LC-MS/MS simultaneous quantification of apomorphine and its major metabolites in human plasma: Application to clinical comparative bioavailability evaluation for the apomorphine sublingual film and a subcutaneous product.

A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been developed and validated for the simultaneous quantification of apomorphine and its metabolites apomorphine sulfate and norapomorphine in human plasma for supporting clinical development of a novel apomorphine sublingual thin film (APL) for the treatment of Parkinson's disease. Analytes and internal standards (IS) were extracted from human plasma by Oasis HLB SPE cartridge, followed by a reversed phase LC-MS/MS analysis using multiple reaction monitoring (MRM) in positive mode (m/z 268 → 237 for apomorphine, 348 → 237 for apomorphine sulfate, and 348 → 237 for norapomorphine). Stable isotope-labeled compounds were used as IS for respective analytes. The validated curve ranges were 0.02-20 ng/mL, 10-1000 ng/mL, and 0.5-20 ng/mL for apomorphine, apomorphine sulfate and norapomorphine, respectively. Extraction recoveries were found to be 73.4 % (apomorphine), 81.1 % (apomorphine sulfate), and 58.6 % (norapomorphine). Established long-term plasma frozen storage stabilities were 504 days at -20 °C and276 days at -60 °C, respectively. The method has been successfully used for analyzing pharmacokinetics (PK) samples collected from a comparative bioavailability study of APL and the marketed apomorphine subcutaneous (s.c.) product Apo-go®. The results demonstrated that the 15-mg APL film administrated via sublingual produced comparable PK characteristics of apomorphine when compared to the commercial product Apo-go (2-mg) via s.c. administration, hence establishing the dose regimen for this sublingual formulation. It was also noticed that the sublingual 15-mg APL film produced a significantly higher apomorphine sulfate metabolite level than the 2-mg s.c. Apo-go, and both treatments yielded a negligible level of norapomorphine metabolite in humans.

Intravenous Administration of Apomorphine Does NOT Induce Long QT Syndrome: Experimental Evidence from In Vivo Canine Models.

Apomorphine is a non-selective dopamine D1/D2 receptor agonist, which has been used for patients with Parkinson's disease and reported to induce QT interval prolongation and cardiac arrest. To clarify their causal link, we assessed the cardiovascular and pharmacokinetic profile of apomorphine with the halothane-anaesthetized canine model (n = 4), whereas pro-arrhythmic potential of apomorphine was analysed with the chronic atrioventricular block canine model (n = 4). In the halothane-anaesthetized model, 0.01 mg/kg, i.v. of apomorphine hydrochloride over 10 min., providing about 10 times of its therapeutic concentration, increased the heart rate and ventricular contraction; 0.1 mg/kg over 10 min., providing about 100 times of the therapeutic, prolonged the ventricular effective refractory period; and 1 mg/kg over 10 min., providing about 1000 times of the therapeutic, decreased the ventricular contraction, mean blood pressure and cardiac output together with the intraventricular conduction delay and prolongation of the effective refractory period, whereas the left ventricular end-diastolic pressure, atrioventricular nodal conduction or ventricular repolarization were hardly affected. Meanwhile, in the atrioventricular block model, 1 mg/kg, i.v. of apomorphine hydrochloride over 10 min. neither prolonged the QT interval nor induced torsade de pointes. These results suggest that apomorphine may possess a wide margin of cardiovascular safety contrary to our expectations.

Reduced dopamine receptor sensitivity as an intermediate phenotype in alcohol dependence and the role of the COMT Val158Met and DRD2 Taq1A genotypes.

