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Dear all,
I am working on a Pegylated protein molecule with MW of ~60,000 kDa.
We had a multiple injection of this cmpd intravenously (once a week)
to rat and dog. We found that the Cp0 (peak serum conc) appeared at
30 minute or even 3 hr post dosing, not 5 min (the first bleeding
time point). My question is that 1) how to explain the "delayed"
Cp0 after an iv dose. It was not a sc or oral dose. Does any one
have similar experience with large molecule? Which circulation
system (blood or lymphatic system) carries the large molecule in the
body?? Is there any reference in this field?? Thanks in advance
for any input.
Thanks and regards,
Jian-ping Tang
Hoffmann-La Roche
973-235-2618 (phone)
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The following message was posted to: PharmPK
Hello Tang
Are you measuring the "free" protein molecule or the "pegylated" conjugate?
I feel that the below mentioned reasons might be contributing for your
finding:
1. In case you are measuring the "free" form then the release rate kinetics
which is based on pH or enzymatic degradation of your protein from the
"pegylated" conjugate might be playing a role.
2. An increase in solubility due to PEG conjugation to proteins might be
leading to its extensive biliary excretion. If you could explore the biliary
excretion of your conjugate it might give some answer. Of course, extensive
and rapid biliary excretion and the reabsorption of your conjugate is also
possible. Is it possible for you to obtain a sample much earlier than 5 min?
It might help you further. Pharmacokinetics of your conjugate in bile duct
cannulated and noncannulated rats will be interesting to study.
This reference might help you more!
Pharmacodynamic and Pharmacokinetic Characterization of Poly(Ethylene
glycol) Conjugation to Met-Enkephalin Analog.
J Pharmacol Exp Ther. 2001 Aug;298(2):848-56.
I hope this helps
Atul
University of Florida
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Hi,
I had a problem like this once before.
The study design involved a single IV administration to the rat via a tail
vein of a protein (tritiated). Distribution of the label was followed by
image analysis and by liquid scintillation counting (lsc). Cmax was at 1 h
and not the first time point taken
We estimated the amount of material in the body from the distribution data
and concluded that in the early time points there was a shortfall.
We looked at the injection site (tail). For the image analysis work we
routinely removed the tail and hence it did not show up on the pictures but
diligent scientists had kept the tails in the freezer. We thawed the tails
and cut them into sections (essentially small cylinders of tail ) and
combusted them before lsc.
Outcome?
We found the missing material in the tail at the injection site at 5 mins.
We think that some of the dose was precipitating out on injection and
forming a depot (up to 60% of the dose ) in the tail, the rest of the dose
was distributed and clearance started. The depot then seemed to get released
so that by 1 h we reached plasma Cmax. The depot release may have been
related to the protein activity (it was a venom extract) affecting the local
tissue.
Using a specific assay we saw a similar 'delayed peak' in dogs after IV
administration which might be related to the effect in rat.
I hope this makes sense and is useful
Dave
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The following message was posted to: PharmPK
I also had a similar experience in humans. We inserted iv catheters in each
of the subject's arms, one for injecting the radioactive study material and
the other for drawing blood. The study material was a murine MAb fragment
radiolabelled with 99m-Tc. In several subjects we noticed a "delayed peak"
and on reviewing the data, we found that the delayed peak occurred in those
subjects where the IV access catheter failed and we drew blood samples from
the arm that the radioactive material was injected into. We also were doing
external gamma scintigraphy and it is clear that there is a considerable
amount of radioactivity remaining in the vein where the material was
infused.
I have spoken to many investigators and in confidence (after a couple of
beers), they will admit to the same "delayed peaks"
Maybe an inverse weighting of the earlier time points will help in analysis.
WW
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