WO1992000735A1

WO1992000735A1 - Ropinirole and domperidone for use in the manufacture of a medicament for the treatment of parkinson's disease

Info

Publication number: WO1992000735A1
Application number: PCT/GB1991/001121
Authority: WO
Inventors: Christian De Mey; Nadarajah Sree Haran
Original assignee: Smith Kline & French Laboratories Limited
Priority date: 1990-07-09
Filing date: 1991-07-08
Publication date: 1992-01-23
Also published as: GB9015095D0; AU8195091A

Abstract

The present invention relates to the dopamine D2-receptor antagonist, domperidone and the D2-receptor agonist, ropinirole for use in the treatment of Parkinson's disease.

Description

ROPINIROLE AND DOMPERIDONE FOR USE IN THE MANUFACTURE OF A MEDICAMENT

FOR THE TREATMENT OF PARKINSON' S DISEASE

The present invention relates to the dopamine D₂- receptor antagonist, domperidone (5-chloro-1- [ 1- [ 3- (2 , 3- dihydro-2-oxo-1H-benzimidazol-1-yl) propyl] -4-piperidinyl ] - 1 , 3-dihydro-2H-benzimidazole-2-one) and the D₂ -receptor agonist ropinirole (4- [2-dipropylaminoethyl] -1 , 3-dihydro- 2H-indol-2-one) for use in the treatment of Parkinson' s disease .

Domperidone is a well established dopamine D₂- receptor antagonist practically devoid of central effects.

Ropinirole is a novel non-phenolic indolone

derivative which acts as a dopamine D₂-receptor agonist (Gallagher et al., J. Med. Chem. 1985 28 , 1533-1536.

Studies in healthy subjects have shown that single doses of ropinirole could cause unwanted side-effects such as nausea, orthostatic hypotension and prolactin inhibition (Acton G. and Broom C. , 1989, Br. J. Clin. Pharmac., 28 , 435 and de Mey et al., 1990, Drug Res., 40, 7-12).

It has now been found that these adverse effects which occur when acute doses of ropinirole are

administered can be avoided by pre-treatment of patients with domperidone.

The present invention therefore provides, in a first aspect, ropinirole and domperidone for use in the

treatment of Parkinson's disease, characterised in that said treatment comprises sequential administration of the domperidone followed by ropinirole. Pre-treatment of subjects in this way has been found to result essentially in the removal of the adverse effects associated with ropinirole acute dosing. SUBJECTS AND METHODS

Subjects and ethics Ten male subjects (22 to 33 years of age) who on the basis of extensive investigation were judged to be healthy, participated. One subject was withdrawn from the study, and the profilings were completed for the intended nine subjects. The study was conducted in accordance with the Declaration of Helsinki (Venice

Amendment, 1983) and the German Drug Law (AMG) . The subjects were informed in detail, also of their right to withdraw from the study at any time and on their own initiative, and their consent was recorded in writing and in the presence of a witness. The protocol was approved by an independent Ethics Committee.

Materials Tablets of 200 μg ropinirole (preparable according to the procedures described in EP-113 964-B) and matched placebo were used. Domperidone tablets of 10 mg

(Motilium^R, commercially available) were used, plus matched domperidone placebo.

Study Design

The subjects were studied on three occasions at least one week apart. On one occasion domperidone placebo was administered followed 1 hour later by an active dose of 800 μg ropinirole (treatment PS) , on another, an active dose of 20 mg domperidone, with an active dose of 800 μg ropinirole 1 hour later (treatment DS) , and on a further occasion, an active dose

of 20 mg domperidone, with a ropinirole placebo 1 hour later (treatment DP). The three treatments were

profiled in a double-blind fashion. The treatment sequences were randomly allocated in a period-balanced within-subject cross-over study design.

Study Procedures

On the day preceding each profiling, the subjects abstained from alcohol, xanthine, or tyramine containing foods or beverages. They were fasted from 22:00 on the night prior to each profiling up to the end of the

profiling. The investigations started at about 07:30 am. The subjects were supine and resting for one hour before the administration of domperidone or placebo (time t=0). At 2 (t=180), 4 (4=300) and 6 hours (t=420) after dosing of ropinirole or its matched placebo (t=60), the subjects stood upright and immobile for 3 minutes after a first minute sitting on the side of the bed with both feet hanging free. Except for these postural tests, the subjects remained recumbent and resting up to 8 hours after dosing. Heart rate (HR) was monitored throughout, and blood pressure was measured every 10 minutes in supine position, and every minute during sitting and standing.

