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Dear Group,
I would like to calculate a definitive F-value from a variety of
preclinical rodent iv/po PK studies which all used the same compound,
routes and vehicles, but occasionally varied the dose (for example
10mg, 20
mg and 40 mg/kg to determine linearity by both the routes i.e po and
iv).
If IV AUCo-infinity is going non linear and PO AUCo-infinity is going
linear then F value will decrease as dose increases whereas it may
remain
constant if only one dose IV AUCo-infinity is consider for
calculating F at
all doses.
In this situtation which is valid approch to calculate F ?
Amol A. Raje/ Pankaj Dixit
[Using AUC to determine F requires linear kinetics. Either use just
the low doses (where linearity might be approximated) and there are
similar Cp values OR a better apporach is to model all the data
simultaneously, include F as a parameter with non-linear parameters
such as Vm/Km describing the disposition. - db]
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The following message was posted to: PharmPK
Amol
I cannot really envision why a drug would have dose proportionality
with respect to the AUC for an extravascular administration, and not
for an intravenous one. Whatever nonlinearity cause is present in the
iv case can only relate to disposition issues, which ought to be
present also in the oral case. I can only think of a flip-flop due to
an absorption rate limiting step keeping concentrations in the linear
range (as David points out). But then you can easily identify that
with a log-linear terminal comparison. Anyway I think that one must
not forget (as it was discussed earlier in this forum) that
bioavailability is really a dynamic parameter that just for the sake
of simplicity we assume constant. In your case you may have an
example of F really being F(dose).
Luis
--
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.at.bos.mcphs.edu
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Hi Amol you might want to look at the following journals where issues
with compounds behaving in a nonlinear fashion has been addressed.
1) Martis L and Levy RH. Bioavailability calculations for drugs
showing simultaneous first order and capacity elimination kinetics.
J. Pharmacokinetics and Biopharmaceutics. 1. 283-294, 1973.
The above work has been used used by Jusko et al
Jusko WJ , Koup JR, Alvan G. Nonlinear assessment of phenytoin
bioavailability. J Pharmacokinet Biopharm. 1976 Aug;4(4):327-36.
and Lettieri and Fung
Lettieri JT and Fung HL (1979) Dose-dependent pharmacokinetics and
hypnotic effects of sodium -hydroxybutyrate in the rat. J Pharmacol
Exp Ther 208: 7-11.
Hope this helps.
Indranil Bhattacharya
Principal Scientist
GlaxoSmithKline
Drug Metabolism Pharmacokinetics
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