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ALPHA TEST VERSION: DO NOT USE FOR CLINICAL PURPOSES

Exogenous Levodopa Equivalent Minute-to-Minute Plasma Levels Calculator

What?

This app uses pharmacokinetic data to estimate, minute by minute, the contribution made by each of your Parkinson's drugs to your total exogenous levodopa equivalent plasma levels, and graphs the results.

Instructions

  • Enter your dose data in the green boxes below.
    • Time
    • Name of drug

      (As it is used here, except where explicitly stated otherwise, the drug name "levodopa" denotes a combined drug levodopa/carbidopa in a 4:1 ratio.)

    • Dose

      (Where a drug contains levodopa and other active components, input the levodopa dose only.)

    • Press the blue "Calculate" button.
 
Time
hh
Time
mm
Drug Dose
mg
Conversion
Factor
LED
mg
CMAX
mg
TMAX
min
THALF
min
AUC
mg.min
Colour Comments
Additional settings
"On" onset (LED mg) Dyskinesia onset (LED mg) Days in treatment
Total, LEDD (mg) =
Total, AUC =

 

Statistics

What this program does

You enter details of your Parkinson's drug regimen:

The program draws a graph showing over a 24 hour period the impact of each drug on a minute-to-minute basis, taking into account the drug's:

(Optional) By inputting estimates of your "on" threshold and your dyskinesia threshold you can read from the graph estimates of the times that you are in these conditions.

(Optional) By inputting longer values of the number of days in treatment you capture the effect of some drugs, those with a long half-life, carrying over their remaining impact to a second and later days. Immediate release levodopa reaches steady state in a day. Some agonists may take five days to reach steady state.

Units used

It is usual to measure plasma concentrations in μg/ml. However, in the hope that it is easier to interpret, a different approach is used here. The units of the y-axis are LED mg, scaled such that 100mg denotes the maximum concentration of 100mg of levodopa (taken with carbidopa). This makes it easy to use. For instance, to correct a trough in plasma levels, the additional dose required can be simply read off from the graph.

Assumptions

It is assumed that in an anti-Parkinson's drug regimen:

The idea of pseudo levodopa plasma levels is central to this program. The agonist does not really become levodopa. It's just a matter of convenience that we make this slight of hand. A similar case is made for the inclusion of MAO-B inhibitors in the analysis. They don't literally turn into dopamine, but they make dopamine levels higher than they would otherwise be by lengthening the life of dopamine.

Model used

The model used to estimate plasma concentrations is:

1. Each drug has a plasma concentration defined by the following parameters (only 3 of the 4 parameters is are needed, the fourth can be generated from the other 3):

2. Starting at the time that the drug is administered it is assumed that plasma concentrations due to this dose rise linearly until CMAX is reached at TMAX. Thereafter, plasma levels halve every THALF.

3. To deal with non-levodopa based drugs a CMAX value is chosen such that the AUC given by the drug matches that of levodopa multiplied by the LED conversion factor.

Pharmacokinetic parameters

The source of the levodopa immediate release pharmacokinetic parameters used here is a paper by Kuoppamaki et al. [5]. These are:

Inconsistencies

There is a considerable variation in the values of the pharmacokinetic parameters reported in the literature. They are often based on small sample sizes. This leads to inconsistencies: with the LED value implying a different AUC than that reported. For instance, a conversion factor for Stalevo is 1.33, yet using the parameters from [5] in the model gives an AUC 15% higher than that implied by the LED conversion factor.

LED conversion factors and pharmacokinetic parameters

The conversion factors used are shown in the table below. Where the literature shows large variations in what is thought to be the correct conversion factor to use, a tuple is shown meaning (lowest estimate/highest estimate/average estimate)

DrugConv FactorCMAXTMAX THALFSources and Notes
Amantadine 1 0.169 126 847 +[14] Choose CMAX to equate AUC. Maximum daily dose is 400mg.
Apomorphine (intranasal) 7.5 1 23 31 +[12] bioavailability cf subcutaneous = 45%
Apomorphine (subcutaneous) 10 1 18 27 +[12]
Levodopa116081[1]*[5]
Levodopa CR 0.7 0.4 120 137 * [13] bioavailability 70%, CMAX 60% lower than IR, TMAX approximately 2 hours, THALF chosen to equate AUC
Madopar116081*[10] Brand name of levodopa with benserazide
Mirapexin 100 1 120 600 +[11] Max concentrations "between 1 and 3 hours",
Neupro Patch 100 1 120 600 [15] Brand name of rotigotine patch.
Pramipexole 100 1 120 600 +[11] Max concentrations "between 1 and 3 hours", elimination half life varies from 8 to 12 hours
Rasagiline10010.72010000[1] Maximum effect found with 1mg. Estimate based on AUC argument and constant effect.
Requip205.5990360Brand name of ropinirole
RequipXL204.34480360Inferred from [3]. Brand name of ropinirole CR
Ropinirole205.5990360[1][2] (16.67,33.3,21.3)[6]+
RopiniroleCR204.34480360See RequipXL.[7]+
Rotigotine Patch 100 1 120 600 +[15] Constant in steady state.
Sinemet 110.726081Brand name of levodopa with carbidopa.*
Sinemet CR 0.7 0.4 120 137 * [13] brand name Levodopa CR
Stalevo 1.331.0890117[1][2] (1.2,1.33,1.25)*[5]