CONTEXT: Alcohol dependence is a common neuropsychiatric disorder with high heritability. However, genetic association studies on alcohol dependence are often troubled by nonreplication. The use of intermediate phenotypes may help make clear the mode of action of various candidate genes and improve the reproducibility of genetic association studies. OBJECTIVE: To test central dopamine receptor sensitivity as an intermediate phenotype for alcohol dependence, specifically evaluating the hypothesis that the dopaminergic genes COMT Val158Met and DRD2 Taq1A affect dopamine receptor sensitivity. DESIGN: Case-control pharmacogenetic challenge study. SETTING: Patients with alcohol dependence admitted for detoxification were compared with healthy control subjects matched for age and level of education. PARTICIPANTS: Patients (n = 110) were a consecutive sample, whereas controls (n = 99) were recruited through advertisements in regional newspapers. INTERVENTION: A dopamine challenge test was subcutaneously administered using the dopamine agonist apomorphine hydrochloride (0.005 mg/kg). MAIN OUTCOME MEASURES: Outcome measures were plasma growth hormone levels and results of a continuous performance task. RESULTS: Central dopamine receptor sensitivity is reduced in alcohol dependence, and this is modulated by dopaminergic genes. Specifically, DRD2 Taq1A genotype affected dopamine receptor sensitivity as measured by plasma growth hormone levels, and COMT Val158Met genotype affected dopamine receptor sensitivity as measured by performance on a continuous performance task. In a logistic regression analysis, reduced dopamine receptor sensitivity on both measures predicted alcohol dependence, without an additive effect of the COMT Val158Met and DRD2 Taq1A genotypes. CONCLUSIONS: COMT Val158Met and DRD2 Taq1A may affect the intermediate phenotype of central dopamine receptor sensitivity. COMT Val158Met and DRD2 Taq1A may confer their risk of alcohol dependence through reduced dopamine receptor sensitivity in the prefrontal cortex and hindbrain, respectively.

Development and evaluation of perfluorocarbon nanobubbles for apomorphine delivery.

Apomorphine is a dopamine receptor agonist for treating Parkinson's disease. However, its clinical application is limited by its instability and the need for frequent injections. The aim of the present work was to develop acoustically active perfluorocarbon nanobubbles (PNs) for encapsulation of both apomorphine HCl and base forms to circumvent these delivery problems. The PNs were prepared using coconut oil and perfluoropentane as the inner phase, which was emulsified by phospholipids and cholesterol. The morphology, size, zeta potential, and drug release of the PNs were characterized. The particle size ranged from 150 to 380 nm, with differences in the oil or perfluorocarbon ratio in the formulations. Atomic force microscopy confirmed oval- or raisin-shaped particles and a narrow size distribution of these systems (polydispersity index = 0.25-0.28). The stability experimental results indicated that PNs could protect apomorphine from degradation. Evaporation of the PNs at 37 degrees C was also limited. Apomorphine HCl and base in PNs showed retarded and sustained release profiles. Ultrasound imaging confirmed the echogenic activity of PNs developed in this study. The apomorphine HCl release by insonation at 1 MHz showed enhancements of two- to fourfold compared to the non-ultrasound group, illustrating a possible drug-targeting effect. On the contrary, apomorphine base showed a decreased release profile with ultrasound application. Apomorphine-loaded PNs showed promising stability and safety. They were successful in sustaining apomorphine delivery.

Determination of apomorphine in canine plasma by liquid chromatography-electrospray ionization mass spectrometry and its application to a pharmacokinetic study.

An LC-ESI-MS method was developed and validated for the assay of apomorphine in canine plasma using one-step liquid-liquid extraction. The analytes were separated on a Phenomenex Gemini C18 (150 mm x 2.0 mm id 3 microm) column and determined by MS in the positive ion mode. The linear range was 0.4-40 ng/mL with an LOD of 0.2 ng/mL for apomorphine in plasma. The intraday and interday precision and accuracy of quality control samples were < 5.9% RSD and < 7.5% bias for apomorphine. Extraction recoveries were > 80%. The validated method was successfully applied to analyze canine plasma samples in a pharmacokinetic study of apomorphine in dogs and detailed pharmacokinetic parameters were calculated.

