Istradefylline: An adenosine receptor antagonist for the treatment of Parkinson disease

Key Points

Abstract

Parkinson disease (PD) is a chronic and progressive neurologic disorder with a prevalence that may be as high as 329 cases per 100,000 population. This movement disorder involves a gradual decline in the neurotransmitter dopamine, which is responsible for facilitating smooth muscle and coordinated muscle movement. Istradefylline, a highly selective adenosine A_2A receptor antagonist, is a new agent being investigated for the adjunctive treatment of the motor signs and symptoms of idiopathic PD. A_2A receptors, which are abundant in the striatonigral outflow pathway from the basal ganglia, are the proposed target region for therapeutic intervention. An NDA for istradefylline was submitted in April 2007; in February 2008, FDA issued a nonapprovable letter for the agent, asking for additional information. The manufacturer has stated they will work closely with the agency to provide this information. The clinical trials available to date suggest that istradefylline is safe and effective in helping to reduce the symptoms of PD while maintaining overall patient tolerability. (Formulary. 2008;43:157–165.)

Parkinson disease (PD) is a progressive neurodegenerative disorder that is marked by a loss of dopaminergic neurons within the substantia nigra region of the brain and within other regions of the brain that demonstrate dopaminergic and nondopaminergic activity. The result is a gradual decline in the neurotransmitter dopamine, which is responsible for facilitating smooth muscle and coordinated muscle movement. A disease that typically affects individuals of an advanced age, PD is often difficult to diagnose before the presentation of the typical signs and symptoms of advancing disease; the lack of an early diagnosis may contribute to increased overall morbidity and decreased quality of life. PD is characterized by motor symptoms such as slowness of movement, muscle rigidity, body tremors, and postural instability. The onset of PD usually occurs at approximately 60 years of age.¹ The prevalence may be as high as 329 cases per 100,000 population.²

The concept of gradual dopamine depletion with resultant parkinsonian symptoms has provided the rationale for the development of pharmacotherapeutic agents. Loss of dopamine manifests as symptoms such as tremors, muscle weakness and stiffness, gait problems, postural imbalances, slowed movements, occupational therapy problems such as gripping or writing, and loss of facial expression. Many of these symptoms significantly deprive patients of the ability to perform normal activities of daily living independently and therefore negatively affect overall quality of life. The role of conventional therapies for PD is replacement and augmentation of dopamine. Conventional dopamine replacement therapies, notably levodopa, and dopamine augmentation therapies, specifically dopamine agonists, have been demonstrated to effectively treat the early motor symptoms of the disease. These agents are considered potential first-line agents for the treatment of PD symptoms according to treatment guidelines. However, levodopa and dopamine agonists are not without risks; these agents have been associated with the development of motor complications, especially when used for a long-term period. Such complications can significantly limit the usefulness of these agents in the late stages of the disease, as can the development of a shortening response to each dose ("wearing-off" phenomenon), the experience or return of symptoms within the dosing interval ("on-off" phenomenon), and the development of involuntary movements (ie, dyskinesias). Such events often require adjustments in therapy via dose reductions, addition of adjunctive therapies, or the conversion to an alternative agent. Other agents that are routinely used to help manage PD and its debilitating effects include monoamine oxidase B (MAO-B) inhibitors, anticholinergics, catechol-O-methyltransferase (COMT) inhibitors, and amantadine.

