PMID- 32715381
OWN - NLM
STAT- MEDLINE
DCOM- 20210301
LR  - 20210301
IS  - 1865-8652 (Electronic)
IS  - 0741-238X (Linking)
VI  - 37
IP  - 9
DP  - 2020 Sep
TI  - Investigation of Safety and Tolerability of ASP3652 Based on Clinical Studies of 
      Cerebrospinal Fluid Transfer After Multiple Doses and Exposure After Single Doses 
      at High Dose Levels.
PG  - 3967-3984
LID - 10.1007/s12325-020-01451-6 [doi]
AB  - INTRODUCTION: The studies described here were conducted to investigate the 
      central nervous system (CNS) transfer of ASP3652, a peripherally acting inhibitor 
      of fatty acid amide hydrolase, after multiple doses at around the anticipated 
      therapeutic dose and the safety, tolerability, and pharmacokinetics after single 
      doses at corresponding supratherapeutic doses in healthy subjects. METHODS: 
      Study 1 was an open-label multiple dose study in which ASP3652 (300 mg bid) or 
      matching placebo was administered in multiple doses to healthy subjects. Study 2 
      was a placebo-controlled, randomized 4 x 4 crossover study in which ASP3652 was 
      given as three single ascending doses of ASP3652 (600-1800 mg) or matching 
      placebo to healthy subjects. Levels of ASP3652 and endocannabinoids (eCBs) in 
      plasma, cerebrospinal fluid (CSF) (study 1 only), and safety were evaluated. 
      RESULTS: In study 1, ASP3652 was readily absorbed to reach C(max) at 1 h after 
      dosing. AUC(tau) and C(max) of ASP3652 in CSF were approximately 0.2% and 0.06% 
      of the AUC(tau) and C(max) in plasma after multiple doses of ASP3652 300 mg bid. 
      At steady state the area under the response-time curve (AURC) from 0 to 12 h and 
      the maximum response for anandamide in plasma were approximately 550-fold and 
      230-fold higher than those in CSF. In study 2, the C(max) and AUC of ASP3652 
      increased higher than dose proportionally in subjects receiving 600-1800 mg 
      ASP3652. For eCBs, although the AURC increased less than dose proportionally, 
      maximum plasma levels were comparable across all treatment groups. The incidence 
      of adverse events (AEs) was similar across all treatment groups including the 
      placebo group. There was no evidence of CNS-related side effects. CONCLUSIONS: 
      ASP3652 showed low CNS penetration at the anticipated therapeutic dose and was 
      well tolerable without any CNS-related AEs at supratherapeutic doses, supporting 
      that the drug can be safely tested at the anticipated therapeutic dose. TRIAL 
      REGISTRATION: ClinicalTrials.gov identifier, NCT02034734 for study 1, NCT01815684 
      for study 2.
FAU - Takizawa, Masaomi
AU  - Takizawa M
AD  - Astellas Pharma Inc, Tokyo, Japan. masaomi.takizawa@astellas.com.
FAU - Cerneus, Dirk
AU  - Cerneus D
AD  - Astellas Pharma Europe B. V., Leiden, The Netherlands.
FAU - Michon, Ingrid
AU  - Michon I
AD  - Astellas Pharma Europe B. V., Leiden, The Netherlands.
FAU - Rijnders, Sanne
AU  - Rijnders S
AD  - Astellas Pharma Europe B. V., Leiden, The Netherlands.
FAU - Meijer, John
AU  - Meijer J
AD  - Astellas Pharma Europe B. V., Leiden, The Netherlands.
FAU - Someya, Akiyoshi
AU  - Someya A
AD  - Astellas Pharma Inc, Tokyo, Japan.
FAU - Sato, Yuichiro
AU  - Sato Y
AD  - Astellas Pharma Inc, Ibaraki, Japan.
LA  - eng
SI  - ClinicalTrials.gov/NCT02034734
SI  - ClinicalTrials.gov/NCT01815684
SI  - ClinicalTrials.gov/NCT02034734
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200726
PL  - United States
TA  - Adv Ther
JT  - Advances in therapy
JID - 8611864
RN  - EC 3.5.- (Amidohydrolases)
RN  - EC 3.5.1.- (fatty-acid amide hydrolase)
MH  - Adolescent
MH  - Adult
MH  - Amidohydrolases/*antagonists & inhibitors/blood/metabolism/*therapeutic use
MH  - Cerebrum/*metabolism
MH  - Cross-Over Studies
MH  - *Dose-Response Relationship, Drug
MH  - Double-Blind Method
MH  - Female
MH  - Healthy Volunteers
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Netherlands
MH  - Young Adult
OTO - NOTNLM
OT  - Anandamide
OT  - Cerebrospinal fluid
OT  - Endocannabinoid
OT  - Fatty acid amide hydrolase
OT  - Healthy subjects
OT  - Pharmacodynamics
OT  - Pharmacokinetics
EDAT- 2020/07/28 06:00
MHDA- 2021/03/02 06:00
CRDT- 2020/07/28 06:00
PHST- 2020/06/09 00:00 [received]
PHST- 2020/07/28 06:00 [pubmed]
PHST- 2021/03/02 06:00 [medline]
PHST- 2020/07/28 06:00 [entrez]
AID - 10.1007/s12325-020-01451-6 [pii]
AID - 10.1007/s12325-020-01451-6 [doi]
PST - ppublish
SO  - Adv Ther. 2020 Sep;37(9):3967-3984. doi: 10.1007/s12325-020-01451-6. Epub 2020 
      Jul 26.