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The following message was posted to: PharmPK
Hello,
Pl. give explanation for my question.
Consider that for one drug, only immediate release formulation is
available.
If I have pharmacokinetic data including compelte plasma concentration
- time profile of that immediate release formulation,
is it possible to predict the plasma concentration - time profile of
sustained release formulation of the same drug
with specific dissolution profile (say 15 hrs. profile at 50 rpm, USP
II, phosphate buffer pH 6.8).
Pl. send me the maximum references.
With regards,
S.Sritharan.
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At 11:52 PM 8/11/2003, seetharaman.sritharan wrote:
Consider that for one drug, only immediate release formulation is
available.
If I have pharmacokinetic data including compelte plasma concentration
- time profile of that immediate release formulation,
is it possible to predict the plasma concentration - time profile of
sustained release formulation of the same drug
with specific dissolution profile (say 15 hrs. profile at 50 rpm, USP
II, phosphate buffer pH 6.8).
Maybe.
If you have good PK parameters (preferably from iv data for the same
subjects as your oral data), and if you have accurate Fa and F for the
immediate release dose, and if the immediate release dose is not
completely absorbed in the proximal small intestine (so a significant
amount of drug reaches ileum and colon), then you can use GastroPlus
(your company has it) to build an absorption model that will let you
determine any regional absorption effects for your drug. For controlled
release, you will typically expect most absorption in the colon, so
it's important to determine the Peff for the colon, which is almost
always significantly different from the small intestine.
The issues you will/may have to deal with include:
(1) regional absorption differences due to ionization, tight junction
gap, and transporter (influx and/or efflux) differences, if involved
(2) regional solubility issues (pH-dependence) which may cause the in
vivo release to be significantly different from your in vitro
experimental dissolution-time data). Your USP method uses a fixed pH
(6.8), but, if you don't know, you should also determine whether there
is any significant pH dependence for your release method.
(3) saturable first pass extraction in gut and/or liver, if involved -
if gut metabolism is significant, then when and where you release the
drug can cause differences in F.
All of these can be simulated within GastroPlus, and it is a common
application of the program to assess the potential differences you
might experience as these factors vary. It can be a complex problem
with many subtle interactions (and it can be incredibly simple if
you're lucky - but in our experience, that doesn't happen most of the
time).
Feel free to call if you'd like to discuss this further.
Best regards,
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (SIMU)
1220 W. Avenue J
Lancaster, CA 93534-2902
U.S.A.
http://www.simulations-plus.com
Phone: (661) 723-7723
FAX: (661) 723-5524
E-mail: walt.aaa.simulations-plus.com
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