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Apokyn

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Apokyn

Apokyn

CLINICAL PHARMACOLOGY

Mechanism of Action

APOKYN (apomorphine) is a non-ergoline dopamine agonist with high in vitro binding affinity for the dopamine D4 receptor (Ki = 4.4 nM), moderate affinity for the dopamine D2, D3, and D5 (Ki = 35-83, 26, and 15 nM, respectively), and adrenergic α1D, α2B, α2C (Ki = 65, 66, and 36 nM, respectively) receptors, and low affinity for the dopamine D1, serotonin 5HT1A, 5HT2A, 5HT2B, and 5HT2C (Ki = 370, 120, 120, 130, and 100 nM, respectively) receptors. Apomorphine exhibits no affinity for the adrenergic β1 and β2 or histamine H1 receptors (Ki > 10,000 nM).

The precise mechanism of action of APOKYN (apomorphine) as a treatment for Parkinson's disease is unknown, although it is believed to be due to stimulation of post-synaptic dopamine D2-type receptors within the caudate-putamen in the brain. Apomorphine has been shown to improve motor function in an animal model of Parkinson's disease. In particular, apomorphine attenuates the motor deficits induced by lesions in the ascending nigrostriatal dopaminergic pathway with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in primates.

Pharmacokinetics

Absorption

Apomorphine hydrochloride is a lipophilic compound that is rapidly absorbed (time to peak concentration ranges from 10 to 60 minutes) following subcutaneous administration into the abdominal wall. After subcutaneous administration, apomorphine appears to have bioavailability equal to that of an intravenous administration. Apomorphine exhibits linear pharmacokinetics over a dose range of 2 to 8 mg following a single subcutaneous injection of apomorphine into the abdominal wall in patients with idiopathic Parkinson's disease.

Distribution

The plasma-to-whole blood apomorphine concentration ratio is equal to one. Mean (range) apparent volume of distribution was 218 L (123 – 404 L). Maximum concentrations in cerebrospinal fluid (CSF) are less than 10% of maximum plasma concentrations and occur 10 to 20 minutes later.

Metabolism and Elimination

The mean apparent clearance (range) is 223 L/hr (125 – 401 L/hr) and the mean terminal elimination half-life is about 40 minutes (range about 30 to 60 minutes).

The route of metabolism in humans is not known. Potential routes of metabolism in humans include sulfation, N-demethylation, glucuronidation and oxidation. In vitro, apomorphine undergoes rapid autooxidation.

Special Populations

The clearance of apomorphine does not appear to be influenced by age, gender, weight, duration of Parkinson's disease, levodopa dose or duration of therapy.

Hepatic Impairment

In a study comparing subjects with hepatic impairment (moderately impaired as determined by the Child-Pugh classification method) to healthy matched volunteers, the AUC0-∞ and Cmax values were increased by approximately 10% and 25%, respectively, following a single subcutaneous administration of apomorphine into the abdominal wall. Studies in subjects with severe hepatic impairment have not been conducted (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Renal Impairment

In a study comparing renally-impaired subjects (moderately impaired as determined by estimated creatinine clearance) to healthy matched volunteers, the AUC0-∞ and Cmax values were increased by approximately 16% and 50%, respectively, following a single subcutaneous administration of apomorphine into the abdominal wall. The mean time to peak concentrations and the mean terminal half-life of apomorphine were unaffected by the renal status of the individual. Studies in subjects with severe renal impairment have not been conducted. The starting dose for patients with mild or moderate renal impairment should be reduced (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Drug-Drug Interactions

Carbidopa/levodopa

Levodopa pharmacokinetics were unchanged when subcutaneous apomorphine and levodopa were co-administrated in patients. However, motor response differences were significant. The threshold levodopa concentration necessary for an improved motor response was reduced significantly, leading to an increased duration of effect without a change in the maximal response to levodopa therapy.

Other Drugs Eliminated Via Hepatic Metabolism

Based upon an in vitro study, cytochrome P450 enzymes play a minor role in the metabolism of apomorphine. In vitro studies have also demonstrated that drug interactions are unlikely due to apomorphine acting as a substrate, an inhibitor, or an inducer of cytochrome P450 enzymes.

COMT Interactions

A pharmacokinetic interaction of apomorphine with catechol-O-methyl transferase (COMT) inhibitors or drugs metabolized by this route is unlikely since apomorphine appears not to be metabolized by COMT.

