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How do we determine the Apparent volume of distribution of a new drug entity?
Thanking you,
Shobha Rani
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its not like you could determine in- vitro. It should be done in-vivo. Once
you know the other two parameters like half life and elimination rate
constant. V is the parameter that is used to convert plasma/serum
concentration of drug /new entity to amount of drug/new entity.
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t 1/2 is not a primary PK parameter, but a result of distribution and
elimination!
t 1/2 = ln2*VD/CL
Thomas Senderovitz
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by way of David_Bourne wrote:
>
> PharmPK - Discussions about Pharmacokinetics
> Pharmacodynamics and related topics
>
> t 1/2 is not a primary PK parameter, but a result of distribution and
> elimination!
>
> t 1/2 = ln2*VD/CL
>
> Thomas Senderovitz---
I fully agree with Thomas and share his religious belief in this matter.
--
Nick Holford, Divn Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand
email:n.holford.at.auckland.ac.nz tel:+64(9)373-7599x6730 fax:373-7556
http://www.phm.auckland.ac.nz/Staff/NHolford/nholford.htm
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Hello:
t1/2 is one of the four primay parameters of disposition ( defines
metabolism, distribution and excretion processes but not the absorption),
the others three are the elimination rate constant, volume of distribution,
and systemic clearance. PK is ADME which means three out of four
are represented by disposition. All these four important parameters help in
calculating a drug dosage regimen.
Thanks,
Naushad
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Naushad
> t1/2 is one of the four primay parameters of
> disposition ( defines
> metabolism, distribution and excretion processes
> but not the absorption),
> the others three are the elimination rate
> constant, volume of distribution,
> and systemic clearance.
I think Thomas Senderovitz (and Nick) hit the nail on the
head here. I am just raising one more point. Half-life
does not have any special attachment to any part of the ADME
process. There is no reason that you couldn't have a
half-life of absorption or indeed a half-life for any
first-order process (be it biological or otherwise).
Regards
Steve
=================
Stephen Duffull
School of Pharmacy
University of Queensland
Brisbane, QLD 4072
Australia
Ph +61 7 3365 8808
Fax +61 7 3365 1688
http://www.uq.edu.au/pharmacy/duffull.htm
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Amen to Tom and Nick!
Roger Jelliffe
Roger W. Jelliffe, M.D. Professor of Medicine, USC
USC Laboratory of Applied Pharmacokinetics
2250 Alcazar St, Los Angeles CA 90033, USA
Phone (323)442-1300, fax (323)442-1302, email= jelliffe.-a-.hsc.usc.edu
Our web site= http://www.usc.edu/hsc/lab_apk
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The following message was posted to: PharmPK
"Stephen Duffull (by way of David_Bourne)" wrote:
> I think Thomas Senderovitz (and Nick) hit the nail on the
> head here. I am just raising one more point. Half-life
> does not have any special attachment to any part of the ADME
> process. There is no reason that you couldn't have a
> half-life of absorption or indeed a half-life for any
> first-order process (be it biological or otherwise).
Let me amplify your last sentence. We can use first-order models
which have some mechanistic basis e.g. absorption input models or
drug elimination models. For drug elimination rates the model is
readily parameterized in terms of clearance:
rate out = conc x clearance
In the case of the model for drug concentration we have to include a
further parameter, volume of distribution to describe the time course
of concentration. For computational convenience it is algebraically
possible to reparameterize the elimination model in terms of a rate
constant (k=clearance/volume).
rate out = conc x k x volume
but it should be recognized that the rate constant parameterization
is an algebraic entity that simply confounds the biologically quite
separate processes of elimination and distribution. These two
processes are clearly quite different in terms of covariates that can
be used to predict individual PK parameters. The rate constant
religion advocates have never addressed this issue as far as I am
aware.
When the model is simply an empirical description of a process
without sufficient info to distinguish underlying mechanism then the
half-life (or rate constant) parameterization seems perfectly
reasonable e.g. the use of effect compartment models to describe
delayed drug effects.
Nick
--
Nick Holford, Divn Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand
email:n.holford.-at-.auckland.ac.nz tel:+64(9)373-7599x6730 fax:373-7556
http://www.phm.auckland.ac.nz/Staff/NHolford/nholford.htm
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Nick,
At 04:23 PM 2/2/01 -0600, you wrote:
>Let me amplify your last sentence. We can use first-order models
>which have some mechanistic basis e.g. absorption input models or
>drug elimination models. For drug elimination rates the model is
>readily parameterized in terms of clearance:
I know that you know this, Nick, but I can't help but post a reply:
While it's true we can sometimes get away with simplified models for absorption
or elimination, the problem is that we often don't know when that is true.
