"New research links antipsychotic use to increased mortality in patients with Parkinson's disease (PD).
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Mechanism Of Action
Selegiline is an irreversible inhibitor of monoamine oxidase (MAO), which regulates the metabolic degradation of catecholamines and serotonin in the central nervous system and peripheral tissues. At recommended doses, selegiline is selective for MAO type B (MAO-B), the major form in the brain. Inhibition of MAO-B activity, by blocking the catabolism of dopamine, may result in increased dopamine levels; however, there is evidence that selegiline may act through other mechanisms to increase dopaminergic activity.
A pharmacodynamic study investigating daily ZELAPAR doses of 2.5 mg, 5 mg, and 10 mg for tyramine sensitivity showed that increased tyramine sensitivity resulting in increased blood pressure (because of MAO-A inhibition and decreased selectivity for MAO-B) occurred with dosing above the recommended level (2.5 mg daily). An increase in tyramine sensitivity for blood pressure responses appears to begin at a dose of 5 mg ZELAPAR daily [see WARNINGS AND PRECAUTIONS].
ZELAPAR disintegrates within seconds after placement on the tongue and is rapidly absorbed. Detectable levels of selegiline from ZELAPAR have been measured at 5 minutes after administration, the earliest time point examined.
Selegiline is more rapidly absorbed from the 1.25 or 2.5 mg dose of ZELAPAR (Tmax range: 10-15 minutes) than from the swallowed 5 mg selegiline tablet (Tmax range: 40-90 minutes). Mean (SD) maximum plasma concentrations of 3.34 (1.68) and 4.47 (2.56) ng/mL are reached after single dose of 1.25 and 2.5 mg ZELAPAR compared to 1.12 ng/mL (1.48) for the swallowed 5 mg selegiline tablets (given as 5 mg bid). On a dose-normalized basis, the relative bioavailability of selegiline from ZELAPAR is greater than from the swallowed formulation.
The pre-gastric absorption from ZELAPAR and the avoidance of first-pass metabolism results in higher concentrations of selegiline and lower concentrations of the metabolites compared to the 5 mg swallowed selegiline tablet.
Plasma Cmax and AUC of ZELAPAR were dose proportional at doses between 2.5 and 10 mg daily.
When ZELAPAR is taken with food, the Cmax and AUC of selegiline are about 60% of those seen when ZELAPAR is taken in the fasted state. Since ZELAPAR is placed on the tongue and absorbed through the oral mucosa, the intake of food and liquid should be avoided 5 minutes before and after ZELAPAR administration [see DOSAGE AND ADMINISTRATION].
Up to 85% of plasma selegiline is reversibly bound to proteins.
Following a single dose, the median elimination half-life of selegiline was 1.3 hours at the 1.25 mg dose. Under steady-state conditions, the median elimination half-life increases to 10 hours. Upon repeat dosing, accumulation in the plasma concentration of selegiline is observed both with ZELAPAR and the swallowed 5 mg tablet. Steady state is achieved after 8 days.
Selegiline is metabolized in vivo to l-methamphetamine and N-desmethylselegiline and subsequently to l-amphetamine; which in turn are further metabolized to their hydroxymetabolites.
ZELAPAR also produces a smaller fraction of the administered dose recoverable as the metabolites than the conventional, swallowed formulation of selegiline.
In vitro metabolism studies indicate that CYP2B6 and CYP3A4 are involved in the metabolism of selegiline. CYP2A6 may play a minor role in the metabolism.
Following metabolism in the liver, selegiline is excreted primarily in the urine as metabolites (mainly as l-methamphetamine) and as a small amount in the feces.
Age: The effect of age on the pharmacokinetics of selegiline following ZELAPAR administration has not been adequately characterized.
Gender: There are no differences between male and female subjects in overall (AUC∞), time to maximum exposure (Tmax), and elimination half-life (t½) after administration of ZELAPAR. Female subjects have an approximate 25% decrease in Cmax compared to male subjects. However, since the overall exposure (AUC∞) is not different between the genders, this pharmacokinetic difference is not likely to be clinically relevant.
Race: No studies have been conducted to evaluate the effects of race on the pharmacokinetics of ZELAPAR.
Renal Impairment: Following once-daily dosing of ZELAPAR 2.5 mg to selegiline steady-state (10 days) in 6 subjects with mild renal impairment (CLcr > 50 to 89 mL/min) and in 6 subjects with moderate renal impairment (CLcr > 30 to 50 mL/min), AUC and Cmax of selegiline and desmethylselegiline were not substantially different from healthy subjects; however, methamphetamine and amphetamine exposures were increased by 3467% in subjects with moderate renal impairment. Following once-daily dosing of ZELAPAR 1.25 mg to steady-state (10 days) in 6 end-stage renal disease patients, off dialysis, selegiline exposure was not substantially different from that in healthy subjects, however methamphetamine and amphetamine exposures were increased approximately 4-fold compared to healthy subjects [see DOSAGE AND ADMINISTRATION and Use In Specific Populations].