Sampling and assays for ropinirole, prolactin and

catecholamines

Venous blood was sampled for assay of plasma

ropinirole, before dosing, and at 30, 60, 90, 120, 150, 180, 240, 300, 360, 480 and 600 minutes, and at 24 hours after dosing. Plasma concentrations of ropinirole were assayed by radioimmunoassay. The antiserum used was raised in sheep to a diazo-derivative of ropinirole conjugated to bovine serum albumin and diluted 1:2500. The assay was shown to have a lower limit of

quantification of 0.31 nmol/l (inter-assay CV < 11%, accuracy ± 7%). Specificity for ropinirole was

determined in the presence of a potential mahor

metabolite in human plasma with which no significant cross-reaction was shown to occur at the concentrations studied.

Venous blood was sampled for assay of plasma

prolactin, before dosing of domperidone, at 30 minutes after dosing of domperidone, at 60 minutes after dosing of domperidone (i.e. immediately prior to dosing of ropinirole) and at 60, 120, 180, 240, 300, 360, 480 and 600 minutes, and 24 hours after administration of

ropinirole. The plasma concentrations of prolactin were assayed by radioimmunoassay using a commercial kit (MAIA clone IRMA, Serono, UK). The concentrations were expressed in units of ng/ml NIH-F1. Venous blood was sampled for assay of catecholamines immediately before dosing of domperidone (t=0),

immediately before dosing of ropinirole (t=60), and then prior to (t=180 and 420) and at the end of standing

(t=184 and 424) at 2 and 6 hours after dosing of

ropinirole. Blood for catecholamines was collected in heparinized chilled tubes which had been spiked with sodiummetabisulphite. Concentrations of noradrenaline and adrenaline in plasma were assayed by ion-exchange high performance liquid chromatography with

electrochemical detection after a clean-up procedure which included liquid/liquid extraction and re-extraction in diluted acid (Meineke et al., 1989, J. Chromatography, 493, 287). The limits of quantitation were 0.296 nmol/l and 0.027 nmol/l for noradrenaline (NE) and adrenaline (E), respectively. Data format and analysis

The supine heart rate (HR) and blood pressure

(SBP/DBP) data were summarised by the area under the time course of the variables during each hourly time zone, divided by time.

Supine observations (circulatory variables,

prolactin and catecholamines) subsequent to dosing were transformed as changes from the pre-dosing observations. Responses to standing were calculated as the postural change relative to the supine observations immediately prior to sitting and standing. These data were then assessed for subject, period and treatment related variance according to a general linear model. The residual variance was used to calculate the 95%

confidence intervals around the estimated treatment differences for [PS-DP], [DS-DP] and [DS-PS] (Scheffe's method for simultaneous evaluation of multiple

comparisons, Biometrika, 40, (1953) , 87-104).

RESULTS

One of the 10 recruited subjects was withdrawn on his second study day, before dosing of ropinirole, because of sinoatrial dysfunction with pauses up to 2 seconds, occurring at 20-30 minutes after administration of 20 mg domperidone. This event was considered not to be drug related.

Supine heart rate and blood pressure

Little difference was observed between the

treatments in terms of supine HR, SBP, DBP and MBP.

There was a trend towards slightly higher mean supine HR-values beyond the first hour after administration of ropinirole, whether pre-treated with domperidone

(treatment DS) or not (treatment PS). The effects relative to treatment DP (domperidone plus ropinirole placebo) were only about 1-4 bpm, and even when reaching statistical significance for certain time zones, hardly likely to be clinically relevant.

