Back to the Top
Dear all,
Can somebody from regulatory or somebody with experience in
requirements for BE for non-linear drugs help me with one problem.
In Q&A document of EMEA there is an explanation how to handel non-
linear drugs in BE studies. EMEA asks for two studies on the highest
and on the lowest dose, but in the same paragraph they give
possibility for conducting only one bioequivalence study if adequately
justified.
For drugs that have more than proportional increase in AUC and Cmax
EMEA recommends conduct of a study on the highest dose as this is the
most sensitive way to detect differences between two formulations.
My question would be, what is the rational of doing a study on the
lowest dose for this kind of drugs? What would be the benefit of
having this information if this dose is not sensitive enough in
detecting differences between formulations?
THX for all you suggestions in advance,
Lidija
Back to the Top
The following message was posted to: PharmPK
Hi Lidija,
As the pharmacokinetics are non-linear, a rationale behind conducting
a BE trial on the lowest dose is to demonstrate that the test product
demonstrates the SAME dose-dependence of PK parameters. Why have a
drug that is bioequivalent at one dose but not another? If the
pharmacokinetics are linear, the justification is considered moot as
long as the test product has acceptable dissolution profiles compared
with the innovator at the strengths of interest.
Hope this helps,
-Dave
Back to the Top
Hi,
Drugs are neither linear nor non-linear.
Disposition behavior of a drug in the body can be appropriately
approximated by a liner or a non-linear model.
With best regards,
Maria Durisova DSc (Math/Phys)
www.uef.sav.sk/durisova.htm
Back to the Top
The following message was posted to: PharmPK
Maria,
I would respectfully disagree with your statement that drugs
are neither linear nor nonlinear.
I think nature is inherently not linear (and is, therefore,
nonlinear). So I would say that all drugs are nonlinear - it
all depends on the dose and sometimes other factors.
We can use linear approximations under certain circumstances
and have a "wrong but useful" model. In other conditions we
use nonlinear models, which are also wrong (because all
models are) but they are more useful under those conditions.
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (NASDAQ: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
E-mail: walt.-a-.simulations-plus.com
Back to the Top
Dear Walt,
to see the definition of linearity, see e.g.:
http://www.dliengineering.com/vibman/definitionoflinearity.htm
Regards,
Maria
Back to the Top
The following message was posted to: PharmPK
Maria,
I completely agree with the definition of linearity.
However, it does not change my opinion that nature is
inherently not linear, and therefore is nonlinear. Not
necessarily nonlinear in some simple nonlinear functional
form, but simply not linear.
Best regards,
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (NASDAQ: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
E-mail: walt.-at-.simulations-plus.com
Back to the Top
Dear Lidija,
With regard to drugs which are used at doses where nonlinearities
arise, it can be the case that it becomes easier to achieve
equivalence, most notably in pharmacodynamics, as the drug is
saturating the effect so all responses end up much the same. The
equivalence acceptance boundaries then must either be made narrower,
or one should assess equivalence at lower doses/concentrations which
are in the "linear region" to provide maximum sensitivity to detect
differences.
Conversely, it is entirely possible that when working in a nonlinear
range, that small differences in, for example bioavailability, are
magnified, such that it can become very difficult to achieve
equivalence against the classical 0.8-1.25 boundaries. See for example
Hayashi 2001 Eur J Pharm Sci 13:151 on GCSF where there is described a
concentration related nonlinearity and the effect on the ability to
assess equivalence (GCSF also shows time non-stationarity of course
due to receptor upregulation).
Nonlinear systems are the like plotting data on elastic graph paper.
When one stretches or compresses the graph in different regions,
either by time and/or by concentration, one will magnify or reduce
differences in those regions. To assess similarity for systems working
in nonlinear ranges requires very precise control of experimental
design and use of appropriate kinetic/statistical analysis
methodology, which may not be the simple non-compartmental join-the-
dots approach which, when done on the original scale, assumes linearity.
Best regards, Phil.
Senior fellow; physiologist, biochemist, modeller
Novartis Pharma AG, WSJ-027.1.22, CH-4056 Basel, Switzerland
phil.lowe.at.novartis.com
Want to post a follow-up message on this topic?
If this link does not work with your browser send a follow-up message to PharmPK@boomer.org with "Bioequivalence for non-linear drugs (EU)" as the subject | Support PharmPK by using the |
Copyright 1995-2011 David W. A. Bourne (david@boomer.org)