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Zelepar: fast-dissolving selegiline tablets » Larry Hoover

Posted by jrbecker on November 3, 2004, at 14:31:43

In reply to Re: Is taking Selegiline under tongue = to patch form? » pseudonym, posted by Larry Hoover on October 28, 2004, at 9:20:56

you might also want to consider trying the new fast-dissolving tablet form of selegiline that is supposed to significantly avoid metabolite accumulation....that is, if it ever comes to market. Amarin Corp recently sold this approvable drug formulation to Valeant Inc. It'll be a while to see if they will attempt to bring it to the drugstore shelf.


http://www.selegiline.com/zydis.html

NEUROLOGY
Volume 63(7) Supplement 2 12 October 2004

pp S2-S6
A novel formulation of selegiline for the treatment of Parkinson’s disease
[Articles]
Tetrud, James W. MD; Koller, William C. MD

From the Parkinson’s Institute, Sunnyvale, California (Dr. Tetrud); and Department of Neurology, Mount Sinai Medical Center, New York, New York (Dr. Koller).
Publication of this supplement was supported by an unrestricted educational grant from Valeant Pharmaceuticals International.
Address correspondence and reprint requests to Dr. James W. Tetrud, The Parkinson’s Institute, 1170 Morse Avenue, Sunnyvale, CA 94089.


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130 K
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Library Holdings


History...
A novel formulation of se...

Outline
Zydis formulations.

Pharmacokinetics.

Pharmacodynamics.

Clinical studies.

Discussion.

Practical considerations and future directions.

References

Graphics
Figure. Metabolite l...

Table 1

Table 2

Table 3


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In the early 1960s, when levodopa was undergoing initial clinical trials in Europe and North America as treatment for Parkinson’s disease (PD), nonselective monoamine oxidase (MAO) inhibitors were used in an attempt to potentiate the effect of levodopa.1,2 However, life-threatening fluctuations in blood pressure prompted early termination of these trials.3 In 1965, Knoll et al.4 developed an irreversible inhibitor of MAO with relative specificity for the B form of the enzyme.5 This new drug, isopropyl-methyl-propargylamine (E-250, Eldepryl®, deprenyl, selegiline), provided for the first time an MAO inhibitor that avoided the so-called “cheese effect” (tyramine-induced sympathomimetic side effects such as hypertension and tachycardia) and allowed its use along with levodopa in the treatment of PD without the need for dietary restrictions. At daily doses of 10 mg, selegiline was shown to inhibit 90% of brain MAO-B, whereas at daily doses above 20 mg the drug was shown to lose selectivity.6,7 Therefore, in most studies, daily oral doses have ranged from 5 to 10 mg.

Based on evidence that selegiline was a selective inhibitor of MAO-B, avoided the cheese effect, and could be used safely with levodopa, clinical trials were initiated in the early 1970s, assessing the drug’s benefit as adjunctive therapy in patients with PD.8–13 These studies clearly demonstrated that selegiline was safe and significantly improved “on” time in PD patients experiencing end-of-dose “wearing off.” However, certain levodopa-related side effects, such as nausea, psychosis, orthostatic hypotension, and dyskinesia, prompted reduction of levodopa, thus negating some of the levodopa-potentiating effects of the drug.

Whereas most of these studies assessed relatively short-term effects of selegiline, Birkmayer et al.15 conducted a retrospective evaluation of patients treated long-term with selegiline and levodopa compared to those treated with levodopa alone. From this analysis, they concluded that the patients treated with selegiline lived, on average, 14 months longer, suggesting that long-term MAO inhibition could slow the progression of PD.15 That same year, several IV drug users developed acute parkinsonism after injection of a “synthetic opioid” contaminated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin that causes a syndrome in humans and nonhuman primates indistinguishable from PD.16,17 It was soon discovered that MPTP itself was not toxic but was metabolized in the brain by MAO-B to 1-methyl-4-phenylpyridinium (MPP+), which is now known to enter dopamine (DA) neurons inhibiting complex I of the mitochondrial respiratory chain, causing dopaminergic neuron death.18,19 Furthermore, this bioconversion of MPTP to MPP+ was found to be completely inhibited by pargyline, a mixed MAO-A and MAO-B inhibitor, as well as selegiline, and completely prevented MPTP-induced parkinsonism in nonhuman primates.20,21 These two independent observations, one a retrospective clinical study and the other in a laboratory model of PD, stimulated considerable interest in study of the neuroprotective properties of selegiline. What further peaked interest in this drug was the emerging belief that dopaminergic neuron degeneration might be hastened by generation of oxyderived free radicals resulting from DA metabolism and that MAO-B inhibition with selegiline could reduce this oxidative stress.22 These lines of reasoning soon led to studies designed to test the hypothesis that selegiline might slow the progression of PD.23,24 Understandably, the notion that selegiline could be neuroprotective took precedence over the symptomatic properties of the drug. Therefore, other than the 1970s studies assessing selegiline as adjunctive treatment for PD, few studies have assessed its symptomatic properties.

