The safety of istradefylline for the treatment of Parkinson’s disease
Thomas Mu¨ller
St. Joseph Hospital Berlin-Weiti ensee, Department of Neurology, Berlin, Germany
Introduction: Antagonism of the A2A receptor improves motor behavior in patients with Parkinson’s disease (PD), according to results of clinical studies which confirm findings of previous experimental research. The xanthine derivative, istradefylline, has the longest half-life out of the available A2A receptor antagonists. Istradefylline easily crosses the blood– brain barrier and shows a high affinity to the human A2A receptor.
Areas covered: This narrative review aims to discuss the safety and tolerability of istradefylline against the background of the currently available drug port- folio for the treatment of PD patients.
Expert opinion: Istradefylline was safe and well tolerated in clinical trials, which have focused on L-DOPA-treated PD patients. The future of istradefyl- line as a complementary drug for modulation of the dopaminergic neuro- transmission also relies on its potential to act like an L-DOPA plus dopamine agonist sparing future treatment alternative and to reduce the risk of pre- dominant L-DOPA-related onset of motor complications in addition to its direct ameliorating effect on motor symptoms. Dopamine-substituting drugs may dose-dependently produce systemic side effects, particularly onset of hypotension and nausea by peripheral dopamine receptor stimulation. Istra- defylline does not interfere with these peripheral receptors and therefore shows a good safety and tolerability profile.
Keywords: adenosine, dopamine substitution, istradefylline, L-DOPA, Parkinson’s disease Expert Opin. Drug Saf. (2015) 14(5):769-775
1.Introduction
Parkinson’s disease (PD) is a chronic, progressive predominant higher age-related neurodegenerative disorder with an increasing prevalence that may amount up to 329 cases per 100,000 humans. Definitive causes and effect relationships for PD have not yet been found. Environmental factors such as exposure to toxic hydrocar- bons and heavy metals are under suspicion as possible risk factors for the develop- ment of PD. Pathological analyses of declined availability of nigrostriatal neurons have elucidated the correlation between the extent of dopamine deficiency and the qualitative severity of clinical signs and symptoms [1]. The main pathological fea- ture of PD is an individual varying sometimes gradual sometimes relapse like slowly increasing reduced production of dopamine and other preponderant bio- genic amines as a consequence of neuronal death in various brain areas. As a result, a variety of motor and non-motor symptoms occur in an individually pronounced fashion [1]. Disturbances of movement behavior such as tremor, increased muscle tone — the so-called rigidity — and slowness of movement termed as bradykinesia occur in combination with balance disturbances as main signs of the disease. The concept of dopamine depletion, which results in the onset of motor symptoms fol- lowing the estimated death of up to 75% of nigrostriatal neurons, was the rationale for the development of dopamine-substituting drugs. They improve symptoms such as tremor — particularly at rest-, muscle weakness and stiffness, gait problems, slowed movements, occupational problems such as gripping or writing, loss of
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Box 1. Drug summary.
Drug name (generic)
Istradefylline — (E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro- 1H-purine-2,6-dione
Phase (for indication under discussion) Approved in Japan, Phase III: rest of the world
Indication (specific to discussion) Parkinson’s disease
Pharmacology description/mechanism of action Expression of A2A receptors in the brain is predominantly in the basal
ganglia, especially in the striatum. At a receptor level, antagonism exists between A2A and D2 dopaminergic receptors and between A1 and D1 receptors. Dopamine allows initiation of movement and adenosine receptor stimulation antagonizes this effect
Route of administration Oral
Chemical structure
O
CH3
H
3
C
H
3
C
N
N
O
CH
3
O N
N O
CH
3
Pivotal trial(s) [16,17,42-44]
facial expression to a considerable extent but not postural imbalances [1]. Thus, the role of conventional therapies for PD is primarily to replace and support the neurotransmis- sion of dopamine. Early motor symptoms of the disease respond to conventional dopamine-replacement therapies. Drug-treatment strategies employ L-DOPA, orally applied in conjunction with the L-DOPA degradation slowing DOPA decarboxylase inhibitors and also optionally with catechol-O-methyltransferase inhibitors, dopamine augmen- tation therapies, specifically dopamine agonists, monoamino- oxidase (MAO)-B inhibitors and N-methyl-D-aspartate antagonists [2,3]. Particularly L-DOPA and to a lesser extent dopamine agonists are not without risks in the long term. These agents are related with the development of motor com- plications, especially when they are applied in a chronic fash- ion. These complications limit the efficacy of these agents, as patients develop a shortening response to each dose (‘wearing-off’ phenomenon), the experience or return of symptoms within the dosing interval (‘on-off’ phenomenon), and involuntary movements (‘dyskinesia’). These obstacles for a straightforward dopamine substitution ask for frequent adjustments in drug therapy via changes of dosing, addition of supplemental therapies, or the use or conversion to an alternative agent [3]. New treatment approaches are expected to result from the development of new brain targets that move the field away from the typical dopamine and dopa- mine agonist-based treatments [4]. One approach out of the ones with nondopaminergic targets for motor features in PD is to modulate dopaminergic neurotransmission via antagonizing of adenosine receptors [4,5].
