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The following message was posted to: PharmPK
hello all
I am using NONMEM to model the clearance of a drug in premature
neonates(first time using this) . Currently my line of program is
CL=(THETA(2)*VANC)+THETA(1)*(GA+PNA/7)+ETA(1)
where GA - gestational age in weeks and PNA - post natal age in days .
Is there a better way of modeling the effect of the age on clearance.
On looking at this i think my equation is suggesting that as
gestational age increases clearance increases linearly however i guess
clearance could also increase exponentially or in a sigmoidal shape.
How can i get NONMEN to model in these ways ??
On a second point im told that clearance is usually proportional to
weight to the power of 0.7 and that this is "a well know fact" Does
anyone know why clearance is related to weight in this way or have any
references to support this ???
Padraig Galbraith
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The following message was posted to: PharmPK
Hi
If you go to the NONMEM users archive
http://www.phor.com/nonmem/nm/
and search for "allometric scaling" you'll find plenty of useful
threads with references explaining the biological reasoning behind the
relationship between clearance and body weight to the power 0.75
P.S. Have you tried an exponential ETA e.g CL=THETA(n)*EXP(ETA(n))
rather than an additive one? Often works well.
Good luck
Ann
Dr. Ann Rigby-Jones
Research Fellow, Anaesthesia Research Group, Peninsula Medical School
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The following message was posted to: PharmPK
Padraig,
Nick Holfords 1996 paper is good place to start for the clearance/body
weight relationship argument.
1. Holford, N. H. G. A size standard for pharmacokinetics. Clinical
Pharmacokinetics 30, 329-332 (1996).
Hope this helps.
Cheers
Alex
Alex MacDonald Ph.D
Project Leader
Drug Metabolism and Pharmacokinetics
F.Hoffmann-La Roche Ltd
Pharmaceuticals Division
Bldg. 070/132
CH-4070 Basel
Switzerland
Tel. +41 (0) 61 688 40 98
Fax +41 (0) 61 688 20 66
alexander.macdonald.-at-.roche.com
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The following message was posted to: PharmPK
Padraig,
Some background about modelling PK in neonates that incorporate weight
and age can be found here:
Bouwmeester NJ, Anderson BJ, Tibboel D, Holford NH. Developmental
pharmacokinetics of morphine and its metabolites in neonates, infants
and young children. Br J Anaesth 2004;92(2):208-17
Anderson BJ, van Lingen RA, Hansen TG, Lin YC, Holford NHG.
Acetaminophen developmental pharmacokinetics in premature neonates and
infants: a pooled population analysis. Anesthesiology 2002;96(6):1336-45
The allometric exponent used in these papers is 0.75. This fact is
predicted by theory and confirmed by experiment in many biological
settings.
Nick
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The following message was posted to: PharmPK
Hello Padraig Galbraith
The following publication will be a very useful reference in your NONMEM
analysis.
Developmental pharmacokinetics of morphine and its metabolites in
neonates,
infants and young children.
Br J Anaesth. 2004 Feb;92(2):208-17.
Bouwmeester NJ, Anderson BJ, Tibboel D, Holford NH.
Also you may want to look at the pharmacometrics review and the printed
label for Betapace (Sotalol) on deriving dosing regimens in pediatrics.
Betapace (Sotalol Hydrochloride). Center for Drug Evaluation and
Research, United States Food and Drug Administration. Available from
http://www.fda.gov/cder/foi/nda/2001/19-865s10_Betapace.htm.
Venkatesh Atul Bhattaram
Pharmacometrics
US Food and Drug Administration
"The contents of this message are mine personally and do not necessarily
reflect any position of the Government or the Food and Drug
Administration."
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Hello,
While I am not a NONMEM modeller, I can answer your final comment re:
clearance in children.
When we discuss clearance in children, there are two considerations
that account for their altered clearance; namely maturity and
physiology. There are also two camps of thinking about clearance and
children; namely allometric scaling (as you mentioned) and mechanistic
scaling. By scaling I mean from adults to children. There are many
differences between these two methods and both have strengths and
weaknesses.
Allometric scaling in children is commonly done based on body weight.
You are correct that the exponent 0.7 is used for allometric scaling,
but this value is commonly used for scaling clearance between species,
not within a species. In the case of intraspecies scaling for humans,
the exponent 0.75 is used (for the procedure see Anderson & Meakin.