Sensitive quantification of apomorphine in human plasma using a LC-ESI-MS-MS method.

An analytical method based on liquid chromatography coupled with ion trap mass spectrometry (MS) detection with electrospray ionization interface has been developed for the identification and quantification of apomorphine in human plasma. Apomorphine was isolated from 0.5 mL of plasma using a liquid-liquid extraction with diethyl ether and boldine as internal standard, with satisfactory extraction recoveries. Analytes were separated on a 5-microm C18 Highpurity (Thermohypersil) column (150 mm x 2.1 mm I.D.) maintained at 30 degrees C, coupled to a precolumn (C18, 5-microm, 10 mm x 2.0 mm I.D., Thermo). The elution was achieved isocratically with a mobile phase of 2 mM NH4COOH buffer pH 3.8/acetonitrile (50/50, vol/vol) at a flow rate of 200 microL per minute. Data were collected either in full-scan MS mode at m/z 150 to 500 or in full-scan tandem mass spectrometry mode, selecting the [M+H]ion at m/z 268.0 for apomorphine and m/z 328.0 for boldine. The most intense daughter ion of apomorphine (m/z 237.1) and boldine (m/z 297.0) were used for quantification. Retention times were 2.03 and 2.11 minutes for boldine and apomorphine, respectively. Calibration curves were linear in the 0.025 to 20 ng/mL range. The limits of detection and quantification were 0.010 ng/mL and 0.025 ng/mL, respectively. Accuracy and precision of the assay were measured by analyzing 54 quality control samples for 3 days. At concentrations of 0.075, 1.5, and 15 ng/mL, intraday precisions were less than 10.1%, 5.3%, and 3.8%, and interday precisions were less than 4.8%, 6.6%, and 6.5%, respectively. Accuracies were in the 99.5 to 104.2% range. An example of a patient who was given 6 mg of apomorphine subcutaneously is shown, with concentrations of 14.1 ng/mL after 30 minutes and 0.20 ng/mL after 6 hours. The method described enables the unambiguous identification and quantification of apomorphine with very good sensitivity using only 0.5 mL of sample, and is very convenient for therapeutic drug monitoring and pharmacokinetic studies.

A cluster-based quantitative procedure in an fMRI study of Parkinson's disease.

Parkinson's disease is a neurological disorder associated with disfunction of dopaminergic pathways of the basal ganglia. In this study, we report the effects of decreasing plasma concentrations of the dopamine-agonist apomorphine on the size and extents of activity clusters observed with functional magnetic resonance imaging during a simple motor task. Eight patients at advanced disease stage and six healthy volunteers were studied during four consecutive sessions. We observed consistent activations in the primary sensorimotor area of the contralateral side and in the supplementary motor area of both patients and controls during the first session. During subsequent sessions, while the drug concentration gradually decreased in patients, they showed a fragmentation of the activity areas, with an overall decrease of involved volume and a decline of activity in the supplementary motor area. The appearing of activity in the ipsilateral motor area matched a partial recovery of supplementary motor area activation. During the last session, when patients showed severe dyskinesia, a widespread region of positive and negative correlations between signal and task was observed. We conclude that the lack of subcortical circuitry is partially reversible by apomorphine and that when the drug effects are reduced, there is a possible mechanism recruitment of alternate subcortical pathways.

Cardiovascular and electrocardiographic effects of the dopamine receptor agonists ropinirole, apomorphine, and PNU-142774E in conscious beagle dogs.