Absorption can be confounded by a number of factors, including, for example,
solubility, dissolution, gut metabolism, chemical instability in
gastrointestinal fluids, efflux, transport, transit times, and pH dependence of
permeability. The approach of using a single constant Ka (half-life) for
absorption is fraught with possibilities for error. I have been amazed at the
numerous publications and presentations that assume Ka is a constant, followed
by "deconvolution" of other parameters that are significantly impacted if the
assumption is incorrect.
In the past year, I have visited over 50 pharmaceutical companies on three
continents. It has amazed me that at a few, "pharmacokineticists" seem ignorant
of basic pharmacokinetics to the extent that I have been requested to predict
plasma concentration-time with only molecular structure as an input. And to use
only a one-compartment model for a drug that clearly exhibits multi-compartment
behavior. IMHO, for some drugs, using a constant Ka for absorption is like
using a one-compartment model for a multi-compartment drug.
It's important that those working in absorption and pharmacokinetics understand
the possibly severe implications of simplifying assumptions.
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.-at-.simulations-plus.com
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[Two more replies - db]
From: Nick Holford
Date: Sat, 03 Feb 2001 18:56:48 +1300
To: david.at.boomer.org
Subject: Re: PharmPK Re: Vd
The following message was posted to: PharmPK
Walt,
"Walt Woltosz (by way of David_Bourne)" wrote:
> At 04:23 PM 2/2/01 -0600, you wrote:
> >Let me amplify your last sentence. We can use first-order models
> >which have some mechanistic basis e.g. absorption input models or
> >drug elimination models. For drug elimination rates the model is
> >readily parameterized in terms of clearance:
>
> I know that you know this, Nick, but I can't help but post a reply:
Thanks for your comments with which I agree. I was somewhat hesitant
to include absorption as an a example of a first order model and
indeed that was why I used the weasel words "have *some* mechanistic
basis". By and large trying to model actual drug absorption data is
much more tricky than deciding on a one or two or more compartment
disposition model or deciding if you need a first order or mixed
order or other elimination model. The more data one has the harder it
gets to describe the variety of absorption patterns seen between and
within individuals.
--
Nick Holford, Divn Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand
email:n.holford.-a-.auckland.ac.nz tel:+64(9)373-7599x6730 fax:373-7556
http://www.phm.auckland.ac.nz/Staff/NHolford/nholford.htm
---
From: Angusmdmclean.-a-.aol.com
Date: Sat, 3 Feb 2001 10:28:46 EST
To: david.-a-.boomer.org
Subject: Re: PharmPK Re: Vd
The following message was posted to: PharmPK
indeed ! the pharmacokineticists are not rocket scientists and perhaps tend
to shy away from complicated mathematics. They seek simplifications in order
to be practical and find solutions to the problems in the data they have.
They want something that "works" in a practical sense. They do get involved
in approximations which in retrospect are ridiculous. Often the cascade of
experimental information needed is not available for example human
permeability.
A engineering background is excellent for working in the modelling aspects of
the pharmcokinetic field.
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The quick determination of Vd relies on a knowledge of exact dose weight
and systemic concentration of drug. As a concentration is related to the
volume within which it is distributed, measurement of the drug
concentration in the species of interest is your main task. This can be
achieved if you have a specific and sensitive assay for the drug in
plasma of the species of interest (see below), a way of dosing the
species intravenously and a rough idea of a dose level that will be
tolerated by the species (again see below). Extrapolation of plasma drug
concentration to zero time (for graphical methods see the literature or
standard text-book) will give you C0 or apparent concentration at time
zero. The Vd (apparent volume of distribution of the central
compartment) then is simply the exact dose administered divided by C0.
There are different ways of determining volume of distribution but this
is the most straight forward - and the one I was first taught.
Part of your problem may be the first establishment of an assay if your
drug is a new entity. You will also need to know something about its
toxicity. Your organisation or licensing authority will be able to help.
Good luck.
*****
William Heybroek PhD
PK Pharma,
PO Box 45, Marple, Stockport,
Manchester SK6 5FX, UK
Tel: +44 (0)161 427 3241
Fax: +44 (0)161 449 0155
*********
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