Recent advances in drug delivery have led to the development of a novel transmucosal form of selegiline that appears to have advantages over the conventional oral form of the drug. This new formulation (Zydis selegiline) is a fast-dissolving dosage form in a unique freeze-dried tablet that does not require water to aid swallowing. When Zydis tablets are put into the mouth, the freeze-dried structure disintegrates instantaneously and releases the drug, which dissolves in the saliva.25

Zydis formulations.
A number of marketed drugs utilize the Zydis orally disintegrating dosage form. For example, Zydis Zyprexa, Klonopin wafers, and Claritin RediTabs are available as Zydis preparations. This technique of drug delivery employs the method of rapid freezing. The drug becomes interlaced as tiny crystals in a matrix of gelatin spindles, allowing rapid disintegration on contact with saliva. Most drugs formulated as Zydis tablets are swallowed, and the drug is absorbed in the normal way. Selegiline, however, is unique among the Zydis preparations in that it has a low molecular weight and a suitable pKa to allow transmucosal absorption through the buccal tissues.25 Therefore, selegiline is absorbed via the buccal mucosa directly into the systemic circulation, bypassing the gut and first-pass hepatic metabolism. The result is increased levels of selegiline and considerable reduction of amphetamine-like metabolites (figure) compared to conventional selegiline tablets.

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Figure. Metabolite levels of Zydis selegiline and conventional selegiline.34

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Pharmacokinetics.
As a result of Zydis selegiline’s transmucosal absorption, the pharmacokinetic profile is different from that of conventional orally delivered selegiline. Table 1 shows the bioavailability of selegiline after a dose of conventional selegiline 10 mg and Zydis selegiline 10 mg. A study was conducted to assess the amount of drug absorbed 1 minute after a Zydis selegiline tablet was taken. This study assessed drug absorption using three different formulations of selegiline each in one of three groups of patients: conventional selegiline 10 mg, Zydis selegiline 10 mg buccally absorbed, then swallowed, and Zydis selegiline 10 mg buccally absorbed, then expectorated after 1 minute. The results showed that 30% of the 10-mg Zydis selegiline dose was buccally absorbed after 1 minute.26 Additional time points were not evaluated.

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Table 1 Pharmacokinetic values of Zydis selegiline and conventional selegiline34

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The plasma levels (Cmax) of selegiline are much higher with the Zydis selegiline preparation than with the conventional formulation of selegiline. When lower doses of Zydis selegiline are used (1.25 mg and 2.5 mg), maximal plasma levels of selegiline are also achieved more rapidly than with conventional oral selegiline 10 mg. These differing pharmacokinetic profiles differentiate the two products. These two formulations of selegiline are not bioequivalent, nor can one be substituted for the other. Conventional selegiline undergoes extensive first-pass metabolism. Desmethylselegiline and l-amphetamine are the main metabolites. As would be expected, the metabolite levels after a dose of conventional selegiline are much higher than those after Zydis selegiline. Although the effect of these metabolites is unknown, there has been concern that they might have detrimental properties ranging from neurotoxicity to cardiovascular effects.27

Pharmacodynamics.
MAO exists in two forms, type A and type B. MAO-A is found extraneuronally and within the presynaptic dopaminergic terminals. MAO-B is confined to the extraneuronal compartment, preferentially in the glia and astrocytes.28,29 MAO-B metabolizes B-phenylethylamine (PEA) to B-phenylacetic acid, whereas MAO-A metabolizes 5-hydroxytryptamine (5-HT) to 5-hydroxyindole acetic acid (5-HIAA). Zydis selegiline increases PEA levels without changing 5-HIAA concentrations indicating that it is a selective MAO-B inhibitor.26 Table 2 summarizes the pharmacokinetics and pharmacodynamics of Zydis selegiline compared to selegiline. These properties of Zydis selegiline make it a unique compound in the treatment of PD. The drug at higher doses may have even greater potential to improve PD symptoms by inhibiting brain MAO-A activity.

