Safinamide Mesylate

Pharmacological Actions and Potencies

Reversible Inhibition of Monoamine Oxidase B (MAO-B): Safinamide acts as a selective and reversible inhibitor of MAO-B, an enzyme responsible for dopamine degradation. This action increases dopamine levels in the brain, enhancing dopaminergic activity. The IC50 for MAO-B inhibition is consistently reported as 98 nM, with a selectivity ratio over MAO-A of approximately 5918-fold, indicated by an MAO-A IC50 of 580 μM. This high selectivity reduces the risk of hypertensive crises associated with non-selective MAO inhibitors.
Blockade of Voltage-Dependent Sodium Channels: Safinamide also blocks voltage-dependent sodium channels, with a noted IC50 of 8 μM at depolarized potentials and 262 μM at resting potentials. This use- and frequency-dependent blockade suggests a preference for active neuronal states, potentially contributing to its effects on neuronal excitability and neurotransmitter release.
Blockade of N-Type Calcium Channels: The drug is known to block N-type calcium channels, a subtype critical for neurotransmitter release. However, specific IC50 values for this action were not found in the reviewed literature, indicating a gap in detailed potency data. This mechanism likely contributes to its neuroprotective effects by modulating calcium-dependent processes.
Inhibition of Glutamate Release: Safinamide inhibits glutamate release, with an IC50 of 8 μM, which may be a downstream effect of its sodium and calcium channel blockade. This action is particularly relevant in Parkinson's disease, where excessive glutamatergic activity can exacerbate motor symptoms and contribute to neuronal damage.

Pharmacokinetic Properties

Half-Life: The terminal half-life ranges from 20 to 26 hours, allowing for sustained effects and steady-state concentrations achieved within 5-6 days of consistent dosing. This duration supports its use in maintaining therapeutic levels over extended periods.
Bioavailability: Oral bioavailability is reported at 95%, with no significant first-pass metabolism. Food slightly delays the time to maximum concentration (Tmax, 2-3 hours) but does not affect the area under the curve (AUC) or maximum concentration (Cmax), ensuring reliable absorption.
Distribution and Metabolism: The volume of distribution at steady state (Vss) is approximately 165 L, with an unbound fraction of 11-12%. Metabolism primarily occurs via non-microsomal cytosolic amidases and minor CYP3A4 activity, producing inactive metabolites like NW-1689 (161% parent exposure), NW-1689 AG (18%), and NW-1153 (11%). Excretion is predominantly renal (76%), with 5% excreted unchanged.
Special Populations: No significant effects on pharmacokinetics were noted for age, race, sex, or renal impairment. However, hepatic impairment increases exposure, with mild impairment raising AUC by 30% and moderate by 80%, necessitating dosage adjustments (maximum 50 mg/day in moderate hepatic impairment, contraindicated in severe).

Dosage and Safety Considerations

Recommended Dosage Range: The standard dosage is 50-100 mg once daily, initiated at 50 mg and potentially increased after two weeks based on individual response and tolerability. Dosages above 100 mg daily have not shown additional benefits and may increase the risk of hypertensive reactions, particularly in the context of MAO-B inhibition.
Minimum Effective Dose: Clinical studies, such as the SETTLE and MOTION trials, indicate that 50 mg/day is effective, improving ON-time without troublesome dyskinesias and motor function, making it the minimum effective dose.
Maximum Safe Dose: The maximum recommended dose is 100 mg/day, as higher doses are not advised due to potential increased adverse effects without therapeutic gain. This is supported by pharmacodynamic data showing no additional benefit and increased risk at higher doses.
LD50 and Toxicity Thresholds: Specific LD50 values for Safinamide were not found in public literature, and there is no human experience with overdose reported. Preclinical toxicology data from the EMA assessment report indicate adverse effects at high doses in animals (e.g., convulsions at ≥70 mg/kg/day in monkeys, hepatotoxicity at NOAEL 45 mg/kg/day in rats), but these do not translate directly to human LD50. Overdose symptoms, as noted in clinical observations, include hypertension, hallucinations, and dyskinesia, with no specific antidote available, requiring supportive care and dietary tyramine restriction for several weeks post-overdose.
When It Starts to Become Too Dangerous: Doses exceeding 100 mg/day are considered potentially dangerous, as they increase the risk of adverse effects without additional benefit, based on clinical trial data and regulatory guidance. However, exact thresholds for severe toxicity are not well-defined due to limited overdose data.

Summary of Pharmacological and Pharmacokinetic Parameters

Parameter	Value
MAO-B Inhibition IC50	98 nM
MAO-A Inhibition IC50	580 μM
Sodium Channel Blockade IC50	8 μM (depolarized), 262 μM (resting)
Calcium Channel Blockade IC50	Not available
Glutamate Release Inhibition IC50	8 μM
Half-Life	20-26 hours
Oral Bioavailability	95%
Recommended Dosage Range	50-100 mg/day
Minimum Effective Dose	50 mg/day
Maximum Safe Dose	100 mg/day
LD50	Not available