Istradefylline (KW-6002; Kyowa Pharmaceutical) is a new and highly selective adenosine A_2A receptor antagonist currently under investigation as an adjunctive therapy to levodopa/carbidopa for the management of the motor signs and symptoms of idiopathic PD. An NDA for istradefylline was submitted to FDA on April 25, 2007. On February 25, 2008, FDA issued a nonapprovable letter for istradefylline; the letter questioned whether the efficacy findings support the clinical utility of the drug. FDA requested an overall summary of nonclinical mineralization findings and clinical pharmacology follow-up information as a phase 4 commitment. Kyowa has stated that they will work closely with FDA to determine the most appropriate path to obtaining drug approval.⁵

CHEMISTRY AND PHARMACOLOGY

Adenosine receptors are abundant in the human brain; however, the A_2A receptors in particular are concentrated in the striatum. Although it is well documented that A_2A receptors are abundant in various regions of the brain, there is little evidence to suggest that they are present or have therapeutic effects in areas beyond the central nervous system (CNS). It is the A_2A receptors (along with A_2B receptors) that activate adenylyl cyclase, and the A_2A receptors have more specifically been associated with control of movement.⁶ Istradefylline [(E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione] is similar to the first A_2A selective compounds developed, but this agent has demonstrated improved in vivo activity compared with the previous compounds, as well as a selectivity for A_2A receptors (compared with A_1A receptors) >60-fold in rats and 800-fold in humans.^7,8 Istradefylline has also demonstrated minimal to no affinity for other receptors, including dopamine, noradrenaline, 5-hydroxytryptamine, and acetylcholine receptors.⁶ Studies of radioactive-labeled istradefylline compounds have supported this demonstration of A_2A receptor selectivity. Carbon-11-labeled istradefylline demonstrated the retention of the highest magnitude, with saturable binding, within the striatum, where the A_2A receptors are known to be concentrated.⁶ Further analysis illustrated that the radiolabeled compound had a low rate of continued activity in the frontal cortex, an area known to have low A_2A receptor activity.⁶

A_2A receptors assist in the suppression of gamma-aminobutyric acid (GABA) release and transmission in the striatum while enhancing its release in the external globus pallidus. This process allows the neurons in the globus pallidus to be suppressed, ultimately inhibiting the activity therein. Istradefylline mechanistically helps to block A_2A receptor stimulation, thereby diminishing the overexcitability of the pathway. The ability of istradefylline to block the excessive excitation of this indirect pathway has clinical implications for the therapeutic management of PD, as blockage of this pathway helps to lessen the motor complications associated with the disease.^6,7 With activity independent of dopaminergic pathways, istradefylline may offer an alternative to patients with PD who have lost response to conventional therapies such as levodopa or to patients who have experienced intolerable, levodopa-related motor complications such as dyskinesias and wearing-off symptoms.

PHARMACOKINETICS

Limited data exist regarding the pharmacokinetic profile of istradefylline in humans. An in vitro study was conducted by Saki et al⁹ to identify the pharmacologic activity of istradefylline as an adenosine A_2A receptor antagonist. In this study, human, dog, mouse, rat, and marmoset adenosine A_2A receptors were used to determine the potency and selectivity of istradefylline as a receptor antagonist. The study demonstrated that istradefylline had a high affinity for A_2A receptors in all species, with a greater selectivity for A_2A over A₁ receptors. Istradefylline demonstrated a high affinity for human A_2A receptors, with a reported equilibrium dissociation constant (K_i value) of 12 nmol/L and a median inhibition concentration (IC₅₀) >1,000 nmol/L, demonstrating little to no affinity for subtype receptors of other neurotransmitters. The half-life of istradefylline receptor binding in humans was demonstrated to be relatively short (0.32 min), illustrating a rapid yet reversible binding activity to A_2A receptors. The elimination half-life of istradefylline is approximately 47 hours.¹⁰

Preliminary results from a single-dose istradefylline study demonstrated that the area under the curve (AUC) and maximum concentration of drug in the serum (C_max) follow a linear kinetic model with doses up to 400 mg daily. Istradefylline administered routinely in a dose-escalated manner demonstrated linear pharmacokinetics over the dose range of 10 to 80 mg daily.⁶

Results of an in vivo study conducted in rats and humans demonstrated that >90% of A_2A receptors were occupied after administration of istradefylline doses >5 mg; the authors concluded that healthy humans who receive istradefylline 20 to 40 mg daily will have a consistent A_2A receptor occupancy of >90%. The authors also observed that regional volume of distribution (Vd) estimates were strongly associated with brain regions known to be saturated with A_2A receptors (specific values not determined).¹¹

