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Hi Everyone:
I am being asked to obtain PK parameters, specifically the amount
absorbed, of a drug (Thyrotropin Releasing Hormone) from its PD
profile (serum prolactin levels). I measured serum prolactin levels
after administering TRH intravenously and also TRH-loaded patches
which were administered by the buccal route. Is it possible to
calculate the amount of TRH absorbed this way and if it is then how
would I go about doing it ?
Any suggestions or advice would be greatly appreciated.
Thanks,
M
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Maimoona,
There is no simple way to do what you want. The only way to calculate
the bioavailability (i.e. amount absorbed) from the patch is make
assumptions.
If you had measured the TRH concentrations after IV and patch dosing
you could make the assumptions that the elimination kinetics were
linear and that the clearance of TRH was the same after both routes.
You could then work out the biovailability from the ratio of the
AUCpatch/AUCiv.
Because you are using a pharmacodynamic response (prolactin) you must
try to predict the TRH concs after each route then use these predicted
concs to compute AUCpatch/AUCiv.
Note that simply using the AUCpatch/AUCiv of prolactin concs will not
give you a reliable estimate of TRH bioavailability unless you can
prove that prolactin concs are linearly proportional to TRH concs. You
might be lucky and be able to show this if you gave several widely
spaced doses of TRH both iv and by patch and to demonstrate that the
AUCpatch/AUCiv of prolactin did not change with dose.
Predicting the TRH concs requires several assumptions. You could
assume that TRH is distributed into a single compartment and is
eliminated by a first order process. With these assumptions you could
fit the time course of prolactin concs and estimate the TRH
elimination rate constant as well as the parameters of a
pharmacodynamic model e.g. Emax and EC50. These parameters will then
allow you to predicte the TRH conc from prolactin conc i.e. you can
use the prolactin concs as a bioassay standard curve.
If you now apply the prolactin to TRH standard curve to the patch
prolactin concs you can predict the time course of TRH concs.
Now you have got the TRH concs after the iv dose (nominally starting
at 1 and decreasing exponentially with an estimated rate constant) and
the TRH concs predicted for the patch. You can then calculate the
AUCpatch and AUCiv and thus compute the bioavailability.
There are many complications you have to deal with when you do this
e.g. TRH PK may be non-linear and multi-compartmental, there will be a
delay between changes in TRH conc and changes in prolactin conc. With
really good data you may be able to identify and describe these
phenomena.
Good luck!
Nick
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
n.holford.aaa.auckland.ac.nz
http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford
[Along these lines another approach 'could' be to model the iv plasma
and effect data IF you have both with a compartmental or similar
model. You might then fit the iv plasma/effect data and the oral
efffect data simultaneously using the same model but adding ka and F
parameter to the combined model - db]
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The following message was posted to: PharmPK
TRH is endogenous and is elevated and/or decreased by various
environmental stressors and has both a circadian and ultradian rhythm-
so doing a before and after approach will not help here. Using TRH
with a label probe would be the cleanest way.
--
Ed O'Connor, Ph.D.
Laboratory Director
Matrix BioAnalytical Laboratories
25 Science Park at Yale
New Haven, CT 06511
Web: www.matrixbioanalytical.com
Email: eoconnor.at.matrixbioanalytical.com
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Dear Ed:
Thanks for your response. Do you mean that I would have to radiolabel
the TRH that is being administered to rats. How would it I detect it
if I am measuring the PD response, i.e. serum prolactin levels. So,
with the PD data that I currently have i.e., increase in serum
prolactin levels compared to the basal levels upon iv and buccal
administration of TRH, it really would not make sense to calculate
the amount of TRH absorbed ?
Thanks,
Maimoona
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