1.1Objectives
This narrative review aims to discuss the safety of istradefyl- line (Box 1) against the background of current therapeutic approaches for drug therapy of PD.
2.Adenosine
Adenosine is synthesized from the hydrolysis of ATP. The actions of adenosine are triggered by G-protein-coupled receptors. They activate second messenger systems mediating effects. Four subtypes of adenosine receptors are known: A1, A2A, A2B and A3. The receptors A1 and A3 are associated with Gi proteins and inhibit adenylyl cyclase. The A2A and A2B receptors induce the activation of Gs proteins. They stimulate adenylyl cyclase and cyclic adenosine monophos- phate production. Adenosine primarily acts as a vasodilator through the activation of A2A receptors [6-8].
2.1Antagonizing the adenosine receptor
There exist over the time continuously modified, complex, partially hypothetical models on the circuits of the basal gan- glia. They are important for the regulation of movement exe- cution and are involved in the underlying mechanisms that cause symptoms of PD. The basal ganglia have a ton of A2A receptors. They are located on the outside of neurons and thus they are co-located next to dopamine receptors. Activa- tion of the dopamine receptor or as an alternative blocking of the A2A receptor is looked upon as promising approach to improve the symptoms of PD. The A2A receptor function may be affected by the intake of certain foods or drinks, such as caffeine-containing nutrients [9-11]. Animal experi- ments, human trials and epidemiological studies revealed a potential benefit of caffeine for PD. The benefit may result from the support proved by the action of caffeine to block the A2A brain receptor. Accordingly, caffeine and more spe- cific A2A antagonists attenuate symptoms in mouse models of PD. Expression of A2A receptors in the brain is predomi- nantly in the basal ganglia, especially in the striatum [9,11,12]. At a receptor level, antagonism exists between A2A and D2
770 Expert Opin. Drug Saf. (2015) 14(5)
dopaminergic receptors and between A1 and D1 receptors. Dopamine allows initiation of movement and adenosine receptor stimulation antagonizes this effect. There is accumu- lating evidence from experimental and clinical research that A2A receptor antagonists facilitate a reduction in the dosage of dopamine-substituting compounds and thus a coincident reduction in side effects of the compounds, particularly L-DOPA [13-15].
3.Istradefylline and competitors
Istradefylline is one of the various available A2A receptor antagonists that is already tested in clinical trials with PD patients. Generally, they show a mild beneficial effect on wearing off, respectively on motor fluctuations [16,17]. Istrade- fylline has only been approved for use in Japan to date and is currently undergoing a Phase III study program again. Caffeine is a nonselective blocker of adenosine receptors (A1, A2A, A2B and A3), early placebo-controlled crossover studies of caffeine as an adjunct to L-DOPA or a dopamine agonist in PD patients showed no motor effect of caffeine other than exacerbation of dyskinesia [18,19]. These small studies assessed caffeine at high doses (1100 mg/day, the equivalent of eight cups of brewed coffee/day). Most subjects reported restlessness and insomnia [18,19]. By contrast, another small study reported that caffeine at a much lower dose of 100 mg/day helped to improve freezing of gait, though tolerance to caffeine seemed to limit benefit [20]. The results of a randomized controlled trial of caffeine showed the value of caffeine as a potential treatment of dopamine replacement related excessive daytime sleepiness in PD and a mild benefit on motor behavior [21]. Another A2A receptor antagonist is tozadenant (SYN115), which also improved off time in clini- cal trials [22]. The adenosine A2A receptor antagonist Preladen- ant also relieved ‘off’ periods in Phase II trials, but three separate Phase III trials did not provide enough evidence for a better efficacy than placebo application [23]. This outcome was a result of high placebo effects in certain study centers. Their investigators probably included PD patients with high expectations to the study participation as a consequence to an insufficient optimized PD drug therapy. One may hypoth- esize, that low quality of country-specific health-care systems in general was the basis for this phenomenon. The develop- ment of Vipadenant was stopped and ST-1535 is still under investigation.
