Drugs

, Volume 67, Issue 12, pp 1725–1747 | Cite as

Rasagiline

A Review of its Use in the Management of Parkinson’s Disease
  • Vicki Oldfield
  • Gillian M. Keating
  • Caroline M. Perry
Adis Drug Evaluation

Summary

Abstract

Rasagiline (Azilect®) is a novel, selective, irreversible second-generation inhibitor of monoamine oxidase type B (MAO-B). It is administered orally once daily and is approved in the US, Canada, Mexico, Israel and the EU for use as monotherapy and as adjunct therapy in the treatment of Parkinson’s disease.

Results of well designed clinical studies indicate that rasagiline is effective as initial monotherapy and improves Parkinson’s symptomatology in patients with early Parkinson’s disease. In addition, when administered in conjunction with levodopa, in patients with moderate to advanced disease and motor fluctuations, rasagiline reduces mean daily ‘off’ time and increases daily ‘on’ time without troublesome dyskinesias, compared with controls. Rasagiline is generally well tolerated as monotherapy and adjunctive therapy and is administered once daily. Thus, rasagiline, administered as a simple and convenient dosage regimen, is a well tolerated and effective option for monotherapy in patients with early Parkinson’s disease and for adjunctive therapy in patients with moderate to advanced disease.

Pharmacological Properties

Rasagiline selectively and irreversibly inhibited MAO-B activity in a number of in vitro and in vivo studies. It was 5- to 10-fold more potent than selegiline at inhibiting MAO-B activity in rats. The inhibition of MAO-B activity by rasagiline is thought to lead to an increase in striatal extracellular dopamine levels and may account for the beneficial effect of rasagiline treatment on motor function observed in animal models of Parkinson’s disease.

Rasagiline has demonstrated neuroprotective activity in animal studies and in vitro. Its main metabolite, l-(R)-aminoindan has shown beneficial effects in vitro and in vivo and does not inhibit the anti-apoptotic activity of rasagiline and has no sympathomimetic effects, unlike the major selegiline metabolites, L-amphetamine (L-amfetamine) and L-methamphetamine (L-metamfetamine), which are neurotoxic and inhibit the neuroprotective activity of the parent drug.

In humans, oral rasagiline is rapidly absorbed, reaching a maximum plasma concentration (Cmax) in ≤0.7 hours. Log Cmax was significantly correlated with the percentage of platelet MAO-B inhibition in healthy volunteers. Rasagiline undergoes extensive hepatic metabolism, with less than 1% of the dose being eliminated in the urine unchanged. The main metabolites are l-(R)-aminoindan, 3-hydroxy-N-propargyl-1-aminoindan and 3-hydroxy-1-aminoindan. Cmax and the area under the plasma concentration-time curve increased by 2-fold and 7-fold, respectively, in patients with moderate hepatic impairment (Child-Pugh score 7–9) compared with healthy individuals, following repeat dose administration for 7 days. The pharmacokinetic parameters of rasagiline in patients with mild or moderate renal impairment are similar to those observed in healthy volunteers.

Therapeutic Efficacy

The therapeutic efficacy of oral once-daily rasagiline has been evaluated in three large well designed clinical trials. Patients with early Parkinson’s disease received rasagiline as early initial monotherapy in the TEMPO trial, which was designed to evaluate the efficacy of rasagiline prior to treatment with dopaminergic agents including levodopa. In the PRESTO and LARGO trials, patients with moderate to advanced disease and motor fluctuations received rasagiline as an adjunct to levodopa plus a dopa decarboxylase inhibitor.

In the TEMPO trial, the change from baseline in mean adjusted total Unified Parkinson’s Disease Rating Scale (UPDRS) scores favoured rasagiline 1 or 2 mg/day versus placebo recipients at 26 weeks and early-start rasagiline 1 or 2 mg/day versus delayed-start (by 6 months) rasagiline 2 mg/day at 52 weeks. At 26 weeks, the change from baseline in UPDRS motor, activities of daily living (ADL), tremor and bradykinesia scores also significantly favoured rasagiline recipients, and health-related quality of life (HR-QOL) remained stable with rasagiline. Significantly more rasagiline 1 and 2 mg/day than placebo recipients responded to treatment (experienced a <3-unit increase in total UPDRS score) at 26 weeks. To date, rasagiline therapy has been shown to adequately control Parkinson’s symptoms in the long term (6.5 years) and the beneficial effect of earlyversus delayedstart rasagiline was maintained during this period.

Rasagiline 0.5 and 1 mg/day together with levodopa and other antiparkinsonian therapy significantly decreased the amount of daily ’off time (primary endpoint) compared with placebo in the PRESTO (0.5 and 1 mg/day) and LARGO (1 mg/day) trials. Additionally, compared with placebo, rasagiline recipients had significantly improved Clinical Global Impression (CGI) scores, UPDRS ADL scores during ‘off’ time and UPDRS motor scores during ‘on’ and ‘off time’. Levodopa-responsive symptoms, including tremor, rigidity and bradykinesia, improved with rasagiline, improving ‘on’ time without troublesome dyskinesias and the response to treatment (≥1 hour decrease in mean total daily ‘off’ time) was significantly greater with rasagiline than placebo in the LARGO trial. Rasagiline treatment had no effect on HR-QOL in the more advanced Parkinson’s disease patients in the PRESTO trial.

Tolerability

Rasagiline was generally well tolerated as monotherapy in patients with early Parkinson’s disease. The most frequently occurring adverse events in rasagiline recipients during the first 26 weeks of the TEMPO trial were infection and headache. During the long-term TEMPO extension (up to 6.5 years) rasagiline was well tolerated with the most common adverse events reported being infection and accidental injury.

Rasagiline was also generally well tolerated when added to other antiparkinsonian medication in patients with moderate to advanced disease and motor fluctuations, with the most commonly occurring adverse events being dopaminergic related. The incidence of dopaminergic adverse events was similar with rasagiline and placebo in the LARGO trial, but in the PRESTO trial rasagiline recipients reported a significantly greater incidence of weight loss, vomiting, anorexia, balance difficulty and dyskinesias. Depression occurred significantly less frequently with rasagiline than with placebo in the PRESTO trial.

Serious adverse events with rasagiline were infrequent and rasagiline treatment had little or no effect on ECG recordings, blood pressure, heart rate or laboratory measurements. No increase in sensitivity to tyramine was observed following a tyramine challenge performed in subpopulations of patients at the end of the TEMPO and PRESTO trials. All three trials were without dietary tyramine restrictions and no cases of hypertensive crisis were reported. Discontinuation rates due to adverse events were low.

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Copyright information

© Adis Data Information BV 2007

Authors and Affiliations

  • Vicki Oldfield
    • 1
  • Gillian M. Keating
    • 1
  • Caroline M. Perry
    • 1
  1. 1.Wolters Kluwer Health ¦ AdisMairangi Bay, North Shore, AucklandNew Zealand

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