Parkinson’s disease (PD) is a neurodegenerative disorder characterised by the loss of dopaminergic neurons in the substantia nigra pars compacta – non-dopaminergic neurotransmission is also involved. In the basal ganglia circuitry there are many non-dopaminergic neurotransmitters and neuromodulators involved in the control of motor symptoms and implicated in the development of motor complications following long-term levodopa (LD) therapy.1–4 Indeed, PD is no longer seen purely as a disease of the dopaminergic system.5 In particular, overactive glutamate transmission plays a role in the progression of PD.6–8 Targeting non-dopaminergic systems is thus a complementary approach to improve and control such motor complications, removing the need for further increases in LD, which may otherwise worsen motor fluctuations.4
Safinamide (see Figure 1) is an oral, once-a-day adjunctive therapy developed for any stage of PD. Safinamide is a unique molecule with novel mechanisms of action (dopaminergic and non-dopaminergic) that include monoamine oxidase-B (MAO-B) inhibition, sodium channel blockade and calcium channel modulation, thus inhibiting the excessive glutamate release. The sodium channel inhibition is concentration- and state-dependent, and does not influence physiological activity, avoiding depressant effects on the central nervous system (CNS). Safinamide does not affect L-type calcium channels (no effects in blood pressure and heart rate).9–12
Safinamide is more selective for MAO-B versus MAO-A than selegiline and rasagiline: 1,000-fold in humans, compared with 127-fold for selegiline and 103-fold for rasagiline.10,13–15 This higher selectivity is related to the absence of diet restrictions pertaining to the clinical use of the drug. Moreover, the MAO-B inhibition is totally reversible, allowing better clinical manageability and limiting possible drug–drug interactions.10,14,15
In animal models, safinamide has been shown to reduce LD-induced dyskinesias.10,16 It may also have neuroprotective effects.8 Safinamide inhibits α-1 receptors in the endoplasmic reticulum.17 These receptors are believed to be multifunctional regulatory proteins with a role in CNS development, plasticity and neurodegeneration. Safinamide has been shown to completely prevent forebrain dopamine depletion and neuronal cell death in the gerbil substantia nigra when administered prior to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.18 In animal epilepsy models, safinamide was shown to counteract neuronal death that had been induced by excitotoxin.19 Possible mechanisms of action for safinamide’s potential neuroprotective properties are MAO-B inhibition20 and reduction in glutamate release.10,11
The efficacy and safety of safinamide has been evaluated in clinical studies as add-on therapy to dopamine agonists (DA) in early-stage PD21–23 and as add-on to LD (with possibly other anti-Parkinson’s drugs) in mid- to late-stage PD.24–26
Evidence from Healthy Volunteers
Four clinical trials in male, healthy volunteers, which included a food interaction trial, covering doses from 25 µg/kg to 10 mg/kg were carried out to investigate the pharmacokinetics, pharmacodynamics and tolerability of safinamide, administered in single or repeated doses to steady state.27 The trials showed that near complete inhibition of MAO-B is achieved with a safinamide dose of 0.3 mg/kg and that enteral absorption of the drug is linear and proportional to the doses administered. The drug is cleared from the body with a half-life (t1/2) approximately equal to 22 h, without producing any clinically relevant accumulation at steady state. No evident MAO-A inhibition was observed at doses up to 10 mg/kg.
In an investigation of the absorption, disposition, elimination and metabolic pathways, a single oral dose of 400 mg 14C-safinamide (as methanesulphonate salt), uniformly labelled in metabolically stable positions, was administered to healthy volunteers.28 Six male, non-smoking healthy male volunteers were included. Maximum concentration was achieved at 1 h (plasma, median Tmax) for parent drug and at 7 and 1.5 h for plasma and whole blood 14C radioactivity, respectively. Terminal t1/2 was about 22 h for unchanged safinamide. By contrast, 14C radioactivity decreased in a biphasic manner with a terminal t1/2 of 80 h. The differences in t1/2 observed between parent safinamide and 14C radioactivity in plasma can be explained by the presence of a varying mixture of metabolites that are cleared from the body compartments at different rates. Safinamide deaminated acid and the N-dealkylated acid were identified as major metabolites in urine and plasma. These results indicated that safinamide can be administered as a single daily dose.
Nonselective MAO inhibitors or MAO A inhibitors can lead to a life-threatening hypertensive crisis through the potentiation of peripheral adrenergic stimulation caused by tyramine ingested with food such as seasoned cheese or chicken liver, i.e. the ‘cheese effect’.29 To assess the risk of inducing this cheese effect, the effect of safinamide on the pressor response to tyramine was compared with placebo in healthy male volunteers.30 The amount of tyramine needed to reach a blood pressure increase was the same after safinamide 2 mg/kg oral load versus placebo, suggesting that dietary restrictions for food high in tyramine should not be necessary with safinamide treatment. Furthermore, in healthy volunteers safinamide 300 mg administered o.d. under fasting conditions did not change the tyramine pressor response at steady state after 6–7 days of treatment.31