Clinical Studies

The effectiveness of APOKYN (apomorphine) in the acute symptomatic treatment of the recurring episodes of hypomobility, “off” episodes (“end-of-dose wearing off” and unpredictable “on/off” episodes), associated with advanced Parkinson's disease was established in three randomized, controlled trials. On average, patients participating in these trials had Parkinson's disease for 11.3 years and were being treated with L-dopa and at least one other agent, usually an oral dopamine agonist. One of the three studies was conducted in patients who did not have prior exposure to apomorphine and two were conducted in patients with at least 3 months of apomorphine use immediately prior to study enrollment. Almost all patients without prior exposure to apomorphine began taking an antiemetic (trimethobenzamide) three days prior to starting apomorphine. After exposure to apomorphine, 50% of patients were able to discontinue use of a concomitant antiemetic, on average 2 months after initiating apomorphine.

Change in Part III (Motor Examination) of the Unified Parkinson's Disease Rating Scale (UPDRS) served as the primary outcome assessment measure in each study. Part III of the UPDRS contains 14 items designed to assess the severity of the cardinal motor findings (e.g., tremor, rigidity, bradykinesia, postural instability, etc.) in patients with Parkinson's disease.

The first trial used a parallel design, randomizing 29 patients with advanced Parkinson's disease to subcutaneous apomorphine or placebo in a 2:1 ratio. Patients had no prior exposure to apomorphine. In an office setting, hypomobility was allowed to occur by withholding the patients' Parkinson's disease medications overnight. The following morning, patients (in a hypomobile state) were started in a blinded fashion on study treatment (placebo or 2 mg of apomorphine) and redosed at increasing doses, after at least 2 hours, until a therapeutic response approximately equivalent to the individual patient's response to their usual dose of levodopa was observed (or until 10 mg apomorphine or placebo equivalent was given). At each redosing, study drug was increased by 2 mg or 0.2 mL (to 4 mg, 6 mg, 8 mg, or 10 mg of apomorphine) or placebo equivalent. Of the 20 patients assigned to apomorphine, 18 achieved a therapeutic response at about 20 minutes that was approximately equivalent to the therapeutic response to a usual dose of levodopa. The average apomorphine dose was 5.4 mg (3 patients on 2 mg, 7 on 4 mg, 5 on 6 mg, 3 on 8 mg, and 2 on 10 mg). In contrast, of the 9 patients assigned to placebo, none reached such a therapeutic response. The mean changes-from-baseline for UPDRS Part III scores at the best dose were 23.9 and 0.1 for the apomorphine and placebo respectively (p < 0.0001).

The second trial used a crossover design, randomizing 17 patients who had been using apomorphine for at least 3 months. Patients received their usual morning doses of Parkinson's disease medications and were followed until hypomobility occurred, at which time they received either a single dose of subcutaneous apomorphine (at their usual dose) or placebo. Their UPDRS Part III scores were then evaluated over time. The average dose of apomorphine was 4 mg (2 patients on 2 mg, 9 on 3 mg, 2 on 4 mg, and 1 each on4.5 mg, 5 mg, 8 mg, and 10 mg). On average, the mean changes-from-baseline UPDRS Part III scores at 20 minutes were 20.0 and 3.0 points for the apomorphine and placebo groups respectively (p < 0.0001).

The third trial used a parallel design, randomizing 62 patients who had been using apomorphine for at least 3 months. Patients were randomized in a 2:1 (active:placebo) ratio to one of four groups and were dosed once. The groups were: apomorphine at the usual dose, placebo at a volume matching the usual apomorphine dose, apomorphine at the usual dose + 2 mg (0.2 mL), or placebo at a volume matching the usual apomorphine dose + 0.2 mL. Patients received their usual morning doses of Parkinson's disease medications and were followed until hypomobility occurred, at which time they received the randomized treatment. The mean changes-from-baseline for UPDRS Part III scores at 20 minutes post dosing were 24.2 and 7.4 points for the pooled apomorphine groups and the pooled placebo groups, respectively (p < 0.0001). The figure below describes the mean change in UPDRS Motor Scores over time after pooled apomorphine and pooled placebo administration.

UPDRS Motor Scores - Illustration

In this third trial, comparing patients randomized to apomorphine at the usual dose (mean dose about 4.5 mg) and patients randomized to apomorphine + 2 mg (mean dose about 6 mg), the mean changes-from-baseline for UPDRS Part III scores at 20 minutes post dosing were 24 and 25, respectively. This suggests that patients chronically treated at a dose of 4 mg might derive little additional benefit from a dose increment of 2 mg. There was an increased incidence of adverse events in patients randomized to apomorphine + 2 mg.

Last reviewed on RxList: 9/23/2010
This monograph has been modified to include the generic and brand name in many instances.

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