To confirm recent in vitro findings, we examined the cardiovascular and electrocardiographic (ECG) effects of the dopamine receptor agonists ropinirole, apomorphine, and PNU-142774E in conscious dogs. Intravenous (i.v.) infusions of ropinirole totaling 20 microg/kg maximally reduced mean arterial pressure (MAP; -16 mm Hg) and the ECG PR interval (-13 milliseconds) and increased heart rate (HR; +29 b/min) and QTc length (+33 ms) at a peak plasma drug concentration (p[drug]) of 3.5 ng/ml. I.V. PNU-142774E was better tolerated through 66 microg/kg and a maximal p[drug] of 5.9 ng/ml with negligible cardiovascular changes and mild QTc reduction (13 ms). Apomorphine (25 microg/kg i.v.) was intermediate to ropinirole and PNU-142774E for emesis and peak changes in MAP (-6 mm Hg), HR (+24 b/min), and QTc (+15 milliseconds) at a mean p[drug] of 3.4 ng/ml. By comparison, the class III antiarrhythmic trecetilide (2.0 mg/kg bolus) increased QTc (+58 ms) without affecting mean arterial pressure or heart rate. This study establishes that in conscious dogs, the selective dopamine receptor agonist PNU-142774E has fewer cardiovascular and emetic effects than ropinirole and apomorphine and supports prior in vitro findings that ropinirole and apomorphine but not the PNU-142774E imidazoquinolin analog sumanirole reduces the delayed rectifier current in HERG transfected cells.

Betamethasone does not prevent nausea and vomiting induced by the dopamine-agonist apomorphine.

PURPOSE: The mechanism of the antiemetic actions of corticosteroids is not known. The purpose of this study was to evaluate if betamethasone can prevent nausea, vomiting or increase of vasopressin induced by apomorphine. Metoclopramide, a dopamine antagonist, was used as a control substance. METHODS: Ten healthy volunteers were studied on three occasions. In a randomized order they were allocated to receive pretreatment with betamethasone 8 mg iv, metoclopramide 10 mg iv, and normal saline 2 mL as placebo on the three different occasions, 15 min before the administration of apomorphine 30 microg x kg(-1) s.c.. After administration of apomorphine, episodes of vomiting were recorded, and the intensity of nausea was estimated by the subject on a visual analogue scale (VAS 0-10 cm). Blood samples for analysis of plasma concentrations of vasopressin were analyzed. RESULTS: One volunteer decided to withdraw, as he experienced akathisia after receiving metoclopramide. During the first two hours after apomorphine, eight of nine volunteers vomited both after betamethasone and placebo. One volunteer did not vomit after betamethasone and placebo but he experienced nausea. None of the volunteers vomited after metoclopramide (P < 0.01 vs betamethasone and placebo). The maximum VAS for nausea was significantly higher after betamethasone and placebo compared to metoclopramide (P < 0.01). The vasopressin levels increased after betamethasone and placebo, but there was no increase in any volunteer after pretreatment with metoclopramide. CONCLUSION: This study demonstrates that betamethasone does not prevent nausea, vomiting and increase of vasopressin induced by apomorphine, whereas metoclopramide prevents apomorphine-induced emesis. Our work suggests that betamethasone does not have dopamine-antagonistic effects.

Improved assay for R(-)-apomorphine with application to clinical pharmacokinetic studies in Parkinson's disease.

A high performance liquid chromatographic assay for the quantitative determination of apomorphine in human plasma is described. Sample clean-up and concentration was optimised using solid-phase extraction on C18 cartridges, enabling rapid and sensitive determination of apomorphine and potential metabolites. The limit of apomorphine quantification, using fluorescence detection, was 0.5 ng/mL. The assay was stability-indicating, and allowed the detection of analytes in the presence of commonly co-administered anti-Parkinsonian drugs. Apomorphine was stable in frozen plasma containing 0.14% (w/v) ascorbic acid for 98 days, and through four freeze-thaw cycles. The assay has been used in clinical pharmacokinetic studies of apomorphine in patients with Parkinson's disease, and in preliminary studies of novel apomorphine delivery devices in volunteers.

Development of a gas chromatographic/mass spectrometric method to quantify R(-)-apomorphine, R(-)-apocodeine and R(-)-norapomorphine in human plasma and urine.