3.1Istradefylline: mechanisms of action in relation to L-DOPA
Istradefylline — (E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl- 3,7-dihydro-1H-purine-2,6-dione — shows high selectivity for A2A receptors > 60-fold in rats and 800-fold in humans in comparison with A1A receptors. The equilibrium dissociation constant (Ki value) was 12 nmol/l and the median inhibition concentration (IC50) was > 1000 nmol/l. Istradefylline showed minimal to no affinity for other receptors, including dopamine, noradrenaline,
5-hydroxytryptamine and acetylcholine receptors [24,25]. Carbon- 11-labeled istradefylline demonstrated saturable binding within the striatum. A2A receptors assist in the suppression of GABA release and transmission in the striatum while enhancing its release in the external globus pallidus. Istradefylline blocks A2A receptor stimulation with diminishing the over excitability of this path- way [26]. Blocking of the excessive excitation of this indirect path- way is under suspicion to lessen the motor complications associated with predominant application of L-DOPA with its short half-life. As a result, a pulsatile brain delivery of L-DOPA and after its presynaptic conversion to dopamine with pulsatile subsequent dopamine receptor stimulation occurs in the nigros- triatal system [27-29].
3.2Pharmacokinetics of istradefylline in relation to L-DOPA
The half-life of istradefylline receptor binding in humans was short (0.32 min), which illustrates a fast but reversible binding activity to A2A receptors. The elimination half-life of istrade-
fylline is ~ 47 h [30]. Istradefylline has the longest half-life of the current available A2A receptor antagonists and easily crosses the blood– brain barrier after oral application. A single-dose istradefylline study showed that the area under the curve and maximum concentration of drug in the serum follow a linear kinetic model with doses up to 400 mg daily. Istradefylline administered in a dose-escalated manner dem- onstrated linear pharmacokinetics over the dose range of 10 — 80 mg daily. Istradefylline did not change the pharmaco- kinetics of L-DOPA/carbidopa in 24 healthy volunteers, who took a single dose of L-DOPA/carbidopa (200/50 mg) either alone or after 2 weeks of treatment with a dose of istradefyl- line (80 mg/daily) [24,31,32]. Administration of L-DOPA/carbi- dopa either alone or after istradefylline treatment was safe and well tolerated; Istradefylline had no effect on the elimination of L-DOPA/carbidopa [33-36].
4.Istradefylline: safety in clinical trials
There are three meta-analysis available on the efficacy and the safety of this compound in the therapy of PD patients in ran- domized clinical trials [37-39]. All of them not only show a more or less moderate effect on wearing off phenomena in PD patients, but also describe the safety and tolerability pro- file of this compound [37-39]. However, one should consider at the present stage that clinical trials are nowadays predomi- nantly conducted in well-selected, nearly healthy study popu- lations excluding patients with severe or many concomitant morbidities. In the long run, this approach avoids polyphar- macy, description of serious interactions with other drugs at the stage before approval. From this point of view, com- pounds enter the real world of pharmacodynamic and phar- macokinetic interactions not before they are finally approved and used in the clinic. Istradefylline is already approved in Japan only. To date, case reports or post-marketing studies are not available with a special focus on side effects in
Expert Opin. Drug Saf. (2015) 14(5) 771
combination with other compounds yet [37-39]. This may sup- port the hypothesis that istradefylline appears to be safe and well tolerated also in the real world. This is not surprising since it was always tested and is currently applied in combina- tion with other available PD drugs. Istradefylline will mostly be used once dopamine agonists and L-DOPA have been introduced in the therapeutic concept for a PD patient with fluctuations, which predominantly result from chronic L-DOPA intake [40].