Rao et al¹² evaluated the effect of istradefylline on the pharmacokinetics of levodopa/carbidopa in 24 healthy volunteers. Participants in this study received a single dose of levodopa/carbidopa (200 mg/50 mg) either alone or after 2 weeks of treatment with a supratherapeutic dose of istradefylline (80 mg/d). At study completion, the researchers observed that the administration of levodopa/carbidopa either alone or after istradefylline treatment was safe and well tolerated; istradefylline had no effect on the elimination of levodopa/carbidopa. Results also demonstrated that other pharmacokinetic parameters (AUC and C_max) in the 2 treatment groups were within 12% of each other (corresponding 90% CI, 80%–125%; within the bioequivalence window), further demonstrating that these agents can be administered in combination.

CLINICAL TRIALS

The efficacy of istradefylline has been evaluated in a number of clinical trials; these trials enrolled patients for whom levodopa therapy was inadequate or in whom "off" time was a problem. To date, most of the efficacy studies have been presented only as posters or abstracts at various professional meetings.

Guttman et al¹³ evaluated the efficacy of istradefylline in a double-blind, placebo-controlled, parallel-group study in 610 patients with motor complications who were being treated with levodopa. Patients were randomized to receive istradefylline 10, 20, or 40 mg/d or placebo for a treatment period of 12 weeks. The primary outcome was the change from baseline in the percentage of awake time per day spent in the off state. At baseline, the average off time was 6.7 hours; 89.9% of patients were currently on other dopaminergic therapy. A dose-ordering response was detected in the istradefylline groups in the change from baseline to study end in off time (10 mg, –1.11 h; 20 mg, –1.14 h; 40 mg, –1.45 h). However, at study completion, all doses of istradefylline had failed to demonstrate a significant difference in the primary end point versus placebo (placebo, –1.42 h).

A randomized, placebo-controlled, multicenter study by Trugman et al¹⁴ assessed the efficacy of istradefylline in 225 patients with PD and motor complications who were experiencing a wearing-off response to levodopa therapy. Over a 12-week period, the percentage of awake time per day in the off state was evaluated in patients who received istradefylline 20 mg/d or placebo. Patients who received istradefylline demonstrated a greater change from baseline in the percentage of awake time per day spent in the off state versus those who received placebo (–9.49% vs –4.92%), a difference that was statistically significant (4.57%; P=.025). Patients treated with istradefylline also demonstrated a greater change from baseline versus those treated with placebo in the daily hours of awake time spent in the off state (–1.58 h vs –0.86 h), a difference that was statistically significant (–0.73 h; P=.03).

LeWitt et al¹⁵ conducted two 12-week, randomized, double-blind, placebo-controlled, multicenter studies to assess the efficacy of adjunctive istradefylline therapy in reducing off time in patients with PD and with motor dysfunction who were experiencing a wearing-off response to treatment with levodopa. A total of 591 patients were randomized to receive istradefylline 40 mg/d or placebo (first study) or istradefylline 20 or 60 mg/d or placebo (second study). At the end of the first study, patients treated with istradefylline 40 mg/d demonstrated a significantly greater reduction in hours of off time (–1.8 h vs –0.6 h; P=.006) and in percentage of hours in the off state (–10.8% vs –4%; P=.007) versus patients treated with placebo. At the conclusion of the second study, the change in percentage of off time was –7.9% among patients treated with istradefylline 20 mg/d, –8.1% among patients treated with istradefylline 60 mg/d, and –4.3% among patients treated with placebo; these differences were not statistically significant (P<.1). However, when the baseline percentage of off time was incorporated into the analysis as a covariate, the differences between patients treated with istradefylline 20 or 60 mg/d and those treated with placebo were statistically significant (P=.026 and P=.024, respectively).

