, CNS Vital Signs.
  
  
  
  TAK-063 was safe and well tolerated at doses up to 1000 mg and demonstrated a pharmacokinetic profile supporting once-daily dosing. Further evaluation of the clinical safety and efficacy of TAK-063 is warranted.
authors: Takeda Development Center Americas, Inc., One Takeda Parkway, Deerfield, IL, 60015, USA.
authors: Max
authors: M
authors: Tsai
authors: Takeda Development Center Americas, Inc., One Takeda Parkway, Deerfield, IL, 60015, USA.
authors: Lambros
authors: L
authors: Chrones
authors: Takeda Development Center Americas, Inc., One Takeda Parkway, Deerfield, IL, 60015, USA.
authors: Jinhui
authors: J
authors: Xie
authors: California Clinical Trials Medical Group, Glendale, CA, USA.
authors: Hakop
authors: H
authors: Gevorkyan
authors: Takeda Development Center Americas, Inc., One Takeda Parkway, Deerfield, IL, 60015, USA. tom.macek@takeda.com.
authors: Thomas A
authors: TA
authors: Macek
mesh_terms: D000328:Adult; D006970:Disorders of Excessive Somnolence / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D005215:Fasting; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007024:Hypotension, Orthostatic / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases; D011720:Pyrazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D011724:Pyridazines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D013610:Tachycardia / Q000139:chemically induced; D055815:Young Adult
chemical_list: C000594749:1-(2-fluoro-4-(1H-pyrazol-1-yl)phenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one; D010726:Phosphodiesterase Inhibitors; D011720:Pyrazoles; D011724:Pyridazines; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases
keywords: Oral; Pharmacokinetics; Phosphodiesterase 10A; Safety; Schizophrenia; Single-rising dose