- On 23 Mar 2006 at 15:25:46, ARaje.-at-.wockhardtin.com sent the message

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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] - On 23 Mar 2006 at 12:37:16, "Pereira, Luis" (Luis.Pereira.-a-.mcphs.edu) sent the message

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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 - On 24 Mar 2006 at 13:45:44, "Indranil Bhattacharya" (ibhattacharya.-at-.gmail.com) sent the message

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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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