- On 9 May 2006 at 09:52:14, "Tata, Prasad N" (Prasad.Tata.at.TycoHealthcare.com) sent the message

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Relatively simple question! while doing dose escalation studies if

the pharmacokinetics parameters fit into linear regression it is

called "linear pharmacokinetics" if we can fit into any other

statistical models like power models, quadratic fit we call the "PK

is dose proportional". Are my assumptions are correct?? or I am

missing something?, any input is highly appreciated.

Prasad

Prasad NV Tata, Ph.D., FCP

Saint Louis, MO 63134

[I think 'dose proportional' and 'linear pharmacokinetics' are

generally considered to be the same thing and are dependent of the

disposition processes (DME) being first order - db] - On 9 May 2006 at 14:33:28, "Zutshi, Anup" (anup.zutshi.-a-.pfizer.com) sent the message

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The following message was posted to: PharmPK

Prasad

Dose proportionality indicates linear PK if and only if increasing the

dose increases the AUC by the same factor. Hence if you double the dose

you should double the AUC (or if you half the dose you should half the

AUC and so on...) to have dose proportionality and hence linearity in

PK. Just showing a "linearity" without proportionality is meaningless

and has nothing to do with PK linearity.

Anup

Anup Zutshi Ph.D.

Pfizer Inc

Pharmacokinetics, Dynamics and Metabolism

T-3O/318E

700 Chesterfield Parkway (W)

Chesterfield, MO 63017

(314) 274-8349

Anup.Zutshi.at.Pfizer.com - On 10 May 2006 at 00:41:38, jbyczkowski.aaa.netscape.net sent the message

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The following message was posted to: PharmPK

>>"..Relatively simple question!...">>

Well, not really ;-)

Linear pharmacokinetics (but not not pharmacodynamics) describes a

linear system, in which the rate of transfer of drug or other

chemical from one compartment to another is directly proportional to

the total mass of the drug in this compartment.

In reality, biological systems are nonlinear and cannot be accurately

described by a single, first order elimination rate constant for a

wide range of concentrations. While the nonlinearities are well

handled by PBPK models, the classic compartmental PK models fail when

applied over doses spanned from the no-effect up to the toxic. Even

if you were able to force fit PK into linear regression for some

narrow dose range, it will fail at the extremes. The same with "dose

proportionality" - especially at the toxic dose range, you can talk

about "dose dependence" but I am not aware of any case of a chemical

that would give a linear (in other words, proportional or fist order)

dependence. Typically, sooner or later you hit a saturation range.

I hope it helps.

Best wishes.

Janusz Z. Byczkowski, Ph.D.,D.Sc.,D.A.B.T.

Consultant

212 N. Central Ave.

Fairborn, OH 45324

voice (937)878-5531

fax: (320)923-8174

e-mail januszb.-at-.AOL.com

homepage: http://members.aol.com/JanuszB/index.html

JZB Consulting web site: http://members.aol.com/JanuszB/consult.htm - On 10 May 2006 at 10:02:34, "Tremblay Pierre-Olivier" (potremblay.at.anapharm.com) sent the message

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The following message was posted to: PharmPK

I recently had an interesting discussion about dose-proportionality with

a statistician friend of mine and we found out during this discussion

that while we both used the same words, we were talking about different

things.

I used the term "linear" or "dose-proportional" in the sense of

first-order kinetics and was arguing that if the kinetics are linear,

then as you double the dose, you get double exposure. My statistician

friend on the other hand was arguing that if you can fit a straight line

model to dose-escalating Cmax and AUC values, then you display

proportionality, meaning that the augmentation is constant between

doses.

Conclusion: we decided that while one may fit a straight line to

dose-escalating PK parameters and hence, obtain a constant augmentation

between doses; actual "dose-proportionality" exists (in the studied dose

range) only if the augmentation factor is the same for the dose and PK

parameters. In all other cases, one may not exclude the presence

saturable processes.

Pierre-Olivier Tremblay

SFBC Anapharm

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