Back to the Top
PharmPK - Discussions about Pharmacokinetics
Pharmacodynamics and related topics
Dear Members of the PharmPK Discussion group:
I am looking for some information about clinically relevant plasma
Levodopa concentrations fluctuations i.e. What percentage change in
steady-state concentrations would be considered clinically relevant,
given the high variability of Levodopa and the unique PK/PD relationship
Also see: http://www.cpb.uokhsc.edu/pkin/pkin.html
Tel +44 (0) 1509 64 4878
Fax +44 (0) 1509 64 5586
Back to the Top
> I am looking for some information about clinically relevant plasma
> Levodopa concentrations fluctuations i.e. What percentage change in
> steady-state concentrations would be considered clinically relevant,
> given the high variability of Levodopa and the unique PK/PD relationship
> of Levodopa.
On the face of it, I do not think there is any very meaningful answer to
your question about "percentage change in steady state concentrations".
Much of the clinical response to levodopa is predictable from the
overall time course of plasma levodopa concentration. The pattern of the
response changes over time (described as "stable" and "fluctuating"
types of response). Provided levodopa concentrations remain above the
EC50 for that patient the response is essentially indpependent of the
fluctuation in plasma concentration because the conc-effect
relationship is steep (Hill coefficient 3 or greater). Adverse effects
(eg dyskinesia) are not clearly correlated with the EC50 for beneficial
effects so finding an optimal concentration for an individual is not
easy especially in the "fluctuating" patient. It is important to
recognise also that there is a component to the inter-dose time course of
Parkinson's disease that is not predictable from plasma concentrations
of levodopa (or other large neutral amino acids) which has been called
"y0yo-ing". The "on/off" phenomenon is also used to describe this effect
but it is frequently confused (not surprisingly) with the rapid but
predictable "end of dose" deterioration that occurs when effect site
concs fall below the EC50.
I suggest you take a look at the review by Nutt & Holford (1996) which
attempts to link the clinical neurology and clinical pharmacology of
levodopa and discusses the above issues at some length.
Nutt JG, Holford NHG. The response to levodopa in Parkinson's disease:
imposing pharmacological law and order. Ann Neurol 1996;39:561-73.
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, Private Bag 92019, Auckland, New Zealand
email:n.holford.-a-.auckland.ac.nz tel:+64(9)373-7599x6730 fax:373-7556
Back to the Top
Dr. Peter Silverman, at the U. of Texas Health Science Center in Houston
has published a proposed animal model for the "on-off" effect seen with
You might find his work interesting.
P. Silverman, Eur. J. Pharmacology, vol 242, 31-36, 1993. On-Off effect of
dopamine receptor agonists in the hemiparkinsonian rat.
At 11:04 AM 8/6/97 -0500, you wrote:
>PharmPK - Discussions about Pharmacokinetics
> Pharmacodynamics and related topics
>> I am looking for some information about clinically relevant plasma
>> Levodopa concentrations fluctuations i.e. What percentage change in
>> steady-state concentrations would be considered clinically relevant,
>> given the high variability of Levodopa and the unique PK/PD relationship
>> of Levodopa.
PharmPK Discussion List Archive Index page
Copyright 1995-2010 David W. A. Bourne (firstname.lastname@example.org)