Note *: This drug contains multiple components. Input the levodopa dose only.

Note +: TMAX and THALF taken from reference. CMAX is then calculated to give the correct AUC to be consistent with the LED conversion factor (CF).

Limitations of this approach

The conversion factors are clearly rounded which shows that they are estimates.

Different sources give different conversion factors. The range of the estimates for ropinirole, a factor of two, is especially large.

The analysis does not take into account the differences in effectiveness from person to person or the time it takes a drug to start to be absorbed.

Some of the pharmacokinetic data comes from healthy people and some from people with PD; some comes from a single dose trials, and some from steady state doses. Also, there may not have been consistency in regards to food intake, specifically protein, at or around the time of the dose.

Many of the pharmacokinetic trials have had a small sample size.

No attempt is made to take into account endogenous levodopa and dopamine.

The analysis here is based on drug pharmacokinetics, i.e. what the body does to the drug. However, what we are really interested in is drug pharmacodynamics, i.e. what the drug does to the body.

Similar tools developed by citizen scientists

Ron Strong's web site is worth looking at [8]. Angela Wensley has implemented an Excel approach [9] to combine multiple pharmacokinetic curves.

References

[1] "Levodopa Dose Equivalency: A Systematic Review"
Dr Claire Smith, Birmingham Clinical Trials Unit
8th June 2010
Smith et al.

[2] "Cálculo de unidades de equivalencia de levodopa en enfermedad de Parkinson"
Amin Cervantes-Arriaga1, Mayela Rodríguez-Violante1, Alejandra Villar-Velarde, Teresa Corona
Arch Neurocien (Mex) Vol. 14, No. 2: 116-119; 2009
Range of estimate data

[3] GSK prescribing information for RequipXL
RequipXL prescribing information

[4] Rytary prescribing information
Revised 1/2015
Rytary prescribing information

[5] "Comparison of pharmacokinetic profile of levodopa throughout the day between levodopa/carbidopa/entacapone and levodopa/carbidopa when administered four or five times daily"
Mikko Kuoppamaki et al.
European Journal of Clinical Pharmacology, May 2009, Volume 65, Issue 5, pp 443-455
Levodopa data

[6] MHRA UK Public Assessment Report, PL 24668/0078-84
Ropinirole data

[7] "Requip XL (ropinirol) - Drug Summary"
GlaxoSmithKline LLC PDR.net
Requip XL data

[8] Ron Strong's website

[9] Angela Wensley, private communication and forum postings
Neurotalk, Parkinson's forum

[10] "Madopar versus Sinemet: A clinical Study on their Effectiveness"
Korten J.J. · Keyser A. · Joosten E.M.G. · Gabreëls F.J.M.
Eur Neurol 1975; 13:65-71
Madopar v Sinemet

[11] "MHRA-UKPAR Pramipexole: PL 29831/0472-5"
March, 2012
MHRA-UKPAR Pramipexole

[12] "Apomorphine pharmacokinetics in parkinsonism after intranasal and subcutaneous application."
Sam E, Jeanjean AP, Maloteaux JM, Verbeke N.
Eur J Drug Metab Pharmacokinetic. 1995
Apomorphine pharmacokinetics

[13] "Sinemet CR and Half Sinemet CR"
emc, 02-Oct-2015
Sinemet CR

[14] "A Randomized, Crossover Study to Evaluate the Pharmacokinetics of Amantadine and Oseltamivir Administered Alone and in Combination"
Dennis Morrison et al..
Plos 1, Dec 12, 2007
Amantadine Pharmacokinetics

[15] "Pharmacokinetics, Safety and Tolerability of Rotigotine Transdermal Patch in Healthy Japanese and Caucasian Subjects"
Willi Cawello, Seong R. Kim, Marina Braun, Jan-Peer Elshoff, Junji Ikeda, and Tomoo Funaki
Clin Drug Investig, 2014.
Rotigotine

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John Turner, last revised 5th October, 2017.
Contact johnt@parkinsonsmeasurement.org