A method was developed and validated for the analysis of R(-)-apomorphine, (R-)-apocodeine and R(-)-norapomorphine in human plasma and urine with N-propylnorapomorphine as internal standard using gas chromatography/mass spectrometry (GC/MS) and single-ion monitoring after a single liquid-liquid extraction and silylation of compounds. The quantification limits were 1 ng/ml for apomorphine and apocodeine and 25 ng/ml for norapomorphine. Calibration curves were linear, within the range 1-100 ng/ml. Variation in intraday and interday precision was below 10%. This method was applied to study apomorphine bioavailability in nine patients with Parkinson's disease before and after coadministration of a catechol-O-methyl transferase inhibitor.

Continuous dopaminergic stimulation reduces risk of motor complications in parkinsonian primates.

Levodopa or short-acting dopamine (DA) agonist treatment of advanced parkinsonian patients exposes striatal DA receptors to non-physiologic intermittent stimulation that contributes to the development of dyskinesias and other motor complications. To determine whether continuous dopaminergic stimulation can delay or prevent onset of motor complications, four MPTP-lesioned, levodopa-naive cynomolgus monkeys were implanted subcutaneously with apomorphine containing ethylene vinyl acetate rods. Three other MPTP-lesioned monkeys received daily injections of apomorphine. Animals receiving apomorphine rods showed improved motor function ('ON' state) within 1 day of implantation, and remained continually 'ON' for the duration of treatment (up to 6 months) without developing dyskinesias. Injected animals also showed similar improvement in motor function after each apomorphine injection. However, these primates remained 'ON' for only 90 min and within 7-10 days all developed severe dyskinesias. Implanted monkeys evidenced local irritation, which was alleviated by steroid co-therapy.

Transdermal apomorphine permeation from microemulsions: a new treatment in Parkinson's disease.

We studied absorption, efficacy, and tolerability in Parkinson's disease (PD) of a new preparation of apomorphine included in a microemulsion and administered by transdermal route (Apo-MTD). Twenty-one PD patients were treated with levodopa plus oral dopamine-agonists (T0), with levodopa alone (T1), finally with levodopa plus Apo-MTD (T2). Apo-MTD provided therapeutic plasma levels for many hours, improved Unified Parkinson's Disease Rating Scale III scores, and reduced total duration of off periods compared to T0 and T1. We concluded that Apo-MTD is absorbed and demonstrates clinical efficacy and long action. Therefore, it seems a promising add-on treatment for uncontrolled prolonged off phases in PD patients, but chronic tolerability needs further study.

Kinetics of the uptake and distribution of the dopamine D(2,3) agonist (R)-N-[1-(11)C]n-propylnorapomorphine in brain of healthy and MPTP-treated Göttingen miniature pigs.

The binding of radioligand agonists to dopamine receptors in living brain can be informative about the abundance of receptors which are coupled to intracellular second messenger systems. Therefore, we developed a radiosynthesis for the dopamine D(2,3) partial agonist (R)-N- [1-(11)C]n-propylnorapomorphine ([(11)C]NPA). The uptake of this tracer in brain of anesthetized Göttingen miniature pigs was recorded by positron emission tomography (PET) and analyzed by compartmental analysis using the metabolite-corrected arterial input, and using reference tissue methods. [(11)C]NPA had a blood-brain unidirectional clearance of approximately 0.35 ml g(-1) min(-1) and an apparent distribution volume of 6 ml g(-1) in cerebellum. The ligand had a binding potential of 1.5 in striatum, comparable to that reported previously for the receptor antagonist [(11)C]raclopride in the same strain of animals. Significant binding was detected in the hypophysis, thalamus, and medial forebrain bundle. The binding in striatum was of comparable magnitude in normal pigs and in pigs with a documented 50% dopamine depletion produced by MPTP-intoxication. Deep brain stimulation of the subthalamus was without conspicuous effect on the binding of [(11)C]NPA in vivo. Results of this preliminary study indicate that this tracer meets many requirements for assaying dopamine agonist binding sites by PET.

