Rotigotine

Rotigotine is a non-ergolinic dopamine agonist for the treatment of signs and symptoms of Parkinson’s disease and Restless Legs Syndrome.

Rotigotine is believed to elicit its beneficial effect on Parkinson’s disease by activation of the D₃, D₂ and D₁ receptors of the caudate-putamen in the brain.

The precise mechanism of action of rotigotine as a treatment of RLS is unknown. It is thought that rotigotine may exert its activity mainly via dopamine receptors.

Pharmacodynamic effects

Regarding the functional activity at the various receptor subtypes and their distribution in the brain, rotigotine is a D₂ and D₃ receptor agonist acting also on D₁, D₄ and D₅ receptors. With nondopaminergic receptors, rotigotine showed antagonism at alpha2B and agonism at 5HT_1A receptors, but no activity on the 5HT_2B receptor.

Absorption

Following application, rotigotine is continuously released from the transdermal patch and absorbed through the skin. Steady-state concentrations are reached after one to two days of patch application and are maintained at a stable level by once daily application in which the patch is worn for 24 hours. Rotigotine plasma concentrations increase dose-proportionally over a dose range of 1 mg/24 h to 24 mg/24 h.

Approximately 45% of the active substance within the patch is released to the skin in 24 hours. The absolute bioavailability after transdermal application is approximately 37%.

Rotating the site of patch application may result in day-to-day differences in plasma levels. Differences in bioavailability of rotigotine ranged from 2% (upper arm versus flank) to 46% (shoulder versus thigh). However, there is no indication of a relevant impact on the clinical outcome.

Distribution

The in vitro binding of rotigotine to plasma proteins is approximately 92%.

The apparent volume of distribution in humans is approximately 84 l/kg.

Biotransformation

Rotigotine is metabolised to a great extent. Rotigotine is metabolised by N-dealkylation as well as direct and secondary conjugation. In vitro results indicate that different CYP isoforms are able to catalyse the N-dealkylation of rotigotine. Main metabolites are sulfates and glucuronide conjugates of the parent compound as well as N-desalkyl-metabolites, which are biologically inactive.

The information on metabolites is incomplete.

Elimination

Approximately 71% of the rotigotine dose is excreted in urine and a smaller part of about 23% is excreted in faeces.

The clearance of rotigotine after transdermal administration is approximately 10 l/min and its overall elimination half-life is 5 to 7 hours. The pharmacokinetic profile shows a biphasic elimination with an initial half-life of about 2 to 3 hours.

Because the patch is administered transdermally, no effect of food and gastrointestinal conditions is expected.

Special patient groups

Because therapy with Neupro is initiated at a low dose and gradually titrated according to clinical tolerability to obtain the optimum therapeutic effect, adjustment of the dose based on gender, weight, or age is not necessary.

Hepatic and renal impairment

In subjects with moderate hepatic impairment or mild to severe renal impairment, no relevant increases of rotigotine plasma levels were observed. Neupro was not investigated in patients with severe hepatic impairment.

Plasma levels of conjugates of rotigotine and its desalkyl metabolites increase with impaired renal function. However, a contribution of these metabolites to clinical effects is unlikely.

Paediatric population

Limited pharmacokinetic data obtained in adolescent patients with RLS (13-17 years, n=24) following treatment with multiple doses of 0.5 to 3mg/24h showed that systemic exposure to rotigotine was similar to that observed in adults. Efficacy/safety data is insufficient to establish a relation between exposure and response.

In repeated dose and long-term toxicity studies, the major effects were associated with the dopamine agonist related pharmacodynamic effects and the consequent decrease of prolactin secretion. After a single dose of rotigotine, binding to melanin-containing tissues (i.e. eyes) in the pigmented rat and monkey was evident, but was slowly cleared over the 14-day observation period.

Retinal degeneration was observed by transmission microscopy at a dose equivalent to 2.8 times the maximum recommended human dose on a mg/m² basis in a 3-month study in albino rats. The effects were more pronounced in female rats. Additional studies to further evaluate the specific pathology have not been performed. Retinal degeneration was not observed during the routine histopathological evaluation of the eyes in any of the toxicology studies in any species used. The relevance of these findings to humans is not known.

In a carcinogenicity study, male rats developed Leydig cell tumours and hyperplasia. Malignant tumours were noted predominantly in the uterus of mid- and high-dose females. These changes are well-known effects of dopamine agonists in rats after life-long therapy and assessed as not relevant to man.

The effects of rotigotine on reproduction have been investigated in rats, rabbits and mice. Rotigotine was not teratogenic in all three species, but was embryotoxic in rats and mice at materno-toxic doses.

Rotigotine did not influence male fertility in rats, but clearly reduced female fertility in rats and mice, because of the effects on prolactin levels which are particularly significant in rodents. Rotigotine did not induce gene mutations in the Ames test, but did show effects in the in vitro Mouse Lymphoma Assay with metabolic activation and weaker effects without metabolic activation. This mutagenic effect could be attributed to a clastogenic effect of rotigotine. This effect was not confirmed in vivo in the Mouse Micronucleus Test in the rat Unscheduled DNA Synthesis (UDS) test. Since it ran more or less parallel with a decreased relative total growth of the cells, it may be related to a cytotoxic effect of the compound. Therefore, the relevance of the one positive in vitro mutagenicity test is not known.