Orally disintegrating Zydis selegiline (Zelapar®) was approved by the U.S. FDA in June of 2006 as an adjunct in the management of patients with PD being treated with carbidopa/levodopa, who exhibited deterioration in the quality of their response to this therapy. The recommended dose is 1.25 mg once a day, which can be increased to 2.5 mg once a day after six weeks if necessary. It is a sublingually absorbed preparation that dissolves rapidly on the tongue (88). This preparation is a drug impregnated, water-soluble polymer matrix that is rapidly absorbed through the oral mucosa. Nearly one-third of a Zydis selegiline 10 mg dose is absorbed pregastrically within one minute in healthy volunteers (89). Zydis selegiline produces nearly five times higher plasma selegiline concentrations and significantly lower (>90%) plasma concentrations of selegiline metabolites compared with oral selegiline (89). Mucosal absorption of the drug bypasses most of selegiline's metabolism to amphetamine compounds such that smaller doses equally inhibit central nervous system MAO-B without compromising systemic MAO-B specificity or accumulating amphetamine metabolites.
Clarke et al. (90) reported three studies of Zydis selegiline. In the first study, both 1.25 mg/day and 10 mg/day Zydis formulations were compared to oral selegiline 10mg/day. In those who switched from oral selegiline 10 mg/day to Zydis selegiline 1.25 mg/day, the mean adjusted total UPDRS score was improved slightly at 12 weeks (-2.50, P = 0.01); however, there was no difference in subjects who switched from oral selegiline 10 mg/day to Zydis selegiline 10 mg/day. In the second study, more PD patients preferred the Zydis formulation to standard oral selegi-line irrespective of swallowing and salivation problems (90). Tyramine pressor effect was measured in healthy volunteers in the third study (90). After 14 days of Zydis selegiline 1.25 mg/day, there was no change in pressor response to 400 mg of tyramine. In contrast, after 14 days of oral selegiline 10 mg/day, the threshold for pressor response was reduced to 200 mg of tyramine (90).
In a three-month study (91), Zydis selegiline significantly reduced off time. PD patients (n = 144) with a minimum of three hours daily off time were randomized 2:1 to Zydis selegiline or placebo. Initial dosage of Zydis selegiline was 1.25 mg/day, and this was increased to 2.5 mg/day at week 6. Overall, the drug was well tolerated and over 90% of each group completed the trial. Drug-related adverse events occurred in 32% of Zydis selegiline and 21% of placebo subjects. The most frequent adverse events in the Zydis selegiline group were dizziness, dyskinesia, hallucinations, headache, and dyspepsia. At weeks 4 to 6, off time was reduced 1.4 hours with Zydis selegiline 1.25 mg/day compared with 0.5 hours for placebo (P = 0.003); at weeks 10 to 12, off time was reduced by 2.2 hours with Zydis selegiline 2.5 mg/day compared with 0.6 hours for placebo (P < 0.001). Dyskinesia-free on time was also significantly increased at weeks 6 and 12. There was no significant difference in daily on time with dyskinesia in the Zydis and placebo groups at weeks 6 and 12. A second, identically designed trial did not show a significant decrease in off time with Zydis selegiline compared to placebo possibly due to a large placebo response. However, when the data of these two studies were pooled, there was a reduction in daily off time of 12.4% with Zydis selegiline versus a 6.9% reduction in the placebo group (P = 0.003) (92).
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