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Dear Vivian,
I think it's impossible to generalise this answer.
It very much depends on which PD situation you are looking at (ie what
disease, which effect parameters etc.).
If the question is whether the models (e.g. the Emax model) differ, I think
this is not the situation.
In order to answer your question properly, more details are needed.
Kind regards,
Thomas Senderovitz, MD
E-mail: senderovitz.-at-.dadlnet.dk
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I am conducting literature research on pharmacodynamics in the
children population. Would someone please explain what the
difference(s) are between children and adults.
Thank you.
Vivian Nolan
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A very interesting question, on which not much is known. For many drugs,
children and adults appear to have the same therapeutic range of plasma
drug concentrations, suggesting there are no inherent pharmacodynamic
differences between adults and children. However, indirect (i.e.
pharmacokinetic) factors can cause pharmacodynamic differences. For
example, differences in morphine action in adults and neonates may be due
to differences in metabolism.
Srikumaran Melethil, Ph.D.
Professor, Pharmaceutics and Medicine
Schools of Pharmacy and Medicine
University of Missouri-Kansas City
203B Katz Hall
Kansas City, Mo 64110
816-235-1794 (fax; 816-235-5190)
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The European Agency for the Evaluation of Medicinal Products: Human
Medicines Evaluation Unit may be able to provide you with some
references (Tel 011-44--171-418-8400, Fax: 011-44-171-418-8551,
e-mail: mail.at.emea.eudra.org, http://www.eudra.org/emea.html) In 1997,
the CPMP (Committee for Propriety Medicinal Products) issued a
guidance for clinical investigation of medicinal products in children.
Some of the differences cited for preterm and newborn infants include
reduced protein binding, immaturity of metabolic pathways and renal
system and unpredictable absorption. In later infancy and early
childhood faster rates of metabolism can necessitate the
administration of higher doses per unit of body weight than in adults
(e.g. digoxin and phenytoin). Also in early development some receptor
functions, effector systems and homeostasis mechanisms are not fully
developed and so can influence PD responses. If they cannot help you
try a Pediatrics unit at a local teaching hospital.
Fiona Stavros
Texas Biotechnology Corp.
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> in children. Some of the differences cited for preterm
> and newborn infants include reduced protein binding,
> immaturity of metabolic pathways and renal system and
> unpredictable absorption.
Reduced protein binding is not a relevant mechanism except
clearance of drugs with high extraction ratios. The
distribution and elimination of unbound, i.e. active, drug
for low extraction ratio drugs is not altered in any
relevant way by changes in plasma protein binding.
In later infancy and early
> childhood faster rates of metabolism can necessitate the
> administration of higher doses per unit of body weight than
> in adults (e.g. digoxin and phenytoin).
It is true that larger doses per kg are usually given to
infants. But this can be explained on allometric grounds
rather than postulating "faster rates of metabolism". I
know of no direct evidence for "faster metabolism". It is
prima facie true that the clearance is smaller in infants
than in adults. The idea of "faster metabolism" arises from
the per kg model used to standardise for differences in
size. More biologically plausible models do not suggest
increased clearance in infants compared with adults. The
transition from neonate to infant is marked by
developmental maturation of metabolism and renal function.
Holford NHG. A size standard for pharmacokinetics. Clin.
Pharmacokin. 1996: 30:329-332
Anderson BJ, McKee D, Holford NHG. Size, myths and the
clinical pharmacokinetics of analgesia in paediatric
patients. Clinical Pharmacokinetics 1997; 33:313-327
--
Nick Holford, L226,Dept of Neurology,OHSU
3181 SW Sam Jackson Park Road,Portland,OR 97201-3098
n.holford.aaa.auckland.ac.nz,(503)494-4778,fax 494-7242
http://www.phm.auckland.ac.nz/Staff/NHolford/nholford.htm
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