Pharmacodynamics

Selegiline (the drug substance of EMSAM) is an irreversible inhibitor of monoamine oxidase (MAO), an intracellular enzyme associated with the outer membrane of mitochondria. MAO exists as two isoenzymes, referred to as MAO-A and MAO-B. Selegiline has a greater affinity for MAO-B, compared to MAO-A. However, at antidepressant doses, selegiline inhibits both isoenzymes (see below).

The mechanism of action of EMSAM as an antidepressant is not fully understood, but is presumed to be linked to potentiation of monoamine neurotransmitter activity in the central nervous system (CNS) resulting from its inhibition of MAO activity. In an in vivoanimal model used to test for antidepressant activity (Forced Swim Test), selegiline administered by transdermal patch exhibited antidepressant properties only at doses that inhibited both MAO-A and MAO-B activity in the brain. In the CNS, MAO-A and MAO-B play important roles in the catabolism of neurotransmitter amines such as norepinephrine, dopamine, and serotonin, as well as neuromodulators such as phenylethylamine. Other molecular sites of action have also been explored and in this regard, a direct pharmacological interaction may also occur between selegiline and brain neuronal α_2B receptors. In in vitro receptor binding assays, selegiline has demonstrated affinity for the human recombinant adrenergic α_2B receptor (K_i = 284 µM). No affinity [K_i > 10 µM] was noted at dopamine receptors, adrenergic β3, glutamate, muscarinic M₁-M₅, nicotinic, or rolipram receptor/sites.

Pharmacokinetics

Absorption

Following dermal application of EMSAM to humans,25%-30% of the selegiline content on average is delivered systemically over 24 hours (range ~ 10%-40%).Consequently,the degree of drug absorption may be 1/3 higher than the average amounts of 6 mg to 12 mg per 24 hours.Transdermal dosing results in substantially higher exposure to selegiline and lower exposure to metabolites compared to oral dosing,where extensive first-pass metabolism occurs (Figure 2).In a 10-day study with EMSAM administered to normal volunteers,steady-state selegiline plasma concentrations were achieved within 5 days of daily dosing. Absorption of selegiline is similar when EMSAM is applied to the upper torso or upper thigh.Mean (95% CI) steady-state plasma concentrations in healthy men and women following application of EMSAM to the upper torso or upper thigh are shown in Figure 3.

Figure 2: Average AUC_inf (ng•hr/mL) of selegiline and the three major metabolites estimated for a single, 24-hour application of an EMSAM 6 mg/24 hours patch and a single, 10 mg oral immediate release dose of selegiline HCl in 12 healthy male and female volunteers.

Figure 3: Average plasma (± 95% CI) selegiline concentrations in healthy male and female volunteers at steady-state after application of EMSAM (selegiline transdermal system) 6 mg/24 hours to the upper torso.

Distribution

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