NONMEM Users Network Archive

Hosted by Cognigen

RE: Scaling for pediatric study planning

From: Masoud Jamei <masoud.jamei>
Date: Sat, 20 Sep 2008 16:31:52 +0100

Dear Nick

Many thanks for your comments. The two years of age is an estimated
post-natal age when most of the CYP enzymes, serum albumin level and =
to some extent, the body composition reach those of adults and the
incorporation of maturation changes improved the predictions (the same
previous paper).
Of course everybody agrees that children are not like test tubes nor =
they be modelled as one-, two- compartmental models. On the other hand, =
tube data can provide very valuable knowledge about compounds that =
should be
mechanistically incorporated into our models (e.g. whether a compound =
metabolised by CYP2D6, its extent and the likelihood of polymorphism can =
determined using in vitro data).
As you once said at one of the PAGE meetings, it is not possible to =
a case where weight doesn’t play a role, however this is sometimes =
taken out
of the context and interpreted as “weight is the only player”. Then =
we tend
to model everything using only weight even enzyme/receptor affinity or
absorption rate.
We are in full agreement that the age and size should be integrated to =
able to make sensible predictions and for that reason these two are the
fundamental elements in our “bottom-up” approach but not the only =
ones. It
is generally accepted that the metabolic clearance is proportional to =
size of the liver and based on more than 5000 data point a good equation =
predicting the size of the liver is developed (Johnson TN, Tucker GT, =
MS, et al. Changes in liver volume from birth to adulthood: a =
Liver Transpl 2005 Dec; 11(12):1481-93 – freely available at: However, the size of the liver is =
not the only determinant of the metabolic clearance and we need to take =
account other relevant covariates such as the enzyme abundances in the
liver, blood flow, plasma protein biding and the haematocrite level =
can be altered by polymorphism, ethnicity, disease states, etc. For
instance, ignoring renal function maturation can simply bring about
incorrect conclusions:
I see lots of common grounds between the “bottom-up” and =
approaches and do not consider these two as competing but complementary
approaches (last few slides of
show and example of the consistency between the two approaches).
Our argument is, let's mechanistically incorporate our collective =
from all reliable sources as much as and whenever possible into
physiologically based models and use empirical models only when there is =
any other alternatives.

Yours Sincerely

PS: I'd greatly appreciate receiving a print out of the Rhodin et al =
whenever it is out please.

Masoud Jamei, PhD, SMIEEE
Senior Scientific Advisor, Head of M&S
Honorary Lecturer, School of Medicine, University of Sheffield
Simcyp Limited
Blades Enterprise Centre, John Street, Sheffield, S2 4SU, UK
Tel +44 (0) 114 292 2327
Fax +44 (0) 114 292 2333
real solutions from virtual populations

-----Original Message-----
From: owner-nmusers
Behalf Of Nick Holford
Sent: 19 September 2008 23:11
To: nmusers
Subject: Re: [NMusers] Scaling for pediatric study planning


I dont know of any good reason to introduce an arbitrary cut-off above
age 2 years for the usefulness of allometric scaling. Allometric theory
is applicable from single cells to very large multicellular organisms.
It should be expected to explain the size related changes in PK
throughout life beginning from conception.

As you point out there are major maturational changes, in addition to
size, which need to be considered and indeed these effects can be
comparable to those of size in young children (less than 1 year of age).

The empirical models used to describe maturation in Johnson et al. 2006
are somewhat limited because they use post-natal age rather than
biological age to describe changes of in vitro enzyme activity. They
also rely on the assumption that children are like test tubes. While it
is can be debated if children are just small adults it seems less likely =

they are big test tubes.

Alternative top-down approaches (i.e. based on intact humans not test
tubes), while still being empirical for the description of maturation,
do at least allow plausible extrapolation from conception to the fully
mature adult because they use post-menstrual age in combination with
allometric scaling for size at all ages (see references).

An important practical application of an integrated age and size
approach is the ability to make sensible predictions of drug clearance
in young children when, as is usually the case, there is no reliable
data available. When making extrapolations it is best to rely on
mechanism based theory whenever possible but when forced to be empirical =

(all maturation models) then at least the model should extrapolate in a
sensible way.

Best wishes,


1. Tod M, Lokiec F, Bidault R, De Bony F, Petitjean O, Aujard Y.
Pharmacokinetics of oral acyclovir in neonates and in infants: a
population analysis. Antimicrob Agents Chemother. 2001;45(1):150-7.
2. Allegaert K, de Hoon J, Verbesselt R, Naulaers G, Murat I.
Maturational pharmacokinetics of single intravenous bolus of propofol.
Paediatr Anaesth. 2007;17(11):1028-34.
3. Anderson BJ, Allegaert K, Van den Anker JN, Cossey V, Holford NH.
Vancomycin pharmacokinetics in preterm neonates and the prediction of
adult clearance. Br J Clin Pharmacol. 2007;63(1):75-84.
4. Anand KJS, Anderson BJ, Holford NHG, Hall RW, Young T, Barton BA.
Morphine Pharmacokinetics and Pharmacodynamics in Preterm Neonates:
Secondary Results from the NEOPAIN Multicenter Trial Br J Anaesth.
5. Potts AL, Warman GR, Anderson BJ. Dexmedetomidine disposition in
children: a population analysis. Paediatr Anaesth. 2008;18(8):722-30.
6. Rhodin MM, Anderson BJ, Peters AM, Coulthard MG, Wilkins B, Cole M,
et al. Human renal function maturation – a quantitative description
using weight and postmenstrual age. Pediatr Nephrol. 2008. In Press.

