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Dear Members,
We are planning to conduct a study on Donepezil Hcl 5 mg
bioequivalence study in fasting conditions. I has gone throug the
literature which states that it has so many adverse reactions. what
all the precautions to be taken during the clinical phase of the
study. what are expected adverse events in healithy human volunteers.
regards,
Kirankumar
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The following message was posted to: PharmPK
Hi Kirankumar,
Donepezil acts similar to organophosphates. But it is "only" a
selective, reversible and non-competitive inhibitor of
acetylcholinesterase. It easily crosses the blood-brain barrier
(therefore use against Alzheimer) and increases the level of
neurotransmitter Acetylcholin throughout the body. Adverse effects
are the same as with organophosphates: dehydratation, loss of body
weight, hot flashes, SLUD symptomatic, dizziness, nausea, headache,
paresthesias, cramps, visual disturbances, miosis, respiratory
arrest, coma, death (ok, this requires high doses!)
To counteract the cholinergic activity, provide some syringes with
atropinsulfate for IV application. Obidoxim-therapy is not indicated
for reversible inhibitors of AChE (the same as with carbamates).
There are two publications available describing the pharmacokinetic
(blood levels) and pharmacodynamic profile (inhibition of RBC ChE) in
healthy human volunteers. Doses of 0.3, 0.6, 0.9, 2.0, 4.0, 6.0 mg
were applied to humans (bw ~75+/-6 kg).
2.0 mg Donepezil induced a 15% RBC ChE Hemmung at Tmax. Some
volunteers had an inhibition up to 25%. This is clearly not
acceptable. We estimated that 0.5 mg Donepezil would be a safe dose.
Another important issues to consider is the half-life time of
Donepezil. It is 70-80hrs. If you assume a complete washout phase
requires 7x the half-life time, then you get = 7x 70h = 490h = 3
weeks of washout!
Rogers SL and Friedhoff LT (1998a). Pharmacokinetic and
pharmacodynamic profile of Donepezil HCL following single oral doses.
Br. J. Clin. Pharmacol. 46 (Suppl 1) 1-6
Rogers SL and Friedhoff LT (1998b). Pharmacokinetic and
pharmacodynamic profile of Donepezil HCL following multiple oral
doses. Br. J. Clin. Pharmacol. 46 (Suppl 1) 7-12
I can send the publications as PDF-file to you if you wish me to do so.
Cheers
Joerg
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Dear KiranKumar,
During a BE study of Donepezil 10mg formulation that we conducted,
the most prominent AE observed was vomiting. It was frequent and
occurred at or before Cmax.
Therefore as a precaution, a pre-medication to counteract the
cholinergic activity (after checking the interaction of this
medication with the donepezil PK) can be suggested, if your protocol
allows it.
All the best.
Rhishikesh MANDKE
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