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Dear all,
I would like to hear some opinion on how people estimate the
bioavailability of a compound which shows nonlinear clearance at the
clinically relevant doses. One of my colleagues suggests that because
of the nonlinearity, one should try to achieve similar concentrations
after the iv and po dose. In other words, we should give a lower iv
dose. Animal studies suggest a bioavailability of 5-60% depending on
the administered dose.
Best regards,
Toufigh Gordi
Associate Director of Clinical Pharmacology
CV Therapeutics Inc.
3172 Porter Dr.
Palo Alto, CA 94304
Tel.: 650-384-8929
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Toufigh,
Bioavailability can be readily estimated if you can construct a
differential equation defined model with mixed order elimination that
describes the IV profile. Then fit the oral data using the IV
disposition parameters and a suitable input model for the oral dose.
Integrate the amount in the central compartment over any suitable
period of interest and compare the amount to the administered oral dose
to get the average bioavailability over the interval. Given that
bioavailability is a time dependent variable in a mixed order system
the usual meaning of bioavailability is best represented as the
'average' over the period of interest.
Nick
--
Nick Holford, Dept 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)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
[In the simplest case, i.e. a single MM eliminaton process, F
(bioavailabilty) doesn't change if you calculate it correctly. Using
AUC ratios isn't valid since disposition (DME) is not linear.
If you use the method Nick suggests or if you fit the IV and oral data
simultaneously using a MM elimination process a reasonably 'constant' F
value should be found across different po doses, assuming the
absorption process doesn't become saturable (solubility issues or
saturable first-pass metabolism, etc.). However, using AUC(po)/AUC(iv)
ratios different values for 'apparent bioavailability' would be
calculated because of the nonlinearity in the disposition. Plotting AUC
versus dose is a useful method of illustrating non-linear disposition -
db]
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Toufigh,
Instead of estimating an average value of bioavailability, you can
have a model that relates bioavailability to the dose/concentration.
Since your animal data suggest that the F ranges from 5-60% depending
on the dose, it could be that your drug shows low extraction behavior
at high doses and high extraction behavior at low doses.
Pankaj Gupta
Department of Pharmaceutics
Virginia Commonwealth University
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Dear Toufigh
You may want to consider a simple system analysis / deconvolution
approach. Normally, the usual handicap people refer is the need for
an IV administration, although it has been shown that relative
deconvolution strategies are available (see P.Veng-Pedersen,
W.Gillespie, D. Verotta). However, if in your case you have both
intra and extravascular data, by all means obtain the input function
by deconvolution and integrate it over time to figure out total
amount absorbed. Linear systems of course assume linear disposition.
But you may use the Disposition Decomposition Analysis method to
model the nonlinearity.
--
Luis M. Pereira, Ph.D.
Assistant Professor, Biopharmaceutics and Pharmacokinetics
Massachusetts College of Pharmacy and Health Sciences
179 Longwood Ave, Boston, MA 02115
Phone: (617) 732-2905
Fax: (617) 732-2228
Luis.Pereira.-a-.bos.mcphs.edu
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For nonlinear behavior, we prefer fitting the model to both iv and po
doses
simultaneously when sufficient data are available. Fitting a model to
the iv
data only, and then applying those PK parameters to oral might prove
challenging when there is significant gut metabolism (e.g., 3A4, 2D6).
But
when a single set of model parameters (which would include, as a
minimum,
fitted Vmax(s) and Km(s) for both gut and liver) can fit all doses for
all
routes, you get a warm feeling that you understand what's happening.
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (AMEX: SLP)
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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