5.Comparison of the tolerability and safety of istradefylline with other PD drugs
Generally in clinical trials, the onset of adverse events of A2A receptor antagonists appeared to be less severe and frequent in comparison with L-DOPA and dopamine agonists, which is for instance in accordance with outcomes described in ani- mal models of psychosis [41]. It is also well known that dopa- mine agonists often support onset of edema, particularly when they applied in high dosages or when two of them are com- bined [3]. Further typical side effects related to dopamine sub- stitution are rare onset of impulse control disorders or frequent manifestations of nausea, dizziness and low blood pressure. The available trial outcomes with A2A receptor antagonists do not report, for example, a pronounced fall of blood pressure related to the A2A receptor antagonist [22,23,42-45]. This is not surprising since the mechanism of adenosine receptor antagonism rather counteracts low blood pressure. Hypotension is a problem particularly in advanced PD patients on a high dopamine substitution regimen. No notable differences appeared in systolic/diastolic blood pres- sure, heart rate or respiration rate in the published trials and meta-analyses with istradefylline [37-39]. These papers also report rates of side effects such as nausea, aggravation of dys- kinesia, dizziness and insomnia to a similar extent also observed in the placebo-treated PD patients on a dopamine- substituting drug regime [37-39]. These observations provide circumstantial evidence that these adverse events were likely more related to the supplemental dopaminergic drugs and not to istradefylline itself in these studies with advanced PD patients [46]. There are also concerns that particularly high dosing of L-DOPA accelerates the progression of PD. More recent clinical findings support this theory. They describe metabolic long-term side effects of L-DOPA, which may has- ten neuronal death in the CNS and peripheral nervous system in general and support onset of neuropsychiatric disorders, vascular changes and neuropathy [47-52]. However, another currently quite popular, more observational long-term register with results primarily based on patients’ questionnaires neglects with its somehow disillusioning and trivializing out- comes these L-DOPA long-term complications [53]. Other PD drugs, that is, the N-methyl-D-aspartate antagonist amantadine, and MAO-B inhibitors, particularly rasagiline, are generally well tolerated. Anticholinergics are only rarely used nowadays.
6.Conclusion
Istradefylline is a novel drug for the treatment of PD patients. In clinical trials, this compound was safe and well tolerated.
7.Expert opinion
The value of a drug for the treatment of PD is not only deter- mined by its effect on motor symptoms. The effect of istrade- fylline on motor behavior is often and well reviewed. In clinical practice, a newly approved compound should demon- strate its value also in the context of disease modification beyond experimental research; for instance, the need for addi- tional dopamine substituting drugs in PD in the long run. Moreover, its quality is also defined by its tolerability and safety in combination with other PD drugs in the long run.
7.1Experimental neuroproctection
Generally, there is some evidence from experimental research that A2A receptor antagonists may also be neuroprotective against toxic agents [54-56]. Both xanthine-based and non-xanthine-based A2A receptor antagonists reduced toxin- induced neuronal cell death in rodent models of PD. Other methylxanthines that effectively block A2A receptors (theophylline and paraxanthine) showed neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mice model of PD [54-56].
7.1.1Animal models of PD do not reflect chronicity of neurodegeneration in PD
A PD like syndrome in animals is mostly generated by a toxin injection causing dopamine depletion due to acute neuronal death in the nigrostriatal system, which does not mimic the slowly ongoing neuronal death in PD patients. Mostly, only one kind of metabolic pathway as cause for the chronic neuro- nal dying is investigated. However, it is well known that sev- eral kinds of neuronal death-causing mechanisms exist finally leading to the manifestation of the disease entity, sum- marized with the term PD. There are various PD subtypes characterized by an individually pronounced expression of motor and non-motor features. There is a lot of experimental research performed with each drug for PD to demonstrate a neuroprotective effect in the available various neuronal death models. Generally, the modes of action, how A2A receptor antagonists may weaken the neuronal death of dopaminergic neurons, are not known in detail yet. This experimental research often provides controversial results, for instance par- ticularly in the case of L-DOPA itself.