Intravenous apomorphine therapy in Parkinson's disease: clinical and pharmacokinetic observations.

Six patients with Parkinson's disease and refractory motor fluctuations, with severe subcutaneous (s.c.) nodule formation as a result of long-term s.c. apomorphine infusions, were switched to intravenous (i.v.) therapy via a long-term in-dwelling venous catheter. Five patients were followed-up for a mean of 7 months (range 0.5-18 months). All patients had plasma apomorphine concentrations measured at baseline during s.c. infusions and three had follow-up measurements when stabilized on i.v. therapy, to test the hypothesis that motor fluctuations in these patients are largely due to impaired absorption of apomorphine. The mean i.v. rate of 9.0 mg/h (range 5-14 mg) and 24-h dose of 256.7 mg (range 90-456 mg) of apomorphine were not significantly reduced compared with the s.c. route (9.24 mg/h and 243.4 mg). However, additional oral anti-parkinsonian medication was reduced by a mean of 59%, and 'off' time was virtually eliminated (mean reduction from 5.4 to 0.5 h per day, P< 0.05). There was also a significant reduction in dyskinesias and markedly improved quality of life. Pharmacokinetic analysis demonstrated more reliable and smoother delivery of apomorphine via the i.v. route, although 'off' periods were not always explained by low plasma apomorphine concentrations. Complication rates were high and included three unforeseen hazardous intravascular thrombotic complications, secondary to apomorphine crystal accumulation, necessitating cardiothoracic surgery. We conclude that i.v. apomorphine therapy holds promise as a more effective way of controlling motor fluctuations than the s.c. route. However, further preclinical research is required before i.v. Britaject apomorphine can be recommended for routine clinical practice. Even when stable plasma apomorphine concentrations were achieved, motor fluctuations could not be totally eradicated, suggesting that postsynaptic receptor changes may also play a role in the refractory 'off' periods in these patients.

In vitro and in vivo long term release of apomorphine from polymer matrices.

Since apomorphine actually reveals high efficacy in treatment of Parkinson's disease but only has a very short half life, it is of only limited clinical significance. To overcome this substantial disadvantage, drug application by long term delivery systems could be one possibility. Based on this background, ethylene vinyl acetate polymeric delivery systems were manufactured that differed in size, with either coated or uncoated surfaces, but were similar in apomorphine loading. Release from uncoated polymeric delivery systems followed first order kinetics, whereas coated polymeric delivery systems showed within the first 40 days a period of first order kinetics release, in which the release rate is approximately half that of the uncoated polymeric delivery systems, followed by a zero order kinetics release for more than 130 days with a daily release rate of 3.1 +/- 0.2 mg. In vivo release was investigated by determining plasma apomorphine concentrations after implanting polymeric delivery systems into the abdominal cavities of rats. Animals with uncoated polymeric delivery systems exhibited symptoms of an apomorphin overdosage within 20 days after surgery. Using coated polymeric delivery systems, a steady state plasma concentration of 15 ng/ml was observed, which was maintained over a period of 130 days after an initial period of high plasma concentrations. Based on our results, it is concluded that polymeric delivery systems might be an appropriate method for applying apomorphine for the treatment of Parkinson's disease.

Nasal mucoadhesive delivery systems of the anti-parkinsonian drug, apomorphine: influence of drug-loading on in vitro and in vivo release in rabbits.

