PMID- 27572830
OWN - NLM
STAT- MEDLINE
DCOM- 20171116
LR  - 20190318
IS  - 1432-2072 (Electronic)
IS  - 0033-3158 (Print)
IS  - 0033-3158 (Linking)
VI  - 233
IP  - 21-22
DP  - 2016 Oct
TI  - A phase 1 study of the safety, tolerability, pharmacokinetics, and 
      pharmacodynamics of TAK-063, a selective PDE10A inhibitor.
PG  - 3787-3795
AB  - RATIONALE: 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. OBJECTIVE: Safety, tolerability, and 
      pharmacokinetics of TAK-063 were evaluated in a phase 1 study. METHODS: 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). RESULTS: 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 T (max) was reached 3 to 4 h 
      postdose. Fed conditions slowed absorption (T (max =) 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. CONCLUSIONS: 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.
FAU - Tsai, Max
AU  - Tsai M
AD  - Takeda Development Center Americas, Inc., One Takeda Parkway, Deerfield, IL, 
      60015, USA.
FAU - Chrones, Lambros
AU  - Chrones L
AD  - Takeda Development Center Americas, Inc., One Takeda Parkway, Deerfield, IL, 
      60015, USA.
FAU - Xie, Jinhui
AU  - Xie J
AD  - Takeda Development Center Americas, Inc., One Takeda Parkway, Deerfield, IL, 
      60015, USA.
FAU - Gevorkyan, Hakop
AU  - Gevorkyan H
AD  - California Clinical Trials Medical Group, Glendale, CA, USA.
FAU - Macek, Thomas A
AU  - Macek TA
AD  - Takeda Development Center Americas, Inc., One Takeda Parkway, Deerfield, IL, 
      60015, USA. tom.macek@takeda.com.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
DEP - 20160830
PL  - Germany
TA  - Psychopharmacology (Berl)
JT  - Psychopharmacology
JID - 7608025
RN  - 0 
      (1-(2-fluoro-4-(1H-pyrazol-1-yl)phenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one)
RN  - 0 (Phosphodiesterase Inhibitors)
RN  - 0 (Pyrazoles)
RN  - 0 (Pyridazines)
RN  - EC 3.1.4.- (PDE10A protein, human)
RN  - EC 3.1.4.- (Phosphoric Diester Hydrolases)
SB  - IM
MH  - Adult
MH  - Disorders of Excessive Somnolence/chemically induced
MH  - Dose-Response Relationship, Drug
MH  - Fasting
MH  - Female
MH  - Healthy Volunteers
MH  - Humans
MH  - Hypotension, Orthostatic/chemically induced
MH  - Male
MH  - Middle Aged
MH  - Phosphodiesterase Inhibitors/administration & dosage/adverse 
      effects/*pharmacology
MH  - Phosphoric Diester Hydrolases
MH  - Pyrazoles/administration & dosage/adverse effects/*pharmacology
MH  - Pyridazines/administration & dosage/adverse effects/*pharmacology
MH  - Tachycardia/chemically induced
MH  - Young Adult
PMC - PMC5063900
OTO - NOTNLM
OT  - *Oral
OT  - *Pharmacokinetics
OT  - *Phosphodiesterase 10A
OT  - *Safety
OT  - *Schizophrenia
OT  - *Single-rising dose
COIS- Compliance with ethical standards Role of funding source Funding for this study 
      was provided by Takeda Pharmaceutical Company, Limited. Conflicts of interest Max 
      Tsai, Thomas Macek, Lambros Chrones, and Jinhui Xie are employees of Takeda 
      Development Center Americas, Inc., Deerfield, IL. Hakop Gevorkyan is an employee 
      of California Clinical Trials Medical Group, Glendale, CA, and was Principal 
      Investigator of the study.
EDAT- 2016/08/31 06:00
MHDA- 2017/11/29 06:00
PMCR- 2016/08/30
CRDT- 2016/08/31 06:00
PHST- 2016/03/23 00:00 [received]
PHST- 2016/08/11 00:00 [accepted]
PHST- 2016/08/31 06:00 [pubmed]
PHST- 2017/11/29 06:00 [medline]
PHST- 2016/08/31 06:00 [entrez]
PHST- 2016/08/30 00:00 [pmc-release]
AID - 10.1007/s00213-016-4412-9 [pii]
AID - 4412 [pii]
AID - 10.1007/s00213-016-4412-9 [doi]
PST - ppublish
SO  - Psychopharmacology (Berl). 2016 Oct;233(21-22):3787-3795. doi: 
      10.1007/s00213-016-4412-9. Epub 2016 Aug 30.