Chemical formula: C₁₇H₁₉FN₂O₂ Molecular mass: 302.349 g/mol PubChem compound: 131682
Safinamide acts through both dopaminergic and non-dopaminergic mechanisms of action. Safinamide is a highly selective and reversible MAO-B inhibitor causing an increase in extracellular levels of dopamine in the striatum. Safinamide is associated with state-dependent inhibition of voltage-gated sodium (Na+) channels, and modulation of stimulated release of glutamate. To what extent the nondopaminergic effects contribute to the overall effect has not been established.
Population PK models developed from studies in patients with Parkinson’s disease indicate that the pharmacokinetic and pharmacodynamics effects of safinamide were not dependent on age, gender, weight, renal function and exposure to levodopa, indicating that dose adjustments will not be required based on these variables.
Pooled analyses of adverse event data from placebo controlled studies in Parkinson’s disease patients indicate that the concomitant administration of safinamide together with a broad category of commonly used medicinal products in this patient population (antihypertensive, beta-blockers cholesterol lowering, non-steroidal anti-inflammatory medicinal products, proton pump inhibitors, antidepressants, etc.) was not associated with an increased risk for adverse events. Studies were not stratified for co-medication, and no randomized interaction studies were performed for these medicinal products.
Safinamide absorption is rapid after single and multiple oral dosing, reaching Tmax in the time range 1.8-2.8 h after dosing under fasting conditions. Absolute bioavailability is high (95%), showing that safinamide is almost completely absorbed after oral administration and first pass metabolism is negligible. The high absorption classifies safinamide as a highly permeable substance.
The volume of distribution (Vss) is approximately 165 L which is 2.5-fold of body volume indicating extensive extravascular distribution of safinamide. Total clearance was determined to be 4.6 L/h classifying safinamide as a low clearance substance.
Plasma protein binding of safinamide is 88-90%.
In humans, safinamide is almost exclusively eliminated via metabolism (urinary excretion of unchanged safinamide was <10%) mediated principally through high capacity amidases, that have not yet been characterized. In vitro experiments indicated that inhibition of amidases in human hepatocytes led to complete suppression of the NW-1153 formation. Amidase present in blood, plasma, serum, simulated gastric fluid and simulated intestinal fluid as well as human carboxylesterases hCE-1 and hCE-2 are not responsible for the biotransformation of safinamide to NW-1153. The amidase FAAH was able to catalyse the formation of NW-1153 at low rates only. Therefore, other amidases are likely to be involved in the conversion to NW-1153. Safinamide’s metabolism is not dependent on Cytochrome P450 (CYP) based enzymes.
Metabolite structure elucidation revealed three metabolic pathways of safinamide. The principal pathway involves hydrolytic oxidation of the amide moiety leading to the primary metabolite ‘safinamide acid’ (NW-1153). Another pathway involves oxidative cleavage of the ether bond forming ‘O-debenzylated safinamide’ (NW-1199). Finally the ‘N-dealkylated acid’ (NW-1689) is formed by oxidative cleavage of the amine bond of either safinamide (minor) or the primary safinamide acid metabolite (NW-1153) (major). The ‘N-dealkylated acid’ (NW-1689) undergoes conjugation with glucuronic acid yielding its acyl glucuronide. None of these metabolites are pharmacologically active.
Safinamide does not appear to significantly induce or inhibit enzymes at clinically relevant systemic concentrations. In vitro metabolism studies have indicated that there is no meaningful induction or inhibition of cytochrome P450, CYP2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A3/5 at concentrations which are relevant (Cmax of free safinamide 0.4 µM at 100 mg/day) in man. Dedicated drug-drug interaction studies performed with ketoconazole, L-dopa and CYP1A2 and CYP3A4 substrates (caffeine and midazolam), did not detect any clinically significant effects on the pharmacokinetics of safinamide, or L-dopa, caffeine and midazolam.
A mass balance study showed that the plasma AUC0-24h of the unchanged 14C-safinamide accounted for approximately 30% of the total radioactivity AUC0-24h, indicative of an extensive metabolism.
Preliminary in vitro studies have shown that safinamide is not a substrate for the transporters P-gp, BCRP, OAT1B1, OAT1B3, OATP1A2 or OAT2P1. Metabolite NW-1153 is not a substrate for OCT2, or OAT1, but it is substrate for OAT3. This interaction has the potential to reduce the clearance of NW1153 and increase its exposure; however the systemic exposure of NW-1153 is low (1/10 of parent safinamide), and as it is metabolised to secondary and tertiary metabolites, it is unlikely to be of any clinical relevance.
Safinamide transiently inhibits BCRP in the small intestine. At concentrations of 50µM, safinamide inhibited OATP1A2 and OATP2P1. The relevant plasma concentrations of safinamide are substantially lower, therefore a clinically relevant interaction with co-administered substrates of these transporters is unlikely. NW-1153 is not an inhibitor of OCT2, MATE1, or MATE2-K up to concentrations of 5µM.
The pharmacokinetics of safinamide are linear after single and repeated doses. No time-dependency was observed.
Safinamide undergoes almost complete metabolic transformation (<10% of the administered dose was found unchanged in urine). Substance-related radioactivity was largely excreted in urine (76%) and only to a low extent in faeces (1.5%) after 192 hours. The terminal elimination half-life of total radioactivity was approximately 80 hours.
The elimination half-life of safinamide is 20-30 hours. Steady-state is reached within one week.
Safinamide exposure in patients with mild hepatic disease increased marginally (30% in AUC), while in patients with moderate hepatic impairment exposure increased by approximately 80%.
Moderate or severe renal impairment did not alter the exposure to safinamide, compared to healthy subjects.
Retinal degeneration was observed in rodents after repeated safinamide dosing resulting in systemic exposure below the anticipated systemic exposure in patients given the maximal therapeutic dose. No retinal degeneration was noted in monkeys despite higher systemic exposure than in rodents or in patients at the maximum human dose.
Long-term studies in animals have shown convulsions (1.6 to 12.8 times human clinical exposure, based on plasma AUC). Liver hypertrophy and fatty changes were seen only in rodent livers at exposures similar to humans. Phospholipidosis was seen mainly in the lungs in rodents (at exposures similar to humans) and monkeys (at exposures greater than 12 fold higher than human).
Safinamide did not present genotoxic potential in in vivo and in several in vitro systems using bacteria or mammalian cells.
The results obtained from carcinogenicity studies in mice and rats showed no evidence of tumorigenic potential related to safinamide at systemic exposures up to 2.3 to 4.0 times respectively, the anticipated systemic exposure in patients given the maximal therapeutic dose.
Fertility studies in female rats showed reduced number of implantations and corpora lutea at exposures in excess of 3 times the anticipated human exposure. Male rats showed minor abnormal morphology and reduced speed of sperm cells at exposures in excess of 1.4 times the anticipated human exposure. Male rat fertility was not affected.
In embryo-foetal developmental studies in rats and rabbits malformations were induced at safinamide exposures 2 and 3-fold above human clinical exposure, respectively. The combination of safinamide with levodopa/carbidopa resulted in additive effects in the embryo-foetal development studies with a higher incidence of foetal skeletal abnormalities than seen with either treatment alone.
In a pre- and postnatal developmental rat study, pup mortality, absence of milk in the stomach and neonatal hepatotoxicity were observed at dose levels similar to the anticipated clinical exposure. Toxic effects on the liver and accompanying symptoms as yellow/orange skin and skull, in pups exposed to safinamide during lactation are mediated mainly via in utero exposure, whereas exposure via the mother’s milk had only a minor influence.
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