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Table 2 Comparison of Zydis selegiline and conventional selegiline25,26

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Clinical studies.
To assess the effects of Zydis selegiline, a 3-month, randomized, placebo-controlled, multicenter study was undertaken by the Zydis Selegiline Study Group.30 Patients with PD, treated with levodopa and experiencing at least 3 hours of “off” time per day were recruited for the study. Exclusionary drugs included selegiline, COMT-inhibitors, opioid analgesics, and selective serotonin reuptake inhibitors; however, anticholinergics and dopamine agonists were allowed. Patients with severe depression, psychosis, and dementia (Mini Mental State Examination score less than 24) were excluded. The primary end point of the study was the percent change in total daily “off” time over 12 weeks of the study based on the subjects’ recording in home diaries (i.e., average percentage “off” time recorded at weeks 10 and 12 compared to average “off” time at weeks –2 and –1). Subjects were instructed to complete the home diary on 2 separate days the week before each scheduled visit and to record in 30-minute intervals if they were “on,” “off,” “on” with dyskinesia, or “asleep.” Secondary end points included reduction in hours “off,” changes in the Activities of Daily Living (ADL) and motor performance subscales of the Unified Parkinson’s Disease Rating Scale (UPDRS), Clinical Global Impression (CGI), and Patients Global Impression (PGI). All subjects underwent oropharyngeal examinations at baseline and at the end of the study by a dentist or oral surgeon to assess any mucosal adverse effects of the drug. Patients were randomized using a 2:1 ratio of Zydis selegiline to placebo. Initially they were administered 1.25 mg/day of Zydis selegiline or placebo. At week 6, the dose was increased to 2.5 mg/day for the remainder of the study.

A total of 140 subjects (94 Zydis selegiline, 46 placebo) were randomized, and there were no statistically significant differences in subjects’ demographics at baseline. There were seven early withdrawals in the Zydis selegiline group (three adverse events, two protocol violations, one lack of efficacy, and one lost to follow-up) and one in the placebo group (adverse effect). A summary of the results is shown in table 3. By week 12, the total “off” time was reduced by 2.2 hours and the “on” time without dyskinesia increased by 1.8 hours in the Zydis selegiline group compared to a reduction of 0.6 hours “off” and an increase of 0.4 hours “on” without dyskinesia in the placebo group. There was no statistically significant difference in the “on” time with dyskinesia between the two groups, and mandatory reduction of levodopa was not required. The CGI and PGI both showed statistically significant improvement in the Zydis selegiline group compared to the placebo group. Motor “on” and “off” scores were significantly better for the Zydis selegiline group at week 6. Motor “off” maintained significance at week 12. Twenty-nine percent of all patients (both groups) reduced their levodopa dose. The percentage change from baseline was 20% for the Zydis selegiline group and 10% for the placebo group. Levodopa dose reductions were not due to dyskinesias as adverse events. Adverse effects in the Zydis selegiline group regarded as drug related included dizziness (6), dyskinesia (4), hallucinations (4), headache (4), and dyspepsia (4). Serious adverse effects in the Zydis selegiline group included chest pain, arthritis, and myasthenia, none of which was regarded as due to the study drug. There were no reported cases of drug-related cardiac arrhythmias or hypertensive events in either arm of the study. There were few clinically significant abnormal lab value changes.

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Table 3 Average daily awake hours “on” without dyskinesia, “on” with dyskinesia, and “off”30

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A responders’ analysis was performed to determine the percentage of patients who had >=1 hour, >=2 hours, and >=3 hours of reduced “off” time. The clinical relevance of the primary end point data was confirmed by this analysis, which showed that daily “off” time decreased by at least 1 hour in 66% of patients in the ZS group (36.2% PB; p < 0.001), by at least 2 hours in 57.5% of patients in the ZS group (17% PB; p < 0.001), and by at least 3 hours in 37.2% of patients in the ZS group (8.5% PB; p < 0.001).34

Discussion.
Reviews of previous studies of conventional selegiline indicate that, although the drug was effective in prolonging the “on” time of PD patients, levodopa-associated side effects, such as nausea, psychosis, and dyskinesia, prompted reduction in the levodopa dose. In this study, Zydis selegiline resulted in an overall reduction in “off” time by an average of 2.2 hours or about 30% compared to placebo, without significantly increasing dyskinesia or the need for mandatory reduction of levodopa. These findings are comparable to those for other anti-parkinsonian drugs used as adjunctive therapy.

