Anticholinesterase and pharmacokinetic profile of phenserine in healthy elderly human subjects.
OBJECTIVE
To evaluate the safety, maximum tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics (PD) of the acetyl-selective anticholinesterase, phenserine tartrate, in healthy elderly subjects.


METHODS
32 healthy elderly volunteers received single oral doses of phenserine tartrate (5-20 mg). Physical and vital signs were monitored over the ensuing 24 hours. Analyses were performed on plasma samples to determine PK, and PD were assessed using an erythrocyte acetylcholinesterase (AChE) inhibition assay.


RESULTS
No serious adverse events (AEs) occurred; the most common were headache and vomiting. The MTD of phenserine tartrate was 10 mg. The Cmax and AUC(0-24) of phenserine increased with dose, but neither were dose-proportional. Subjects receiving 10 mg of phenserine tartrate had a Cmax of 1.95 ng/mL at 1.5 hours, and the mean peak inhibition (Imax) of AChE was 26% (range: 18-34%) at 1.75 hours (tImax) following dosing. The half-life of AChE inhibition (tI1/2) was 11 hours. Evaluation of PK/PD relationships suggested a linear correlation between plasma phenserine concentration and AChE inhibition in the blood.


CONCLUSIONS
Phenserine tartrate was safe and well tolerated when administered as a single oral dose of either 5 mg or 10 mg. An increase in the severity and frequency of AEs occurred at the 20 mg dose level.
Greig
Nigel H
NH
Drug Design & Development Section, Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224 USA. Greign@grc.nia.nih.gov
Ruckle
Jon
J
Comer
Patrick
P
Brownell
Lidia
L
Holloway
Harold W
HW
Flanagan
Douglas R
DR
Canfield
Craig J
CJ
Burford
Robert G
RG
D000110:Acetylcholinesterase / Q000187:drug effects; D000368:Aged; D019540:Area Under Curve; D002800:Cholinesterase Inhibitors / Q000009:adverse effects* / Q000493:pharmacokinetics*; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010830:Physostigmine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
D002800:Cholinesterase Inhibitors; D010830:Physostigmine; D000110:Acetylcholinesterase; C092280:phenserine