Lyophilized polyacrylic acid powder formulations loaded with apomorphine HCl were prepared and the influence of drug loading on in vitro release and in vivo absorption studied after intranasal administration in rabbits. These formulations prepared with Carbopol 971P, Carbopol 974P and polycarbophil sustained apomorphine release both in vitro and in vivo. The in vitro release rate and mechanism were both influenced by the drug loading. There was no large influence of drug loading on the time to achieve the peak (Tmax) for a particular polymer, but Tmax differed between different polymers. For a particular drug loading, the Tmax from Carbopol 971P was the slowest compared with that for Carbopol 974P and polycarbophil; however, only the Tmax from Carbopol 971P loaded with 15% w/w of apomorphine was significantly longer than polycarbophil of similar drug loading (P=0.0386). The trend further observed was that increasing drug loading led to increased peak plasma concentration and area under the curve (AUC). In the second part of this study, a mixture containing an immediate release component and sustained release formulation was administered in an attempt to increase the initial plasma level, as this could be therapeutically beneficial. Only one peak plasma concentration was observed and the initial plasma concentrations were no higher than those obtained with solely sustained release formulation. The Tmax, the peak plasma drug concentration (Cmax) and AUC from the lactose-containing formulation were lower than the formulation without lactose but the differences were only marginally statistically significant for Cmax (P=0.0911) and AUC (P=0.0668), but not Tmax (P=0.2788).

Bioavailability of apomorphine following intranasal administration of mucoadhesive drug delivery systems in rabbits.

PURPOSE: The purpose of this study was to investigate both the in vitro and in vivo release of apomorphine from mucoadhesive powder formulations of Carbopol 971P and polycarbophil. METHODS: The in vitro drug release from the mucoadhesive formulations was studied using a modified USP XXII rotating basket. The pharmacokinetics of apomorphine given as a solution was determined after subcutaneous and intranasal administrations to rabbits. The animals also received intranasally the mucoadhesive dosage forms and immediate release lactose powder mixture. Comparisons were made between the salient pharmacokinetic parameters of the different dosage forms. RESULTS: Sustained in vitro drug release was obtained from the mucoadhesive formulations. Apomorphine was absorbed more rapidly in rabbits when administered intranasally than as a subcutaneous injection. The mucoadhesive formulations both gave sustained plasma drug concentrations and bioavailabilities comparable to subcutaneous injections. The times taken to achieve peak plasma drug concentrations from these mucoadhesive formulations were more than three-fold that of lactose. With these mucoadhesive formulations apomorphine lasted longer in the blood. It could be detected for up to 6-8 h compared to approximately 3 h for the other forms of administration. CONCLUSIONS: The nasal bioavailability of powders is higher than that of solutions. Drug release from the mucoadhesive powders was sustained and there was no significant difference between Carbopol 971P and polycarbophil.

Dose response and concentration response relationship of apomorphine in patients with Parkinson's disease and end-of-dose akinesia.

The motor response and the PK-PD relationship of the dopamine agonist, apomorphine, after ascending single doses (0.5, 1, 2, 4 mg s.c.), was investigated in 10 patients with advanced Parkinson's disease presenting end-of-dose motor fluctuations. Aim of the study was to investigate the exact pharmacodynamic effects of different apomorphine doses on the magnitude and duration of motor responses in parkinsonian fluctuators. The average improvement in the magnitude of the motor response (% change of baseline score in the Columbia University Rating Scale) elicited by apomorphine was negligible with 0.5 mg, 10% after the 1 mg dose, 22% after 2 mg, and 25% after 4 mg. If a 20% improvement is considered clinically relevant, a response was seen in 0/10 patients (0.5 mg), 2/10 patients (1 mg), 6/10 patients (2 mg), and 6/8 patients (4 mg). The duration of response was about 0.25 h (1 mg), 0.58 h (2 mg), and 0.72 h (4 mg). An explorative analysis of individual plasma concentration vs. effect curve, yielded a steep, sigmoidal concentration effect relationship with fast equilibrium at the effect site. The EC50 of the individual curves averaged 20 pMol/ml. However, several curves exhibited proteresis, making the application of a PK-PD model impossible. The reason for proteresis is not clear, it might indicate acute tolerance as well as a redistribution of apomorphine from the effect site.