Based on the results of this study, Zydis selegiline appears as effective as the DA agonists and entacapone when used as adjunctive therapy to reduce “off” time. The surprising result from this study was that dyskinesia did not worsen, unlike results of studies using the conventional oral form of selegiline. Presumably, inhibition of MAO-B should increase available DA in the brain in both cases. However, with transmucosal absorption of selegiline and avoidance of first-pass metabolism, Zydis selegiline may result in increased levels of selegiline in the brain. Furthermore, DA is equally well deaminated oxidatively by MAO-A and MAO-B. If larger amounts of Zydis selegiline could safely be delivered to the brain while avoiding significant passage through the gut and liver, it may be possible to inhibit MAO-A and MAO-B in the brain without the cheese effect.

Further studies will be required to evaluate the long-term efficacy of Zydis selegiline.

Practical considerations and future directions.
Zydis selegiline is an important new addition to the PD armamentarium. It has shown benefit in reducing “off” time as an adjunctive treatment and is especially useful for patients with swallowing difficulties and/or predisposition to development of dyskinesias. Patients should be instructed to place Zydis selegiline on the tongue. The tablet is flavored with an artificial grapefruit taste and dissolves almost immediately on contact with saliva. Therapy should be initiated with 1.25 mg or 2.5 mg daily; however, increased efficacy has been shown with the 2.5 mg daily dose. Therapeutic effect may be evident within 1 week of therapy.

It is important to note that Zydis selegiline and conventional oral selegiline are not bioequivalent and hence cannot be substituted dose for dose. Because Zydis selegiline does not undergo first-pass metabolism, levels of plasma selegiline are much higher than with the conventional formulation.

Up to 50% of PD patients experience depression.31 In the Zydis selegiline clinical study, selective serotonin reuptake inhibitors (SSRIs) were excluded but tricyclic antidepressants (TCAs) were allowed. The question of whether to begin antidepressant treatment in a PD patient taking Zydis selegiline has not been extensively studied. However, practically speaking, although there is a possibility for increased serotonin levels when an MAO-B inhibitor and an SSRI are combined, clinical experience suggests that these compounds are safe to be used together if both the patient and the treating physician are aware of the potential risks involved.32,33

Due to its novel properties of transmucosal drug delivery and higher plasma levels of selegiline, there is great interest in further study of the use of Zydis selegiline beyond PD adjunctive therapy in phase IV clinical trials. Its use as monotherapy and as a neuroprotective compound needs to be elucidated. In addition, it is possible that higher doses may provide greater reduction in “off” time for PD patients and may also show some effect in the treatment of depression. It would also be of interest to study its effect on nonmotor symptoms (e.g., anxiety, somnolence), quality of life, and freezing of gait.

References
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2. Birkmayer W, Hornykiewicz O. The L-3,4-dioxyphenylalanine (DOPA)-effect in Parkinson-akinesia. Wien Klin Wochenschr 1961;73:787–788. [Context Link]

3. Birkmayer W, Mentasti M. Features of medical therapy of Parkinson’s syndrome [in German]. Wien Klin Wochenschr 1962;74:700–702. [Context Link]

4. Knoll J, Ecseri Z, Kelemen K, et al. Phenylisopropylmethylpropinylamine (E-250), a new spectrum psychic energizer. Arch Int Pharmacodyn Ther 1965;155:154–164. Library Holdings Bibliographic Links [Context Link]

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10. Birkmayer W, Riederer P, Youdim MB, et al. The potential of the anti akinetic effect after L-dopa treatment by an inhibitor of MAO-B, Deprenil. J Neural Transm1975;36:303–326. [Context Link]

11. Lees AJ, Shaw KM, Kohout LJ, et al. Deprenyl in Parkinson’s disease. Lancet. 1977;2:791–795. Library Holdings Bibliographic Links [Context Link]

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13. Csanda E, Antal J, Antony M, Csanaky A. Experiences with L-deprenyl in parkinsonism. J Neural Transm 1978;43:263–269. [Context Link]