Hepatic Impairment: Subjects with mild hepatic impairment (Child-Pugh score 5 to 6), received once-daily dosing of ZELAPAR 2.5 mg to selegiline until they attained steady-state (10 days). The AUC and Cmax of selegiline were 1.5-fold higher and the AUC and Cmax of the metabolite desmethylselegiline were 1.4-fold and 1.2-fold higher. In subjects with moderate hepatic impairment (Child-Pugh score 7 to 9), the AUC of selegiline and desmethylselegeline increased 1.5-fold and 1.8-fold, respectively, whereas the Cmax of selegiline and demethylselegiline were comparable to healthy subjects. Patients with severe hepatic impairment (Child-Pugh score > 9) had a 4-fold increased AUC of selegiline, 3-fold increased Cmax of selegiline, a 1.25-fold increased AUC of desmethylselegeline and 50% reduced Cmax of desmethylselegeline. Methamphetamine and amphetamine metabolite AUC values were not affected by liver dysfunction [see DOSAGE AND ADMINISTRATION and Use in Specific Populations].
Drug Interactions: No studies have been conducted to evaluate drug interactions on the pharmacokinetics of ZELAPAR.
Effect of CYP3A inhibitor itraconazole: Itraconazole (200 mg QD) did not affect the pharmacokinetics of selegiline (single 10 mg oral, swallowed dose).
Although adequate studies to investigate the effect of CYP3A4-inducers on selegiline have not been performed, drugs that induce CYP3A4 (e.g., phenytoin, carbamazepine, nafcillin, phenobarbital, and rifampin) should be used with caution.
Drug Interaction Studies
No drug interaction studies have been conducted to evaluate the effects of other drugs on the pharmacokinetics of ZELAPAR or the effect of selegiline on other drugs. In vitro studies have demonstrated that selegiline is not an inhibitor of CYP450 enzymes. Selegiline and two of its metabolites, methamphetamine and desmethylselegiline, have little or no potential to induce CYP1A2 and CYP3A4/5 under clinical conditions.
The effectiveness of ZELAPAR as an adjunct to levodopa/carbidopa in the treatment of Parkinson's disease was established in a multicenter, randomized, placebo-controlled trial (n=140; 94 received ZELAPAR, 46 received placebo) of three months' duration. Patients randomized to ZELAPAR received a daily dose of 1.25 mg for the first 6 weeks, and a daily dose of 2.5 mg for the last 6 weeks. All patients were treated with concomitant levodopa products and could additionally have been on concomitant dopamine agonists, anticholinergics, amantadine, or any combination of these during the trial. COMT (catechol-O-methyl-transferase) inhibitors were not allowed.
Patients with idiopathic Parkinson's disease receiving levodopa were enrolled if they demonstrated an average of at least 3 hours of “OFF” time per day on weekly diaries collected during a 2-week screening period. The patients enrolled had a mean duration of Parkinson's disease of 7 years, with a range from 0.3 years to 22 years.
At selected times during the 12-week study, patients were asked to record the amount of “OFF,” “ON,” “ON with dyskinesia,” or “sleep” time per day for two separate days during the week prior to each scheduled visit. The primary efficacy outcome was the reduction in average percentage daily “OFF” time during waking hours from baseline to the end of the trial (averaging results at Weeks 10 and 12). Both treatment groups had an average of 7 hours per day of “OFF” time at baseline. Table 2 shows the primary efficacy results. Patients treated with ZELAPAR had a 13% reduction from baseline in daily “OFF” time, compared with a 5% reduction for patients treated with placebo. ZELAPAR-treated patients had an average reduction from baseline of “OFF” time of 2.2 hours per day, compared with a reduction of 0.6 hours in placebo-treated patients.
Table 2: Mean Percentage Change from Baseline in Daily
“Off” Hours at End of Treatment (Average of Weeks 10 and 12) for
|Treatment||Change from Baseline|
Figure 1 shows the mean daily percent “OFF” time during treatment over the whole study period for patients treated with ZELAPAR vs. patients treated with placebo.
Figure 1: Mean daily percent “OFF” time during
treatment over the whole study period for patients treated with ZELAPAR vs.
patients treated with placebo
Dosage reduction of levodopa was allowed during this study if dopaminergic side effects, including dyskinesia and hallucinations, emerged. In those patients who had levodopa dosage reduced, the dose was reduced on average by 24% in ZELAPAR-treated patients and by 21% in placebo-treated patients.
No difference in effectiveness based on age (patients > 66 years old vs. < 66 years) was detected. The treatment effect size in males was twice that in females, but, given the size of this single trial, this finding is of doubtful significance.
Last reviewed on RxList: 9/29/2014
This monograph has been modified to include the generic and brand name in many instances.
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