2002. Scaling for size: some implications for paediatric anaesthesia
dosing. Paediatic Anaesthesia 12: 205-219). This procedure is based
on the differences in body weight between children and adults. These
authors have found it to be useful (and easy) for scaling clearance
among different ages of children. However, allometric scaling is only
based on size and says nothing about the maturity of the processes
involved in the clearance of the compound. This is understood, which
is why the authors, when scaling doses based on clearance
considerations, had to further reduce the dose by half for immaturity
considerations (see Table 2). For your particular case (premature
neonates), scaling clearance using allometric scaling does not tell you
much since it does not take into account maturity of the processes of
clearance.
The other method of scaling clearance is the mechanistic method. This
considers each mechanism involved in the clearance process of the drug
in question and individually scales each process separately. It is
well known that different enzymes and/or the processes of glomerular
filtration and tubular secretion mature at a different rate. Some are
fully mature at birth thus making the ratio of child to adult weight
normalized clearances based only on physiological differences between
them (e.g. liver weight to body weight ratio, consideration of
eliminating organ blood flow...). When the process matures slowly (e.g.
CYP1A2 metabolism), the ratio of weight-normalized clearances is due to
both maturity and physiological considerations. There are some very
good papers available to explain this method (Alcorn & McNamara.
Ontogeny of hepatic and renal systemic clearance pathways in infants:
part I and part II. Clinical Pharmacokinetics. 2002. 41 (12):
959-998 and 41 (13): 1077-1094) and (Bjorkman. Prediction of drug
disposition in infants and children by means of physiologically based
pharmacokinetic (PBPK) modelling: theophylline and midazolam as model
drugs. 2004. 59(6): 691-704.). Our group has also submitted a paper
for peer-review on this topic; working from the earlier work of the
authors stated above. The disadvantage of this method is that it is
more difficult than allometric scaling; however, the advantage, I
believe, is that it is more relevant.
For premature neonates, the situation is further exaggerated. Their
level of immaturity is dependent on both their gestational and
postnatal age (as you have already indicated). Knowing their size will
not be sufficient enough to explain their clearance. The mechanism of
clearance of the drug you are interested in and the maturity of that
mechanism in premature neonates (from in vitro liver data if its the
common hepatic clearance situation) is required.
From what I understand, you want to correlate clearance to gestational
and postnatal age and to determine which is the most important
parameter for the determination of clearance. While this is indeed
important, the underlying processes, regarding for example, curve
shape, will not be understood. Empirical correlations are sufficient
for retrospective analysis, but any prospective analysis will lack a
mechanistic basis from which to draw conclusions.
Of course, when we move from the arena of clearance determination to
dosing determination in children, which is the primary use of
determining clearance in children, there occurs another important
parameter; volume of distribution. Only with accurate clearance and
distribution volume prediction can dosing be consistently and reliably
determined for children; especially in your case with premature
neonates. To do this we used the age-specific PBPK model and our
clearance scaling module that is within the software, PK-Sim. I have a
poster from a conference I attended on the clearance scaling method if
you would like me to send it to you.
Take care,
Andrea Edginton
Bayer Technology Services GmbH
Process Technology, Biophysics
Leverkusen, Germany
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The following message was posted to: PharmPK
Dear Padraig,
> On a second point im told that clearance is usually proportional to
> weight to the power of 0.7 and that this is "a well know fact" Does
> anyone know why clearance is related to weight in this way or
have any
> references to support this ???
What you are talking about here is allometric scaling.
There is enough literature on this subject.
West GB, Brown JH, Enquist BJ. Science 1997 A general model for the
origin of allometric scaling laws in biology.
West GB, Brown JH, Enquist BJ. Science 1999 The fourth dimension of
life: fractal geometry and allometric scaling of organisms.
Holford NHG. Clinical Pharmacokinetics 1996 A size standard for
pharmacokinetics.
A good allometric model for clearance indeed is CL= CLstd x (Wt/
Wtstd)**(3/4) -----> (** means to the power). I usually use a
standard weight of 70 kilograms, but of course this depends on your
population.
>looking at this i think my equation is suggesting that as
>gestational age increases clearance increases linearly however i guess
>clearance could also increase exponentially or in a sigmoidal shape.
>How can i get NONMEN to model in these ways ??
By expressing the equations differently (with a power or a formula
which expresses a sigmoidal curve).
An good source for all your NONMEM questions is the NONMEM usersnet
archive: http://www.cognigencorp.com/nonmem/nm/
Yours sincerely,
Rob ter Heine
--
Rob ter Heine, MSc, PharmD
Department of Pharmacology, Slotervaart Hospital
Amsterdam, The Netherlands
E: aprth.-at-.slz.nl
T: 020-5124737
PharmPK Discussion List Archive Index page
Copyright 1995-2010 David W. A. Bourne (david@boomer.org)