Mark et al¹⁶ evaluated the long-term efficacy of istradefylline in an open-label study consisting of 496 patients with PD. These patients had previously been enrolled in double-blind, placebo-controlled trials involving istradefylline. In this study, 2 groups were formed for an efficacy analysis. Group 1 consisted of patients who had received istradefylline in previous trials (total baseline off time, 4.4 h), whereas Group 2 included patients who had received placebo in previous trials, in addition to patients who had not received either active drug or placebo drug for >2 weeks before the beginning of this trial (total baseline off time, 5.6 h). In all patients, istradefylline was initiated at a dose of 40 mg/d, but the dose could be adjusted to either 20 mg/d or 60 mg/d. Study results demonstrated that total hours in the off state continued to be stable among patients in Group 1 for up to 52 weeks, whereas patients in Group 2 had a decrease in off time of approximately 0.7 to 0.9 hours within 2 weeks of istradefylline treatment; this reduction was maintained for up to 52 weeks.

Hauser et al¹⁰ evaluated the efficacy of istradefylline in a 12-week, randomized, double-blind, placebo-controlled clinical trial. The trial enrolled 83 patients with levodopa-treated PD who were experiencing motor fluctuations and peak-dose dyskinesias. Patients were randomized to receive istradefylline (up to 20 or 40 mg/d) or placebo. At study completion, patients who received istradefylline demonstrated a significant decrease of 7.1% in the proportion of awake time spent in the off state compared with those who received placebo, in whom an increase of 2.2% in off time was observed (P=.008). Patients treated with istradefylline also demonstrated an increase in "on" time with dyskinesias versus those treated with placebo (P=.001); however, the severity of dyskinesias remained the same in both groups. No statistically significant differences in Unified Parkinson Disease Rating Scale (UPDRS) scores were reported between the istradefylline and placebo groups.

In a double-blind, placebo-controlled, 6-week study by Bara-Jimenez et al,¹⁷ 15 patients with moderate-to-advanced PD were randomized to receive either istradefylline 40 mg/d (increased to 80 mg/d after 2 wk) or placebo, either alone or in combination with a stable intravenous (IV) infusion of an optimal or suboptimal dose of levodopa. At study end, istradefylline as monotherapy or in combination with optimal-dose levodopa demonstrated no effect on disease severity. Compared with baseline, istradefylline 40 mg/d enhanced the antiparkinsonian effect of low-dose levodopa by 24% as measured by UPDRS score (from 30 to 23; P<.05), and istradefylline 80 mg/d enhanced the effect by 36% (from 30 to 19; P<.02). Additionally, istradefylline prolonged levodopa motor response half-time by an average of 76% (from 62 min to 109 min; P<.05). The combination of istradefylline and suboptimal-dose levodopa demonstrated similar antiparkinsonian results to those observed with optimal-dose levodopa; however, a lower occurrence of dyskinesias was observed with istradefylline plus suboptimal-dose levodopa compared with optimal-dose levodopa alone.

ADVERSE EVENTS

Overall, istradefylline has been well tolerated in clinical trials; the most commonly reported adverse events have been nausea, vomiting, aggravated dyskinesias, insomnia, and dizziness.

Pourcher et al¹⁸ assessed the safety and tolerability of istradefylline in a double-blind, parallel-group study that enrolled 605 patients who had PD with motor fluctuations and who were receiving levodopa therapy. Patients were randomized to receive 1 of 3 doses of istradefylline (10, 20, or 40 mg/d) or placebo over a 12-week treatment period. Although the primary efficacy variable was the change from baseline to study completion in the percentage of awake time per day spent in the off state as recorded by the patient, the authors only reported safety and tolerability results. At study end, the frequency of adverse events was slightly higher in the istradefylline treatment groups compared with the placebo group; this difference was not statistically significant. The types of adverse events that were reported did not differ between the active treatment groups and the placebo group. Dys- kinesias, insomnia, and hallucinations were reported in all groups, with a slightly higher frequency of each observed in patients who received istradefylline 40 mg/d. Although hallucinogenic events were reported in this study, there have not been any studies to date in humans addressing the abuse potential of istradefylline. Dropout rates were not reported for any of the study groups, but the authors concluded that istradefylline was both safe and tolerable at doses of 10, 20, and 40 mg/d in patients with motor complications who were being treated with other therapies.