7.1.2Neuronal death acceleration by L-DOPA
As described above, long-term and high dosing of L-DOPA may induce clinical signs of neuronal death, for instance neu- ropathies. Thus, L-DOPA sparing with dopamine transmis- sion supporting compounds, such A2A antagonists, may
772 Expert Opin. Drug Saf. (2015) 14(5)
contribute to a better safety and less onset of long-term side effects of L-DOPA. Long-term trials in the clinic with a focus on L-DOPA need reducing strategies may describe these positive effects. For instance, a design similar to the SELEDO study may be employed for the demonstration of L-DOPA plus dopamine agonist-sparing effects. The SELEDO trial was a prospective, double-blind study, lasting 5 years and assessing the benefits of selegiline addition to L-DOPA ther- apy. First an optimum titration of L-DOPA to individual requirements was performed. Then the participants received either selegiline or placebo. Subsequent necessary L-DOPA dose escalation was dependent on the clinical status. The pri- mary endpoint was reached when the needed L-DOPA dose to control symptoms was 150% or more of the initial dose [57]. Such L-DOPA-sparing effects may support a certain resur- gence of the discussion on disease modification or neuro- protection with istradefylline against the background that long-term L-DOPA therapy may accelerate chronic neurode- generation, as described above. This scenario is also essential for the determination of the value of a compound in the treat- ment of PD.
7.2Less side effects and more safety of dopamine substitution by A2A antagonists?
Currently, there is accumulating evidence from clinical research that istradefylline is safe, well tolerated and not harm- ful in terms of accelerating the progression of PD. The clinical studies also showed tendencies by circumstantial evidence, that generally A2A receptor antagonists may provide some advantages particularly for PD patients, who are predisposed for a fall of blood pressure during therapy with dopamine ago- nists and/or L-DOPA. This is often a problem in clinical prac- tice and may support falls due to syncope. This drug-induced autonomic dysregulation is often accompanied by a feeling of dizziness. Therapeutic options for this syndrome are rare and compounds like midodrine only provide a limited benefit. However, prevention of hypotension due to lower dosing of dopamine-substituting drugs for instance with the concomi- tant use of istradefylline or other A2A receptor antagonists would represent an advantage in clinical practice. To date, there is a lack of convincing data from randomized clinical tri- als of the somewhat restrictive artificial study world with well- defined and selected study participants, for instance with the exclusion criterion of severe concomitant disorders. Future observational, naturalistic long-term investigations in the real world on the efficacy of A2A receptor antagonists on the appearance of such non-motor symptoms, respectively auto- nomic failures in PD and related syndromes, such as multi system atrophy, would be interesting in relation with the con- comitantly applied dopamine substitution. These outcomes
may also underline discussion on the safety and tolerability of a drug for PD. It is a certain therapeutic breakthrough when combination of A2A receptor antagonists with L-DOPA and/or dopamine agonists enables lower dosing of the dopamine-substituting compounds in the long run. Optimum dopamine replacement is often limited in PD patients by hypotension, induced by dopaminergic drugs.
7.2.1The nausea issue in PD
It is also well known that dopamine-substituting agents often cause nausea particularly during titration but also during long-term application. The reason for this side effect is the stimulation of peripherally located dopamine receptors. The use of peripheral dopamine receptor blockers, particularly domperidone, is restricted worldwide, for instance in the US, and gets more and more limited even now in the EU. Domperidone was added to the list of compounds with Qtc time prolonging properties. As a result, the titration and application of dopamine-substituting drugs with prevention of nausea with temporary or chronic domperidone applica- tion gets more and more complex.
7.3How will A2A antagonists integrate themselves in the therapeutic drug regime in terms of safety and tolerability in PD?
A future role of A2A receptor antagonism in the therapeutic regime for PD may be that for instance istradefylline repre- sents a L-DOPA plus dopamine agonist-sparing treatment alternative. The application, safety and side effect profile of istradefylline is superior to the one of L-DOPA and of the dopamine agonists and similar to the one of MAO-B inhibi- tors such as rasagiline. In the bottom line, one should consider that hurdles for approval of new compounds by the authori- ties should be lowered and more easily extended to drugs, which show for example in small and well-designed studies beneficial effects in terms of safety and tolerability in compar- ison with available drugs for the treatment of the disease entity. In summary, A2A antagonists increase the therapeutic index ratio between the therapeutic and unwanted side effects of L-DOPA and dopamine agonists.
Declaration of interest
The author has no relevant affiliations or financial involve- ment with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, con- sultancies, honoraria, stock ownership or options, expert testi- mony, grants or patents received or pending, or royalties.
Expert Opin. Drug Saf. (2015) 14(5) 773
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Affiliation
Thomas Mu¨ller MD
St. Joseph Hospital Berlin-Weitiensee, Department of Neurology, Gartenstr. 1, 13088 Berlin, Germany
Tel: +49 30 92790223; Fax: +49 30 92790703;
E-mail: [email protected]; [email protected]
Expert Opin. Drug Saf. (2015) 14(5) 775