to respected sir,Back to the Top
can any one predict in vivo data like plasma concentration time profile
from the in vitro data like dissolution testing (and additional data
like ka or dose or volume of distribution or clearance for that drug
)for drug following one compartment open model or any drug ?
if yes then tell me the exact references of that or give me website
name or links or any journal or book reference.
is it possible without software ?
and if we have to use software for that then suggest the name of
please reply with good references
Dhaivat,Back to the Top
To predict plasma concentration-time profiles you need to know at least:
(1) In vivo solubility as a function of pH
(2) In vivo permeability as a function of location in the gut (duodenum,
jejunum, ileum, caecum, colon - all can be, and usually are, different)
(3) Pharmacokinetic parameters - volume of distribution and clearance
for one-compartment drugs, additional peripheral distribution rate
constants for multi-compartment drugs
You can get a decent estimate of the in vivo solubility if you do your
experiments the right way (simulated in vivo fluids). Many solubility
experiments are fine for screening purposes, but do not provide
sufficient information for accurate prediction in an environment where
ionization and solubility can change significantly.
You can get an estimate (not always decent) of human jejunal
permeability from certain in vitro permeability experiments (caco-2,
MDCK, PAMPA), but it is not always a good indicator of permeability in
other regions of the gastrointestinal tract (in fact, it is not always a
good indicator of permeability in jejunum).
PK parameters are the most different. In general, in vitro experiments
have not provided reliable human PK parameters, although considerable
progress has been made with PBPK approaches (which require a lot of data
for individual tissues such as muscle, bone, heart, lungs, fat, lever,
These are the basics for a "simple" drug - no significant degradation in
the lumen (add stability data), no saturable absorption (add transporter
data if you can get it), no saturable metabolism (add Vmax and Km for
each saturable pathway - in gut and liver), no self-inhibiting or
self-inducing metabolism, etc.
It's a very complex issue. Can it be done without software?
In my opinion, no. It cannot be done even with very sophisticated
software (like our GastroPlus program) unless you have sufficient good
data (we have seen a lot of data that was not very useful for modeling).
Without data, you can use software to test the possible results under a
variety of posed conditions, and get a feel for the range of variability
in results you might expect.
On the other hand, once you have enough in vivo data, you can deduce
many of the needed parameters, including the regional dependencies.
Software is very good for this, because it can let you test various
hypotheses to explain your data. For example, are secondary peaks caused
by enterohepatic circulation or simply by the increased hepatic blood
flow rate after meals? Or, is the permeability in colon higher, lower,
or about the same as in jejunum? Or, is efflux or influx transport
So in answer to your question, I would say that, in general, to predict
plasma concentration-time from in vitro data (i.e., no animal data) is
just about impossible - again, in general. On the other hand, if you
have good data from animals along with good in vitro data, then you can
probably come up with some ballpark estimates - but don't expect them to
be perfect. I'd say that if you got Cmax and AUC within 2:1, you would
be getting magnificent results!
Chairman & CEO
Simulations Plus, Inc. (AMEX: SLP)
1220 W. Avenue J
Lancaster, CA 93534-2902
Phone: (661) 723-7723
FAX: (661) 723-5524
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the prediction of in-vivo pharmacokinetics is posible with physiology
pharmacokinetic (PBPK) simulations. But, as was extensively discussed
comment of Walt Woltosz the accuracy of such predictions depends of
strongly on the quality of the in vitro data used as input for such a
simulation. For each process which has an impact on the ADME behavior
compound you need reliable in-vitro information in order to make
Without a software such predictions are impossible if you are really
in concentration time profiles and not only in certain PK-paramters as
absorbed or volume of distribution. Our software PK-Sim (see:
http://www.pk-sim.com ) is based on a sophisticated whole body PBPK
model and is
moreover able to calculate the parameters of such a model as e.g.
from easily obtainable in-vitro data (physicochemical properties,
rates ...). Therefore it should be well suited for your problem. For
estimates of pharmacokinetics after oral or i.v. application you only
information about lipophilicity, solubility, plasma protein binding and
metabolic rates. If you have more information, for example about active
transport, this can of course be regarded as well.
Bayer Technology Services GmbH
Internet : http://www.bayertechnology.com
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PBPK modelling can use in vitro data to obtain in vivo predictions
to the usual modelling caveats).
There are a list of PBPK modelling resources at http://www.pbpk.org
PharmPK Discussion List Archive Index page
Copyright 1995-2010 David W. A. Bourne (firstname.lastname@example.org)