The safety and tolerability of istradefylline were evaluated by Shulman et al¹⁹ in a randomized, double-blind, placebo-controlled, multicenter study in patients with PD and motor complications who were taking levodopa/carbidopa. A total of 115 patients were randomized to receive either istradefylline 20 mg/d or placebo for the duration of the 12-week study. At study completion, the istradefylline and placebo groups demonstrated similar frequencies of treatment-emergent adverse events (79% vs 76%) and serious adverse events (4% vs 5%); however, patients treated with istradefylline demonstrated a frequency of dyskinesia nearly twice that observed with placebo (23% vs 12%). No cardiac effects were detected during the study, and no significant difference was detected between the groups in the rate of discontinuation because of adverse events (5% vs 6%). Overall, istradefylline was reported to be well tolerated and generally safe.

Watts²⁰ evaluated the long-term safety of istradefylline in a multicenter, open-label study consisting of 496 patients with PD not adequately controlled with levodopa/carbidopa or other antiparkinsonian medications. These patients had been previously enrolled in double-blind trials involving istradefylline. Patients in this study received istradefylline 40 mg/d, but the regimen could be adjusted to 20 or 60 mg/d. At study completion, the most commonly reported drug-related adverse events were dyskinesia (22.6%), nausea (11.3%), and dizziness (12.7%). Incidence rates were similar to those described in the previous double-blind studies. A total of 8 patients (1.6%) experienced serious adverse events (severity of events not defined by authors) that were determined to be possibly or probably related to istradefylline, with 27 patients (5.4%) discontinuing istradefylline because of possible/probable drug-related adverse events. The hours of off time (approximately 4.6 h) remained stable for patients treated with istradefylline during this extension study.

DRUG INTERACTIONS

Currently, there is no published information pertaining to drug interactions with istradefylline.

DOSING AND ADMINISTRATION

Dr Pomfret is a clinical consultant pharmacist, Clinical Pharmacy Services, Commonwealth Medicine at the University of Massachusetts Medical School, Shrewsbury; a clinical assistant professor, Northeastern University, School of Pharmacy, Boston; and an adjunct assistant professor of Pharmacy Practice, Massachusetts College of Pharmacy and Health Sciences, Worcester. Dr Gagnon is associate director of Clinical Services, Clinical Pharmacy Services, Commonwealth Medicine at the University of Massachusetts Medical School, Shrewsbury, and an adjunct assistant professor of Pharmacy Practice, Massachusetts College of Pharmacy and Health Sciences, Worcester. Ms Pietarinen is a PharmD candidate at the Massachusetts College of Pharmacy and Health Sciences, Boston.

Disclosure Information: The authors report no financial disclosures as related to products discussed in this article.

In each issue, the "Focus on" feature reviews a newly approved or investigational drug of interest to pharmacy and therapeutics committee members. The column is coordinated by Robert A. Quercia, MS, RPh, clinical manager and director of Drug Information, Department of Pharmacy Services, Hartford Hospital, Hartford, Conn, and adjunct associate professor, University of Connecticut School of Pharmacy, Storrs, Conn; and by Craig I. Coleman, PharmD, assistant professor of pharmacy practice, University of Connecticut School of Pharmacy, and director, Pharmacoeconomics and Outcomes Studies Group, Hartford Hospital.

EDITORS' NOTE: The clinical information provided in "Focus on" articles is as current as possible. Due to regularly emerging data on developmental or newly approved drug therapies, articles include information published or presented and available to the author up until the time of the manuscript submission.

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