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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]
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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
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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
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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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