http://www.diva-portal.org

Preprint

This is the submitted version of a paper presented at Twentieth International Congress of Parkinson'sDisease and Movement Disorders, Berlin, Germany, June 19-23, 2016.

Citation for the original published paper:

Senek, M., Aquilonius, S-M., Askmark, H., Bergquist, F., Constantinescu, R. et al. (2016)Levodopa/carbidopa microtablets in Parkinson disease: pharmacokinetics and blinded motorassessment.In: Twentieth International Congress of Parkinson's Disease and Movement Disorders

N.B. When citing this work, cite the original published paper.

Permanent link to this version:http://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-51026

Levodopa/carbidopa microtablets in

Parkinson disease – pharmacokinetics and

blinded motor assessment

Objective

The objective was to investigate the plasma concentration profiles of levodopa and carbidopa and the motor function

following a single-dose microtablet administration in Parkinson’s disease patients.

Marina Senek1, Sten-Magnus Aquilonius1, Håkan Askmark1, Filip Bergquist2, Radu Constantinescu3, Anders Ericsson4, Sara Lycke5, Alexander Medvedev6, Mevludin Memedi7,8, Fredrik Ohlsson4, Jack Spira9, Jerker Westin7, Dag

Nyholm1

1 Dept. of Neuroscience, Neurology, Uppsala University, 2 Dept. of Pharmacology, University of Gothenburg, 3Dept. of Clinical Neuroscience, University of Gothenburg, 4Acreo Swedish ICT, 5Cenvigo, 6 Dept. of Information Technology,

Uppsala University, 7Computer Engineering, Dalarna University, 8Informatics, School of Business, Örebro University, 9Sensidose AB

In a PD population, with a median 9 year of disease duration,

following administration of levodopa/carbidopa in fasting state, the

Cmax and AUC0-4/dose were found to be higher compared with the

levodopa pharmacokinetics in young healthy subjects. Our data our

line with previous data showing that pharmacokinetics of levodopa is

age dependent.2

The mean time to maximum improvement in

UPDRS item score was 78 (±59) minutes

(n=16), and the mean time to TRS score effect

maximum was 54 (±51) minutes (n=15).

Mean time to onset of dyskinesia was 41

(±38) minutes (n=13, excluding 6 patients

that did not develop dyskinesia).

Results

AUC0-4/dose and Cmax/dose for levodopa was

found to be higher in patients (p=0.0008 and

p=0.026 respectively), compared with younger

healthy subjects from a previous study 1 (mean

age 27 (±7) years).

Introduction

Methods

Assessment of motor function with rating scales

in relation to the plasma concentration of

levodopa may increase the understanding of

how to individualize and fine-tune treatments.

This was a single-center, open-label, single dose

study in 19 patients with Parkinson’s disease

experiencing motor fluctuations. • Mean age 71.4 (±6.3) years

• Years since diagnosis 9.7 (±6.8)

• 18/19 reported wearing-off symptoms

• 13/19 reported to experience dyskinesia

All patients were video recorded and the

motor function was assessed with three rating

scales by three movement disorder

specialists blinded with respect to time from

dose intake

The motor function was rated according to

(Figure 1):

• six UPDRS motor items

• Dyskinesia score

• The Treatment response scale (TRS)

score, ranging from parkinsonism (-3) to

normal mobility (0) to severe choreatic

dyskinesia (+3).

Figure 3. Mean (±SD) A. UPDRS item score,

B. dyskinesia and C. TRS scores (n=19)

Figure 2. A: Mean (±SD) baseline- and dose adjusted plasma

levodopa concentrations in patients (n=14) and data from

healthy (n=18) (data for healthy subjects from Nyholm et al.

20121). B: Mean baseline- and dose adjusted plasma

carbidopa concentrations in patients (n=14) and healthy (n=18)

(data for healthy subjects from Nyholm et al. 20121).

*Contact : marina.senek@neuro.uu.se

• Patients received 150% of their individual

levodopa equivalent morning dose in

levodopa-carbidopa dispersible microtablets

(levodopa [5 mg] and carbidopa [1.25 mg]).

• Blood-samples were collected at pre-specified

time points.

Figure 1. General overview of a test cycle, with the six

included UPDRS items, rated by the movement disorder

specialists.Reference:

1. Nyholm D, Lewander T, Gomes-Trolin C, et al. Pharmacokinetics of levodopa/carbidopa microtablets versus levodopa/benserazide and levodopa/carbidopa in healthy volunteers. Clin

Neuropharmacol. 2012;35:111–117.

2. Robertson DR, Wood ND, Everest H, et al. The effect of age on the pharmacokinetics of levodopa administered alone and in the presence of carbidopa. Br J Clin Pharmacol. 1989;28:61–69.

Table 2. Pharmacokinetic parameters of levodopa and

carbidopa

*Reused with permission from Wolters Kluwer Health, Inc. (Clinical Neuropharmacology).

**One patient did not have descending time points at end of trialaBaseline and dose adjusted bTime points 0-240min (0-4h). Five patients were excluded because they did not have data until

240 min. cat least three descending concentration time points were used for the calculation of t½. All time

points included.†not significant, compared with healthy volunteers from previous study11

††p < 0.05, compared with healthy volunteers from previous study11

A large between subject

variability in response and

duration of effect was

observed.

Conclusions

Patients

Levodopa Carbidopa

N Mean SD Min Median Max N Mean SD Min Median Max

Cmax/dose

(µg/mL)a 19 1.17†† 0.43 0.31 1.16 1.96

19 0.09† 0.03 0.03 0.09 0.14

Tmax (min) 19 32 23 15 30 100 19 134 47 80 120 240

AUC0-4h/doseab

(min*µg/mL/mg) 14 1.15 †† 0.31 0.38 1.21 1.74

14 0.67† 0.26 0.23 0.68 1.14

t½c (min) 14 106† 16 85 104 144 13** 171†† 37 117 173 248

Healthy

volunteers11

Levodopa Carbidopa

N Mean SD Min Median Max - N Mean SD Min Median Max

Cmax (µg/mL) 18 0.90 0.25 0.51 0.88 1.38 18 0.09 0.05 0.03 0.09 0.21

Tmax (min) 18 37 23 20 35 120 18 109 48 40 100 180

AUC0-4h/doseb

(min*µg/mL/mg) 18 0.77 0.17 0.53 0.75 1.13

18 0.58 0.32 0.17 0.52 1.44

t½c (min) 18 91 34 45 85 198 18 125 72 56 101 315