Pharmacotherapeutic Group: Antiparkinson drugs, monoamine oxidase-B inhibitors. ATC Code: N04BD02.
Pharmacology: Pharmacodynamics: Mechanism of Action: Rasagiline was shown to be a potent, irreversible monoamine oxidase (MAO)-B selective inhibitor, which may cause an increase in extracellular levels of dopamine in the striatum. The elevated dopamine level and subsequent increased dopaminergic activity are likely to mediate rasagiline's beneficial effects seen in models of dopaminergic motor dysfunction.
1-Aminoindan is an active major metabolite and it is not a MAO-B inhibitor.
Clinical Studies: The efficacy of rasagiline was established in 3 studies: As monotherapy treatment in study I and as adjunct therapy to levodopa in the studies II and III.
Monotherapy: In study I, 404 patients were randomly assigned to receive placebo (138 patients), rasagiline 1 mg/day (134 patients) or rasagiline 2 mg/day (132 patients) and were treated for 26 weeks, there was no active comparator.
In this study, the primary measure of efficacy was the change from baseline in the total score of the Unified Parkinson’s Disease Rating Scale (UPDRS, parts I-III). The difference between the mean change from baseline to week 26/termination Last Observation Carried Forward (LOCF) was statistically significant [UPDRS, parts I-III: For rasagiline 1 mg compared to placebo -4.2, 95% CI (-5.7, -2.7); p<0.0001; for rasagiline 2 mg compared to placebo -3.6, 95% CI (-5, -2.1); p<0.0001, UPDRS motor, part II: For rasagiline 1 mg compared to placebo -2.7, 95% CI (-3.87, -1.55), p<0.0001; for rasagiline 2 mg compared to placebo -1.68, 95% CI (-2.85, -0.51), p=0.005]. The effect was evident, although its magnitude was modest in this patient population with mild disease. There was a significant and beneficial effect in quality of life (as assessed by PD-QUALIF scale).
Adjunct Therapy: In study II, patients were randomly assigned to receive placebo (229 patients), or rasagiline 1 mg/day (231 patients) or the catechol-O-methyl transferase (COMT) inhibitor, entacapone 200 mg taken along with scheduled doses of levodopa (LD)/decarboxylase inhibitor (227 patients), and were treated for 18 weeks. In study III, patients were randomly assigned to receive placebo (159 patients), rasagiline 0.5 mg/day (164 patients), or rasagiline 1 mg/day (149 patients), and were treated for 26 weeks.
In both studies, the primary measure of efficacy was the change from baseline to treatment period in the mean number of hours that were spent in the "OFF" state during the day (determined from "24-hr" home diaries completed for 3 days prior to each of the assessment visits).
In study II, the mean difference in the number of hours spent in the "OFF" state compared to placebo was -0.78 hr, 95% CI (-1.18, -0.39), p=0.0001. The mean total daily decrease in the OFF time was similar in the entacapone group [-0.8 hr, 95% CI (-1.2, -0.41), p<0.0001] to that observed in the rasagiline 1 mg group. In study III, the mean difference compared to placebo was -0.94 hr, 95% CI (-1.36, -0.51), p<0.0001. There was also a statistically significant improvement over placebo with the rasagiline 0.5 mg group, yet the magnitude of improvement was lower. The robustness of the results for the primary efficacy endpoint was confirmed in a battery of additional statistical models and was demonstrated in 3 cohorts (ITT, per protocol and completers).
The secondary measures of efficacy included global assessments of improvement by the examiner, activities of daily living (ADL) subscale scores when OFF and UPDRS motor while ON. Rasagiline produced statistically significant benefit compared to placebo.
Pharmacokinetics: Absorption: Rasagiline is rapidly absorbed, reaching peak plasma concentration (Cmax) in approximately 0.5 hr. The absolute bioavailability of a single rasagiline dose is about 36%. Food does not affect the Tmax of rasagiline, although Cmax and exposure (AUC) are decreased by approximately 60% and 20%, respectively, when the medicinal product is taken with a high fat meal. Because AUC is not substantially affected, rasagiline can be administered with or without food.
Distribution: The mean volume of distribution following a single IV dose of rasagiline is 243 L. Plasma protein-binding following a single oral dose of 14C-labelled rasagiline is approximately 60-70%.
Metabolism: Rasagiline undergoes almost complete biotransformation in the liver prior to excretion. The metabolism of rasagiline proceeds through 2 main pathways: N-dealkylation and/or hydroxylation to yield: 1-Aminoindan, 3-hydroxy-N-propargyl-1 aminoindan and 3-hydroxy-1-aminoindan. In vitro experiments indicate that both routes of rasagiline metabolism are dependent on cytochrome P-450 system, with CYP1A2 being the major isoenzyme involved in rasagiline metabolism. Conjugation of rasagiline and its metabolites was also found to be a major elimination pathway to yield glucuronides.
Excretion: After oral administration of 14C-labelled rasagiline, elimination occurred primarily via urine (62.6%) and secondarily via faeces (21.8%), with a total recovery of 84.4% of the dose over a period of 38 days. Less than 1% of rasagiline is excreted as unchanged product in urine.
Linearity/Non-Linearity: Rasagiline pharmacokinetics are linear with dose over the range of 0.5-2 mg. Its terminal half-life is 0.6-2 hrs.
Characteristics in Patients: Patients with Hepatic Impairment: In subjects with mild hepatic impairment, AUC and Cmax were increased by 80% and 38%, respectively. In subjects with moderate hepatic impairment, AUC and Cmax were increased by 568% and 83%, respectively.
Patients with Renal Impairment: Rasagiline's pharmacokinetics characteristics in subjects with mild [creatinine clearance (CrCl) 50-80 mL/min] and moderate (CrCl 30-49 mL/min) renal impairment were similar to healthy subjects.
Toxicology: Preclinical Safety Data: Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity and reproduction toxicity.
Rasagiline did not present genotoxic potential in vivo and in several in vitro systems using bacteria or hepatocytes. In the presence of metabolite activation, rasagiline induced an increase of chromosomal aberrations at concentrations with excessive cytotoxicity which are unattainable at the clinical conditions of use.
Rasagiline was not carcinogenic in rats at systemic exposure, 84-339 times the expected plasma exposures in humans at 1 mg/day. In mice, increased incidences of combined bronchiolar/alveolar adenoma and/or carcinoma were observed at systemic exposures, 144-213 times the expected plasma exposure in humans at 1 mg/day.