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The following message was posted to: PharmPK
Dear readers,
Also as an extension to my previous question, if the concentration-time
curve displays second humps towards the later time points (which could
or could not be due to ent.recirculation), how is one supposed to
determine the half-life? Shall we always consider the whole profile and
have it fitted or should we draw the tangent based on the first
elimination phase, and ignore the small hump that falls in the region
near the detection threshold?
Thanks for any suggestions.
Panteha
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[Two replies - Traffic seems to have picked up a little on the list -
this is great - however, if it means too many single messages in your
email in-box remember there is a digest mode for the list - db]
From: Walt WoltoszDate: Wed, 20 Feb 2002
22:03:16 -0800
To: david.-at-.boomer.org
Subject: Re: PharmPK Re: Enterohepatic recirculation and determination
of half-life
The following message was posted to: PharmPK You don't say whether your
data is in human or an animal. Nevertheless:
Both of your postings imply the need for a simulation with a
sophisticated oral absorption model that can be used simultaneously with
IV data to fit PK parameters across both data sets simultaneously using
a built-in nonlinear optimizer. We do this routinely with
GastroPlus(tm).
Modeling oral absorption with a constant Ka and IV pharmacokinetics
parameters will often result in underpredicting Cmax (because the true
Ka is higher than your average value initially) and then overpredicting
Cp well after Cmax (because the true Ka is lower than your average Ka at
those times). Ka is not constant - it varies with region and with the
concentration difference between lumen and enterocytes (assuming passive
diffusion).
We have been very successful predicting oral plasma concentration-times
using IV pharmacokinetics since we switched to a concentration gradient
based absorption model (which results in a constantly varying Ka).
Second humps can be caused by a number of factors, including the
solubility-permeability tradeoff with pH for ionized compounds (as
ionization increases, solubility increases and permeability decreases).
If your compound is a base with a pKa of, say, 6-7 or so, you might
expect a second hump at about 6 hours. Actually, you might think of it
as a trough at about 3 hours (in human), produced by a drop in
solubility as the pH increases in the distal small intestine, followed
by improved solubility going into caecum (at lower pH). We see this in
our saquinavir predictions (with a base pKa just above 7), where a
pronounced second hump is predicted without any form of enterohepatic
circulation or food effect in the model.
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (SIMU)
1220 W. Avenue J
Lancaster, CA 93534-2902
U.S.A.
http://www.simulations-plus.com
E-mail: walt.-at-.simulations-plus.com
---
From: Stephen Day
Date: Thu, 21 Feb 2002 10:04:40 -0500 (EST) To: david.aaa.boomer.org
Subject: Re: PharmPK Re: Enterohepatic recirculation and determination
of half-life
The following message was posted to: PharmPK
Dear Panteha,
If you have a second hump in your concentration-time curve than you
cannot determine an elimination half-life from taking a tangent on the
part of the curve prior to the hump. This because the hump will
ultimately affect your half-life (and drug accumulation and dosing
regime)... so you should not ignore it.
Here is a paper on the concept of "effective half-life" which may help
with you problem:
Boxenbaum H, Battle M. Effective half-life in clinical pharmacology. J
Clin Pharmacol 1995;35(8):763-6.
Steve
Stephen Day
Merck-Frosst Centre for Therapeutic Research Kirkland, QC CANADA
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Dear Panteha,
The model in the form of the transfer function presented on page 659 in
the theoretical study:
Segre G (1988) The sojourn time and its prospective use in pharmacology.
J Pharmacokin Biopharm 16: 657-666
and implemented in our software, see e.g. the studies: Durisova M, Dedik
L (1997) Modeling in frequency domain used for assessment of in vivo
dissolution profile. Pharm Res 14: 60-64, Dedik L, Durisova M (2001)
Modeling drug absorption from enteric-coated granules.
Meth Find Exp Clin Pharmacol 23: 213-217 can by used to model behavior
of a drug in a situation when the concentration-time profile displays a
second hump without any problem as shown in the example presented in our
study: Dedik L, Durisova M (1997) New general formulas for estimation of
mean residence time and its variance,
Pharmazie 52:404-405.
The modeling procedure is fast and it does not require initial estimates
of model parameters.
Regards,
Maria Durisova
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