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Rotigotine for the Treatment of Advanced Parkinson’s Disease
focus primarily on rotigotine for advanced PD; for data about its effect in Table 1: Receptor Affinity Profiles of Rotigotine,
early PD, please see references 18 and 19.
Pramipexole and Ropinirole
Pharmacodynamics of Rotigotine
Ligand hD1 hD2L hD3
Rotigotine has agonistic activity at all dopamine receptor subtypes
Pramipexole
22
>10,000 1,698 10.5
(D
Ropinerole
22
>10,000 933 37.2
1
–D
5
), but demonstrates its highest affinity for the D
3
receptor.
20
In vitro
profiling using recombinant human receptors revealed that the affinity
Rotigotine
20
83.2 13.5 0.71
of rotigotine for the D
K values are shown (unit of measurement: nM). h = human.i
3
receptor was approximately 20-fold and 100-fold
For further information, see references 20 and 22.
greater than its affinity for the D
2
and D
1
receptors, respectively
20
– a
profile consistent with that seen in other, earlier investigations.
15
A was observed at 16 hours after administration (time to maximum
comparison of the affinity of rotigotine for dopamine receptors with plasma concentration [t
max
]), with an area under the plasma
those of other non-ergot agonists is shown in Table 1. Rotigotine has a concentration–time curve from time zero to the last time-point
similar affinity ratio to dopamine itself, with a preference for the (AUC
0–tz
) value of 3.94ng.hr/ml.
30
Following patch removal at 24 hours,
D
3
/D
2
/D
1
receptors – the three major dopamine receptor subtypes the rotigotine plasma concentration decreased with a median
expressed in the striatum.
21
Compared with pramipexole or ropinirole, terminal elimination half-life of 6.82 hours.
30
In PD patients, steady-
rotigotine shows a higher affinity and similar selectivity for D
2
-like state pharmacokinetic studies showed a mean (± standard deviation
dopamine receptor subtypes.
20,22,23
In addition, rotigotine acts as an [SD]) plasma concentration of rotigotine of ~0.9ng/ml after daily
antagonist at the α
2
-adrenergic receptor and as an agonist at the 5HT
1A
applications of an 8mg/24 hours patch.
31
Six different body sites were
receptor.
15,16
In vitro functional assays have also demonstrated its used for patch application.
31
In subjects with moderate hepatic
inhibition of dopamine uptake and prolactin secretion.
15
impairment or mild to severe renal impairment, no relevant increases
of rotigotine plasma levels were observed. Rotigotine was not
A slow-release form of rotigotine generated constant extracellular investigated in patients with severe hepatic impairment.
17
drug levels in the brains of freely moving rats following subcutaneous
administration.
12
These levels were maintained for at least 48 hours Approximately 45% of the active drug substance within the patch is
and were accompanied by a concomitant and maintained reduction in released to the skin in 24 hours.
17,32
Rotigotine’s volume of distribution
extracellular dopamine to about 20% of vehicle control levels.
12
As in humans is 84l/kg. Due to the transdermal administration route, food
dopamine synthesis is controlled by pre-synaptic receptors, this and/or gastrointestinal conditions are not expected to influence its
observation supports rotigotine’s potential to induce continuous pharmacokinetics.
17
The majority of the rotigotine dose is excreted in
stimulation of dopamine receptors.
12
the urine (71%), with approximately 23% excreted in the faeces.
17
Rotigotine has demonstrated benefits in several animal models of PD. The development of crystals in rotigotine patches, resulting from the
In 6-hydroxy dopamine (6-OHDA)-lesioned rats, subcutaneous presence of another polymorphic form of the drug substance, was
rotigotine induced dose-dependent contralateral turning behaviour.
15
recently noted.
19,33
In theory, occurence of rotigotine crystals may
Further to this, in a study of hemi-parkinsonian (1-methyl-4-phenyl- reduce rotigotine’s bioavailability, and therefore refrigerated storage
1,2,3,6-tetrahydropyridine [MPTP]-induced) monkeys, intramuscular of the patches was introduced, substantially reducing the formation
rotigotine also induced contralateral turning behaviour, as well as of crystals and addressing the problem. Nonetheless, because of this
exploratory activity and contralateral limb usage.
15
In the MPTP- issue, marketing is suspended in the US at present.
lesioned common marmoset, subcutaneous rotigotine produced a
dose-dependent increase in well co-ordinated locomotor activity, with Drug–Drug Interactions
a concomitant reduction in disability scores.
24
This was observed at Rotigotine showed no pharmacokinetic drug–drug interactions with
even the lowest dose of rotigotine (0.019mg/kg).
24
omeprazole,
17
domperidone
34
or levodopa/carbidopa.
35
However, as
with other dopamine agonists, when given concomitantly rotigotine
With the aim of investigating the induction of dyskinesia, pulsatile may potentiate the adverse reactions of levodopa, including the
administration of rotigotine or levodopa was compared with exacerbation of pre-existing dyskinesia.
continuous delivery of rotigotine in 6-OHDA-lesioned rats.
25
Discontinuous delivery of rotigotine and levodopa produced increased Clinical Studies of Rotigotine
sensitisation of locomotor activity to approximately the same extent, Currently published clinical studies of rotigotine in advanced PD
whereas continuous delivery of rotigotine did not produce this include two large-scale phase III studies and three phase II trials (see
sensitisation.
25
These initial observations may indicate a lower risk of Table 2). Overall, these studies indicated that rotigotine is effective for
dyskinesias with continuous drug administration. In a separate the treatment of levodopa-related motor complications as well as for
investigation, it was noted that high doses of rotigotine produced motor symptom control in advanced PD.
hyperactivity and restlessness in hemi-parkinsonian monkeys.
19
Treatment of Motor Complications
Recent data indicate that rotigotine may also have neuroprotective Phase II data indicate that rotigotine treatment can produce a
effects,
26–29
but these results have not been further explored in humans. decrease in OFF time in patients with advanced PD. Early uncontrolled
studies showed reductions in mean daily OFF time and increases in
Pharmacokinetics of Rotigotine mean ON time without dyskinesias.
19,36,37
A larger-scale placebo-
Rotigotine pharmacokinetics were dose-proportional.
17
After controlled phase II study of rotigotine revealed a decrease in OFF time
administration of a rotigotine patch (2mg/24 hours) to eight healthy of 1.72 hours/day and 2.44 hours/day for the 8mg/24 hours and
volunteers, a median maximum concentration (C
max
) of 0.215ng/ml 12mg/24 hours doses, respectively.
38
Although this magnitude of
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