Masoud Jamei wrote:
> I can't agree more with Jeff's comments that we should "pursue more
> physiologic expressions" and this is a "place where "bottom-up"
> are advantageous.
> The allometric scaling may be useful for children older than 2 years =
> younger subjects surely the developmental factors should be considered =
> explained in: Johnson TN, Rostami-Hodjegan A and Tucker GT (2006)
> of the clearance of eleven drugs and associated variability in =
> infants and children. Clin Pharmacokinet 45:931-956.
> Regards
> Masoud
>> -----Original Message-----
>> From: owner-nmusers
>> nmusers
>> Sent: 19 September 2008 16:54
>> To: Joachim.Grevel
>> Cc: nmusers
>> Subject: Re: [NMusers] Scaling for pediatric study planning
>> Leonid / Joachim,
>> I think we're pushing the envelope on empiricism here. Two facts of
>> reality prevail here:
>> 1) we seldom collect enough data during the absorption phase to =
>> any meaningful age/developmental dependencies across the age =
>> The fisrt-order assumption is always bad even in adults but we live
>> with it because we seldom have absorption as a primary phase of
>> interest.
>> 2) a physiologic approach, in addition to a more fundamental
>> approximation of reality also has more options with respect to
>> functional expressions that can accomodate developmental factors such
>> as changes in pH dependency, the surface area of the GI tract, or the
>> site and expression of presystemic P450 enzymes all of which factor
>> into the size surrogacy issue.
>> Hence, I'm not sure that I would consider the allometric
>> characterization of absorption in the same manner as one would treat =
>> or V considerations as it is indeed a hybrid process. I will defer to
>> Nick's wisdom on this but if I am pressed for a guess, I would not
>> scale but pursue more physiologic expressions. In actuality, this is =
>> place where "bottom-up" approaches would seem to have a decided
>> advantage.
>> Jeff
>> Jeffrey S. Barrett, Ph.D., FCP
>> Research Associate Professor, Pediatrics Director, Pediatric
>> Pharmacology Research Unit, Laboratory for Applied PK/PD Clinical
>> Pharmacology & Therapeutics Abramson Research Center, Rm 916H The
>> Children's Hospital of Philadelphia
>> 3615 Civic Center Blvd.
>> Philadelphia, PA 19104
>> KMAS (Kinetic Modeling & Simulation)
>> Institute for Translational Medicine
>> University of Pennsylvania
>> email: barrettj
>> Ph: (267) 426-5479
>>>>> Leonid Gibiansky <LGibiansky
>> Just to add:
>> c) how do we allometrically scale a VM rate constant of the =
>> Menten elimination model:
>> C1=A(1)/V1
>> DADT(1)= ... -A(1)*VM/(KM+C1)
>> d) do we need to allometrically scale a KM constant of the =
>> Menten elimination model ?
>> any experience with these quantities (for example, if they were
>> estimated, what were the estimates, with the precision)?
>> My suggestion would be NOT to scale a), b) and d), and scale VM as =
>> rate constant (~ WT**(-0.25)) but I do not have "rock-solid" data to
>> support those suggestions.
>> Leonid
>> --------------------------------------
>> Leonid Gibiansky, Ph.D.
>> President, QuantPharm LLC
>> web:
>> e-mail: LGibiansky at
>> tel: (301) 767 5566
>> Joachim.Grevel
>>> Dear NM_Users,
>>> we have all been good students and listened to Nick when he told us
>>> again and again the rock-solid truths of allometry:
>>> Volume: *(WT/70)
>>> CL: *(WT/70)**0.75
>>> any rate constant related to distribution or elimination:
>> *(WT/70)**(-0.25)
>>> Here my questions:
>>> a) how do we allometrically scale a first-order rate constant of
>>> absorption after oral dosing?
>>> b) how do we allometrically scale a first-order rate constant of
>>> absorption from a subcutaneous injection site?
>>> Thank you for your thoughts,
>>> Joachim
>>> __________________________________________
>>> Joachim GREVEL, Ph.D.
>>> MERCK SERONO International S.A.
>>> Exploratory Medicine
>>> 1202 Geneva
>>> Tel: +41.22.414.4751
>>> Fax: +41.22.414.3059
>>> Email: joachim.grevel
>> =
>> -
>>> This message and any attachment are confidential, may be privileged
>> or
>>> otherwise protected from disclosure and are intended only for use by
>> the
>>> addressee(s) named herein. If you are not the intended recipient, =
>>> must not copy this message or attachment or disclose the contents to
>> any
>>> other person. If you have received this transmission in error, =
>>> notify the sender immediately and delete the message and any
>> attachment
>>> from your system. Merck Serono does not accept liability for any
>>> omissions or errors in this message which may arise as a result of
>>> E-Mail-transmission or for damages resulting from any unauthorized
>>> changes of the content of this message and any attachment thereto. =
>>> verification is required, please request a hard-copy version. Merck
>>> Serono does not guarantee that this message is free of viruses and
>> does
>>> not accept liability for any damages caused by any virus transmitted
>>> therewith.

Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New =

Received on Sat Sep 20 2008 - 11:31:52 EDT

The NONMEM Users Network is maintained by ICON plc. Requests to subscribe to the network should be sent to:

Once subscribed, you may contribute to the discussion by emailing: