Dataset Information

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.

ABSTRACT: 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-? (A?) 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 A? 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 A?1-40 and A?1-42 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.

SUBMITTER: Qiu R

PROVIDER: S-EPMC6839502 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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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.

Qiu Ruolun R Ahn Jae Eun JE Alexander Robert R Brodney Michael A MA He Ping P Leurent Claire C Mancuso Jessica J Margolin Richard A RA Tankisheva Ekaterina E Chen Danny D

Journal of Alzheimer's disease : JAD 20190101 2

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-β (Aβ) 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 dai ...[more]

PMID: 31424395

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Dataset Information

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.

Publications

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.

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