PMID- 31424395
OWN - NLM
STAT- MEDLINE
DCOM- 20201104
LR  - 20210917
IS  - 1875-8908 (Electronic)
IS  - 1387-2877 (Print)
IS  - 1387-2877 (Linking)
VI  - 71
IP  - 2
DP  - 2019
TI  - Safety, Tolerability, Pharmacokinetics, and Pharmacodynamic Effects of 
      PF-06751979, a Potent and Selective Oral BACE1 Inhibitor: Results from Phase I 
      Studies in Healthy Adults and Healthy Older Subjects.
PG  - 581-595
LID - 10.3233/JAD-190228 [doi]
AB  - PF-06751979 is a selective inhibitor of the beta-site amyloid precursor protein 
      cleaving enzyme-1, which is a key aspartyl protease in the generation of 
      amyloid-beta (Abeta) peptides, thought to be critical for the cerebral degeneration 
      observed in Alzheimer's disease. Two Phase I studies (NCT02509117, NCT02793232) 
      investigated the safety/tolerability, pharmacokinetics (PK), and pharmacodynamics 
      (PD) of PF-06751979. Single-ascending doses up to 540 mg and multiple-ascending 
      doses up to 275 mg once daily (QD) in healthy adults, and multiple doses of 50 mg 
      or 125 mg QD in healthy older subjects were assessed. PF-06751979 was well 
      tolerated at all doses given, and all treatment-related adverse events (AEs) were 
      mild to moderate. PK parameters remained consistent across the PF-06751979 QD 
      dosing regimens, and no notable food effects were observed. PD analysis showed 
      that PF-06751979 reduced the cerebrospinal fluid (CSF) and plasma levels of Abeta 
      peptides in a dose-dependent manner, with the greatest reductions observed in 
      subjects treated with 275 mg QD (approximately 92% and 93% reduction in CSF 
      Abeta1-40 and Abeta1-42 observed at 24 h after Day 14 dose, respectively). A drug 
      interaction study (NCT03126721) using midazolam indicated that there was no 
      clinically meaningful effect of multiple doses of PF-06751979 100 mg QD on the PK 
      of single-dose midazolam in healthy adults. Overall, these data suggest that 
      PF-06751979 with daily dosing is favorable for further clinical development.
FAU - Qiu, Ruolun
AU  - Qiu R
AD  - Pfizer Inc, Cambridge, MA, USA.
FAU - Ahn, Jae Eun
AU  - Ahn JE
AD  - Pfizer Inc, Cambridge, MA, USA.
FAU - Alexander, Robert
AU  - Alexander R
AD  - Takeda Pharmaceuticals International Co, Cambridge, MA, USA.
FAU - Brodney, Michael A
AU  - Brodney MA
AD  - Vertex Pharmaceuticals, Boston, MA, USA.
FAU - He, Ping
AU  - He P
AD  - Biogen Inc, Cambridge, MA, USA.
FAU - Leurent, Claire
AU  - Leurent C
AD  - Samsung Ventures, Boston, MA, USA.
FAU - Mancuso, Jessica
AU  - Mancuso J
AD  - Pfizer Inc, Cambridge, MA, USA.
FAU - Margolin, Richard A
AU  - Margolin RA
AD  - Clinical Research Solutions LLC, Cambridge, MA, USA.
FAU - Tankisheva, Ekaterina
AU  - Tankisheva E
AD  - Pfizer Clinical Research Unit Brussels, Belgium.
FAU - Chen, Danny
AU  - Chen D
AD  - Pfizer Inc, Cambridge, MA, USA.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
PL  - Netherlands
TA  - J Alzheimers Dis
JT  - Journal of Alzheimer's disease : JAD
JID - 9814863
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (PF-06751979)
RN  - 0 (Protease Inhibitors)
RN  - 0 (Pyrans)
RN  - 0 (Thiazines)
RN  - 0 (Thiazoles)
RN  - EC 3.4.- (Amyloid Precursor Protein Secretases)
RN  - EC 3.4.23.- (Aspartic Acid Endopeptidases)
RN  - EC 3.4.23.46 (BACE1 protein, human)
SB  - IM
MH  - Administration, Oral
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Amyloid Precursor Protein Secretases/*antagonists & 
      inhibitors/blood/cerebrospinal fluid
MH  - Amyloid beta-Peptides/*antagonists & inhibitors/blood/cerebrospinal fluid
MH  - Aspartic Acid Endopeptidases/*antagonists & inhibitors/blood/cerebrospinal fluid
MH  - Cross-Over Studies
MH  - Double-Blind Method
MH  - Female
MH  - Healthy Volunteers
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - *Protease Inhibitors/administration & dosage/adverse effects/pharmacokinetics
MH  - *Pyrans/administration & dosage/adverse effects/pharmacokinetics
MH  - *Thiazines/administration & dosage/adverse effects/pharmacokinetics
MH  - *Thiazoles/administration & dosage/adverse effects/pharmacokinetics
MH  - Young Adult
PMC - PMC6839502
OTO - NOTNLM
OT  - Alzheimer's disease
OT  - BACE1 protein-human
OT  - Phase I
OT  - amyloid-beta peptides
OT  - pharmacodynamics
OT  - pharmacokinetics
OT  - safety
OT  - tolerability
COIS- Authors' disclosures available online 
      (https://www.j-alz.com/manuscript-disclosures/19-0228r1).
EDAT- 2019/08/20 06:00
MHDA- 2020/11/05 06:00
PMCR- 2019/11/08
CRDT- 2019/08/20 06:00
PHST- 2019/08/20 06:00 [pubmed]
PHST- 2020/11/05 06:00 [medline]
PHST- 2019/08/20 06:00 [entrez]
PHST- 2019/11/08 00:00 [pmc-release]
AID - JAD190228 [pii]
AID - 10.3233/JAD-190228 [doi]
PST - ppublish
SO  - J Alzheimers Dis. 2019;71(2):581-595. doi: 10.3233/JAD-190228.