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15. Birkmayer W, Knoll J, Riederer P, Youdim MB. (-)-Deprenyl leads to prolongation of L-dopa efficacy in Parkinson’s disease. Mod Probl Pharmacopsychiatry 1983;19;170–176. Library Holdings Bibliographic Links [Context Link]

16. Langston, JW, Ballard P, Tetrud JW, Irwin I. Chronic parkinsonism in humans due to a product of meperidine-analog synthesis. Science 1983;219:979–980. Library Holdings Bibliographic Links [Context Link]

17. Burns RS, Chiueh CC, Markey SP, et al. A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydopryidine. Proc Natl Acad Sci USA 1983;80:4546–4550. [Context Link]

18. Chiba K, Trevor AJ, Castagnoli N, et al. Active uptake of MPP+, a metabolite of MPTP, by brain synaptosomes. Biochem Biophys Res Commun 1985;128:1228–1232. Library Holdings Bibliographic Links [Context Link]

19. Langston JW, Irwin I, Langston EB, et al. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): identification of a metabolite of MPTP, a toxin selective to the substantia nigra. Neurosci Lett 1984;48:87–92. [Context Link]

20. Langston JW, Irwin I, Langston EB, et al. Pargyline prevents MPTP-induced parkinsonism in primates. Science 1984;225:1480–1482. Library Holdings Bibliographic Links [Context Link]

21. Mytilineou C, Cohen G. Deprenyl protects dopamine neurons from the neurotoxic effect of 1-methyl-4-phenylpyridinium. J Neurochem 1985;45:1951–1953. Library Holdings Bibliographic Links [Context Link]

22. Cohen G. The pathobiology of Parkinson’s disease: biochemical aspects of dopamine neuron senescence. J Neural Transm Suppl 1983;19:103. Abstract. [Context Link]

23. Tetrud JW, Langston JW. The effect of deprenyl (selegiline) on the natural history of Parkinson’s disease. Science 1989;245:519–522. [Context Link]

24. Parkinson’s Study Group. DATATOP: a multicenter controlled clinical trial in early Parkinson’s disease. Arch Neurol 1989;46:1052–1060. [Context Link]

25. Seager H. Drug-delivery products and the Zydis fast-dissolving dosage form. J Pharm Pharmacol 1997;50:375–382. [Context Link]

26. Clarke A, Brewer F, Johnson ES, et al. A new formulation of selegiline: improved bioavailability and selectivity for MAO-B inhibition. J Neural Transm 2003;110:1241–1255. [Context Link]

27. Ricaurte GA, Seiden LS, Schuster CR. Further evidence that amphetamines produce long-lasting dopamine neurochemical deficits by destroying dopamine nerve terminals. Brain Res 1984;303:359–364. Full Text Library Holdings Bibliographic Links [Context Link]

28. Sieradzan K, Channon S, Ramponi C, et al. The therapeutic potential of moclobemide, a reversible selective monoamine oxidase A inhibitor in parkinson’s disease. J Clin Psychopharmacol 1995;15(4 suppl 2):51S–59S. Ovid Full Text Library Holdings Bibliographic Links [Context Link]

29. Riederer P, Konradi C, Schay V, et al. Localization of MAO-A and MAO-B in human brain: a step in understanding the therapeutic action of L-deprenyl. Adv Neurol 1987;45:111–118. Library Holdings Bibliographic Links [Context Link]

30. Waters CH, Sethi KD, Hauser RA, et al. Zydis selegiline reduces “off” time in Parkinson’s disease patients with motor fluctuations: a 3-month, randomized, placebo-controlled study. Mov Disord 2004;19:426–432. [Context Link]

31. Dooneief G, Mirabello E, Bell K, et al. An estimate of the incidence of depression in idiopathic Parkinson’s disease. Arch Neurol 1992;49:305–307. Library Holdings Bibliographic Links [Context Link]

32. Richard IH, Kurlan R, Tanner C, et al. Serotonin syndrome and the combined use of deprenyl and an antidepressant in Parkinson’s disease. Neurology 1997;48:1070–1077. Ovid Full Text Library Holdings Bibliographic Links [Context Link]

33. Laine K, Anttila M, Heinonen E, et al. Lack of adverse interactions between concomitantly administered selegiline and citalopram. Clin Neuropharmacol 1997;20:419–433. Library Holdings Bibliographic Links [Context Link]


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