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I am seeing an IV plasma concentration versus time curve wherein the Tmax occurs 4 hrs after a bolus
dose. In one case the first 4 sampling times (15 min, 30 min, 1 hr, 2 hr) have similar
concentrations and then there is a decrease. Is this likely due to precipitation of the drug
in-vivo, bioanalytical issues or some other problem? This is a lipophilic compound (log D of ~8)
and is being dosed in a PEG 400 combination.
Many thanks,
Laura
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Hi Laura,
I'm assuming this is an LS/MS/MS assay. Are you using a stable isotope labeled internal standard? If
not, it is almost certainly a case of ion suppression by PEG400. It is notorious for it. The early
samples have higher concentrations of PEG, and therefore get suppressed more; hence the flat or even
increasing concentration readings. It is very easy to check - simply analyze one of the early
samples, then spike this sample with a known amount of standard, and analyze again. See if you are
getting the expected difference. If the difference is smaller than what you spiked, there is ion
suppression.
Hope this helps,
Andrew
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Hi Laura,
I am in total agreement with Andrew. PEG 400 has a tendency to show high impact on NCE's IV profile.
U can also try sample clean up and dilution of initial time points.
Regards,
Sreekanth Dittakavi
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Laura:
Thanks for sharing your PK results. You have raised an important issue that many of us have
encountered in DMPK/Bioanalysis. There are two parts to the data that you have shared. Andrew
answered the second part that we have encountered with PEG related formulations in PK studies from
bioanalysis perspective. The first part is how does PEG get into the plasma samples.
During a PK study with a compound with high log P value, PEG400 or higher grades are the usual
solubilizing agents. They are generally added at >10% in the formulation to dose animals. But, how
does PEG get into the plasma samples to give the results that you have shared. PEG and other PEG
related excipients have the ability to interact with certain compounds by forming a complex. These
complexed compounds can have a long half-life in plasma (longer that you have observed depending on
the molecular size). In addition, PEG and other PEG related excipients (depending on the molecular
size) can cross the Tight Junctions (TJ) that maintain the integrity of the cellular framework in
the body that can contribute to the long half-life.
It would be interesting to see if you would observe similar results with higher grade PEG excipients
(maybe 4000, 8000) than PEG 400. The higher grade PEGs would probably not cross the TJs and you
would be able to see the typical IV PK curve for your compound.
A Prospective Analysis of Co-Processed Non-Ionic Surfactants in Enhancing Permeability of a Model
Hydrophilic Drug
MM Alvi, P Chatterjee, AAPS PharmSciTech (2014) 15 (2), 339-353.
Parnali Chatterjee
E-mail: Parnalic.at.hotmail.com
parnali_chatterjee.-at-.yahoo.com
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Hi Laura,
In case not bioanalytical:
Was administration solution, administration itself and administration site ok? What about blood
collecting and sample stability?
Is it in human or?
Elke
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I am not sure about the precipitation but same kind of trend we do observed when there is
bioanalytical issue. Laura as you mention formulation contain the PEG 400 so it good idea to revisit
your bioanalytical extraction method.
I will advise that please do 10 fold dilutions of your initial 4 time points and also work for
chromatographic separation of PEG 400 to your analyte of interest.
Hope you will get some positive result.
Tarun Sharma
Associate Director - DMPK
Head Bioanalytical and Biotransformation
Sai Life Sciences, Pune
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What do you mean by a PEG combination, is it a pegolated drug or is it in a peg formulation?
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