Observations on immobile upright standing

Orthostatic symptoms occurred on 10/26 occasions after treatment PS (ropinirole preceded by domperidone placebo). Only one event was recorded after

administration of treatment DS (ropinirole preceded by 20 mg domperidone). The postural symptoms occurred after approximately only 1 minute standing in 2/9 incidents after treatment PS, after 2 minutes in 2/9 cases, and at the end of 3 minutes standing in the remaining 5/9 incidents. In most cases faintness was observed, with pallor, dizziness and sweatiness. Often the incidents were associated with yawning. In 7/9 cases nausea was the main feature. Frank, relative or clinical

hypotension was observed in 7/11 of these symptomatic incidents, in the remaining 4, postural blood pressure responses appeared normal. None of these incidents was associated or followed by absolute or relative

bradycardia. The reactions were essentially postural in nature and rapidly transient after resuming the supine position. There was no indication of altered

orthostatic heart rate and blood pressure control in those who could sustain standing uneventfully.

Supine and standing catecholamines There was no indication that any of the treatments altered the supine catecholamine levels in a clinically relevant fashion. The treatment means and contrasts for noradrenaline are shown in Table 1. There were

furthermore no treatment effects with regard to the catecholamine responses to standing, even in those

subjects who could not sustain standing (for those

subjects the sample was taken immediately at onset of the symptoms). Plasma prolactin

The time course of the median plasma prolactin concentrations is detailed in Figure 1. Plasma prolactin thus was clearly stimulated by domperidone (treatment DP) and inhibited by ropinirole (treatment PS).

Administration of ropinirole 1 hour after administration of domperidone tended to blunt prolactin's response to domperidone, but the differences were small and not likely to be clinically relevant.

Plasma pharmacokinetics of ropinirole

The time course of the median plasma concentrations of ropinirole is detailed for treatments PS and DS in Figure 2. The curves were often characterised by

multiple peaks, and appropriate points failed to estimate the terminal slope with reasonable accuracy. The

maximum observed plasma concentration, Cmax, ranged from 3.57 to 12.6 nmol/l (mean: 6.24) and from 3.48 to 13.4 nmol/l (mean: 7.05) for treatments PS and DS, respectively. The 95% interval estimate of the true ratio DS/PS was 0.96 to 1.14. The area under the time course of the quantifiable plasma concentrations, AUC, ranged from 11.6 to 48.0 nmol.h/l (mean:26.7) and from 10.1 to 68.1

nmol.h/l (mean: 28.4) for treatments PS and DS, respectively. The 95% interval estimate of the true ratio DS/PS was 0.77 to 1.28. There thus was no

indication that pre-treatment with domperidone altered ropinirole's plasma pharmacokinetics.

In view of the foregoing data it can be concluded that single doses of 800 μg of ropinirole caused

orthostatic faintness and malaise on 10/26 occasions of 3 minutes immobile erect standing in 6/9 subjects.

Pre-treatment with a single dose of 20 mg domperidone prevented these events in all but one subject; and ropinirole's plasma pharmacokinetics remained unaltered. No treatment effects were identified in terms of supine and postural catecholamine levels.

In a further aspect, the invention provides the use of domperidone and ropinirole in the manufacture of a medicament for the treatment of Parkinson's disease, characterised in that the treatment comprises first the administration of domperidone followed by the ropinirole.

In a still further aspect, the present invention provides a medicament pack comprising at least one unit dose of domperidone and at least one unit dose of

ropinirole, said pack being suitable for use in the administration of the two drugs as hereinbefore described.

S

* a t

Figure 1 : Time course of the median plasma prolactin levels for treatments PS: placebo + ropinirole, DS: domperidone + ropinirole, and DP: domperidone + placebo. Domperidone or its placebo was administered at time t=0; ropinirole or its placebo was administered at time t=60 min.

Figure2 : Time course of the median plasma concentrations of ropinirole for treatments PS: placebo + ropinirole, and DS: domperidone + ropinirole.

Claims

Claims :

1. Ropinirole and domperidone for use in the treatment of Parkinson's disease, characterised in that the domperidone is administered prior to the ropinirole.

2. Ropinirole and domperidone for use in the manufacture of a medicament for the treatment of

Parkinson's disease, characterised in that the treatment comprises first the administration of the domperidone followed by ropinirole.

3. A medicament pack comprising at least one unit dose of domperidone and at least one unit dose of ropinirole.