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Hi,
When investigating the toxicology of a new dopamine agonist we have done
comparative PK studies with levodopa/carbidopa. We have found that at high
concentration of levodopa/carbidopa the Tmax value was increased
from 1h to 4h.
The Cmax and AUC 0-t values remained linear relative to the low dose of
Levodopa/Carbidopa. Can you suggest a mechanism for these changes?
Thank you
Liat Lomnitski
Preclinical Department
Teva R&D Division
Israel
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[Two replies - db]
Date: Mon, 29 Nov 1999 00:56:20 -0700 (MST)
X-Sender: ml11439.aaa.pop.goodnet.com
To: PharmPK.aaa.boomer.org
From: ml11439.at.goodnet.com (Michael J. Leibold)
Subject: Re: PharmPK Change in tmax with dose
Hello Liat,
Larger doses can sometimes result in slower absorption, as
in the case of phenytoin. This translates mathematically into a
decrease in Ka, which causes an increase in Tmax according to the
following equation:
Tmax= [1/(Ka-Ke)][Ln(Ka/Ke)]
Larger doses of phenytoin form complexes in the GI tract, resulting
in slower absorption.
A decrease in Ka or rate of absorption would not change the AUC, which
is determined by F and Ke. However, the Cmax should decrease as the Tmax
increases according to the following equation:
Cmax= [FXo/V]e-KeTmax
Mike Leibold, PharmD, RPh
ML11439.at.goodnet.com
---
From: "Lunnon, Martin W"
To: "'PharmPK.-a-.boomer.org'"
Subject: RE: PharmPK Change in tmax with dose
Date: Mon, 29 Nov 1999 10:35:20 -0000
Dear Liat,
I seem to remember that dopamine can alter GI function, in this case
slowing gastric emptying.
I believe that Charles George and Any Renwick in Southampton have
done work here, you could try searching on their names in MedLine,
Martin L
Martin W Lunnon
CVS Clinical Pharmacology, Greenford.
Phone: ..181 966 4456, Fax: ..181 966 4363
E-mail: MWL12467.-a-.glaxowellcome.co.uk
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[Two replies - db]
Sender: acy62.aaa.pop.dial.pipex.com
Subject: Re: PharmPK
Date: Tue, 30 Nov 99 11:09:04 +0000
x-sender: acy62.-at-.pop.dial.pipex.com
From: Andrew Sutton
To: "David Bourne"
Subject: Re: PharmPK Change in tmax with dose;
Martin Lunnon's comment on slowing gastric emptying might refer to=20
the paper from the Southampton group on levodopa which showed that it=20
slowed gastric emptying in 8 normal volunteers from a mean 90%=20
emptying time of 32=B124min to 81=B120 min. (Br J Clin Pharmacol, 1990=20
29, 47-53). Gastric emptying was interrupted by a plateau phase in 6=20
of the 8 subjects and double peaks in the plasma concentration-time=20
curves for both levodopa and paracetamol (aminocetophen).
Another well known compound that slows gastric emptying is morphine.=20
That should have similar effects on all co-administered drugs taken=20
by mouth.
Andrew Sutton
------------
Andrew Sutton MD FFA
ASutton.at.gcpl.co.uk
Guildford Clinical Pharmacology
Innovators in Phase 1 model design
and leaders in Phase 2 recruiting.
Telephone +44 (0) 1483 406886
------------
Date: Tue, 30 Nov 1999 11:25:15 -0800
From: Jeff Wald
X-Accept-Language: en
To: PharmPK.aaa.boomer.org
Subject: Re: PharmPK Change in tmax with dose
Liat - Standard compartmental models will not allow for the relationship that
you have seen. I see three likely possibilities:
1.) Absorption/disposition of drug is 'peculiar'. For example, the absorpti=
on
profile may be irregular. This may be elucidated by modeling the data or us=
ing
deconvolution methodologies. Biopharmaceutical factors may be the cause, or
dopaminergic action in the GI tract (remember, because of its high
concentration of 'neuro'-transmitters and receptors the GI tract has been
called the visceral brain!)
2.) The AUC 0-t is not sensitive to nonlinearities in the disposition of the
agonist. There may be insufficient evidence to figure out what is going on
using noncompartmental methods which waste a lot of information. Again
modeling which can leverage information from all the doses may shed more lig=
ht
on your data.
3.) The Cmax is actually different with different doses. Unless you planned
ahead for this phenomenon your study design may not include sufficient point=
s
around 4 hours to characterize the Cmax well. You guessed it, model the dat=
a
and look at the model predicted values of Cmax.
Regards, Jeff
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Liat,
The absorption of levodopa is via the LNAA system (= saturable,
sodium-independent, facilitated transport mechanism for the aromatic and
branched chain amino acids). The levodopa metabolite, 3-O-methyldopa, is
also transported by this LNAA system. If you administer levodopa together
with carbidopa, an amino acid decarboxylase inhibitor, the dopamine
formation will be decreased and the fraction metabolized to 3-O-methyldopa
will increase. These processes take already place in the gut and result in
higher amounts of 3-O-methyldopa in the gut which compete with levodopa for
the transport system. The capacity of the transport system is limited.
Therefore, the competition between substrates (e.g. levodopa and
3-O-methyldopa) determines the flux of each competeing substrate across the
membrane. Because the transport process is saturable we observe only for low
doses a first order process and for high doses it becomes a mixed order
process finally ending in a 0 order process when the transport system ist
saturated. Thus, at high doses of levodopa and carbidopa this could be the
reason for nonlinearity in Tmax. However, this would not only effect Tmax,
but also Cmax (as already explained in the answer of Mike Libold). I might
help more if I get additional information about the study design.
Hope this is of some help.
Susan Grange
Dept. PRNS Bldg. 69/101
F. Hoffmann-La Roche Ltd.
4070 Basel
Switzerland
email: susan.grange.at.roche.com
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