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The following message was posted to: PharmPK
Dear PK people,
TDM of Parkinson medication seems not to be common practice, probably
because of the poor correlation between plasmaconcentrations and effect.
Does anyone know if this is being done or advocated? I don't mean
measurements for scientific purposes only.
Kind regards,
Erik Pomp, DI-pharmacist
tel. +47 55 97 53 61
fax. +47 55 29 07 18
e-mail efpo.aaa.haukeland.no
www.relis.no/
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The following message was posted to: PharmPK
In our population pharmacokinetic (PK) analysis of levodopa, we found that
the between occasion variability (BOV) for the central compartment volume
(V1) and total body clearance (CL) were very large, 80% and 59% of the
population parameter variability (PPV) respectively (in comparison with
between subject variability (20% (V1) and 31% (CL) of PPV)). The use of TDM
is to optimize the dosing regimen by studying individual
dose-concentration-effect relationship. Studying the individual time course
of dose-concentration and/or concentration-effect only eliminate the between
subject variability but do not provide any information on BOV. As in
levodopa, due to a large variability in PK parameters from occasion to
occasion, it is not possible to predict the dose-concentration-effect
relationship using previous PK parameters. Therefore, TDM is not
appropriate for levodopa in the treatment
of Parkinson's disease.
For levodopa (and other medications), there is an indirect relationship
between plasma concentrations and clinical marker such as tapping rate. The
equilibration delay is caused by the time required for transportation of
levodopa from the site of absorption to the site of action. Because of this
indirect relationship, pharmacokinetic-pharmacodynamic (PKPD) modeling is
used to correlate plasma concentrations to motor effect. This is done by
estimating the drug concentration in an hypothesized effect compartment.
The first PKPD modeling was done by Nelson et al (Nelson MV, Berchou RC,
Lewitt PA, Kareti D, Kesaree N, Schlick P, et al. Pharmacokinetic and
pharmacodynamic modeling of L-dopa plasma concentrations and clinical
effects in Parkinson's disease after Sinemet. Clinical Neuropharmacology
1989;12(2):91-97.)
Other PKPD studies:
Contin M, Riva R, Martinelli P, Baruzzi A. Pharmacodynamic modeling of oral
levodopa: Clinical application in Parkinson's disease. Neurology
1993;43:367-371.
Contin M, Riva R, Martinelli P, Cortelli P, Albani F, Baruzzi A.
Longitudinal monitoring of the levodopa concentration-effect relationship in
Parkinson's disease. Neurology 1994;44:1287-1292.
Contin M, Riva R, Martinelli P, Albani F, Baruzzi A. Relationship between
levodopa concentration, dyskinesias, and motor effect in parkinsonian
patients - a 3-year follow-up study. Clinical Neuropharmacology
1997;20(5):409-418.
Harder S, Baas H, Bergemann N, Demisch L, Rietbrock S. Concentration-effect
relationship of levodopa in patients with Parkinson's disease after oral
administration of an immediate release and a controlled release formulation.
British Journal of Clinical Pharmacology 1995;39:39-44.
Harder S, Baas H. Concentration-response relationship of levodopa in
patients with different stages of Parkinson's disease. Clinical Pharmacology
and Therapeutics 1998;64:183-191.
Nutt JG, Woodward WR, Carter JH, Gancher ST. Effect of long-term therapy on
the pharmacodynamics of levodopa. Relation to On-Off phenomenon. Archives of
Neurology 1992;49:1123-1130.
Triggs EJ, Charles BG, Contin M, Martinelli P, Cortelli P, Riva R, et al.
Population pharmacokinetics and pharmacodynamics of oral levodopa in
parkinsonian patients. European Journal Clinical Pharmacology 1996;51:59-67.
Phylinda.
Miss Phylinda LS Chan (MSc)
Division of Pharmacology and Clinical Pharmacology
School of Medicine and Health Sciences
The University of Auckland
Private Bag 92019
Auckland 1030, New Zealand
Ph: +64-9-3737599 ext 6947 Fax: +64-9-3737556
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[Two replies - db]
From: "Bies, Robert"
Date: Thu, 4 Oct 2001 10:41:14 -0400
To: david.-a-.boomer.org
Subject: RE: PharmPK Re: TDM of Parkinson medication
You make a very interesting point here regarding the utility of TDM under
these conditions. However, I was curious how the dosing histories (i.e.,
precise dosing times) were ascertained for your population PK study of
levodopa. Were doses directly observed and the pattern of dosing leading to
each analysis (or each occasion where sampling occurred) noted carefully by
an observer or were they electronically monitored or were the times self
reported by a patient or home care giver? Was it several occasions taken
under conditions of chronic administration or a combination of early and
chronic administration?
Best Regards,
Rob Bies
University of Pittsburgh
---
From: "Roberto Riva"
Date: Fri, 5 Oct 2001 14:20:15 +0200
To: david.aaa.boomer.org
Subject: Re: TDM of Parkinson medication
The following message was posted to: PharmPK
Dear Dr. Pomp,
we have set up a levodopa therapy monitoring in PD patients based on
simultaneous measurements of plasma levodopa concentrations and objective
motor tests (finger tapping test) after a standard levodopa oral dose, and
we are using it in the optimization of therapy in our patients. We have
summarized and described this kinetic-dynamic monitoring approach in a
paper which is going to be published in the forecoming issue of Therapeutic
Drug Monitoring.
You can also look at this series of our related papers:
Clin Neuropharmacol 1990;13:19-28
Neurology 1993;43:367-371
Clin Pharmacokinet 1996;30:463-481
Best regards,
Manuela Contin, Pharm. D., Contin.aaa.neuro.unibo.it
Roberto Riva, M.D., Riva.aaa.neuro.unibo.it
Dept.of Neurological Sciences
University of Bologna,
Italy
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The following message was posted to: PharmPK
The study design of the longitudinal PK analysis is as follows:
Twenty parkinsonian patients with no prior levodopa treatment were followed
for 4 years. At each visit (0, 6, 12, 24 and 48 months), patients were
hospitalized for 5 days with levodopa withheld at midnight of day 1. A
2-hour constant rate levodopa IV infusion (1 mg/kg/h) with concomitant oral
carbidopa (25 mg starting an hour before the infusion and repeats every 2
hours for a total of 3 doses) was given in two occasions separated by 72
hours. Patients received no levodopa treatment in between the two
infusions. Plasma levodopa concentrations were collected at 0, 0.25, 0.5,
1, 1.5, 2, 2.25, 2.5, 3, 4, 5 hours. A total of 166 time-concentration
profiles with 1477 concentration observations were collected over the 4 year
period from the 20 patients.
We used a zero order input two compartment PK model (parameterized as CL,
V1, Q, and V2) to describe the data. An allometric model was applied to
standardize the PK parameters with an assumption of a standard body weight
of 70 kg. The pre-dose levodopa concentration was determined by two
components:
(1) an unknown dosing history prior to the observation period;
(2) an endogenous component which accounts for the endogenously existing
levodopa.
The unknown dosing history was modeled by a steady state infusion dose which
ended at the time of levodopa infusion started. Its rate of infusion was
determined by CL and the steady state concentration. Since all patients
were naive prior to the baseline visit and no levodopa was given in between
the two infusions within a visit, the rate of infusion was set to be 0 for
these patients.
The endogenous drug was assumed to be at steady state with a linear
kinetics. Its effect was simply added on to the NONMEM predicted levodopa
concentration induced by the IV infusions.
Phylinda.
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)