The P-I-E-N-O Parkinsn's List Drug Database

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ropinerole / Requip^TM Insert Page 2

Ropinirole is widely distributed throughout the body, with an apparent volume of distribution of 7.5L/kg(cv=32%). It is up to 40% bound to plasma proteins and has a blood-to-plasma ratio of 1.1.

The major metabolic pathways are N-despropylation and hydroxylation to form the inactive N-despropyl and hydroxy metabolites. In vitro studies indicate that the major cytochrome P450 isozyme involved in the metabolism of ropinirole is CYP1A2, an exzyme known to be stimulated by smoking and omeprazole, and inhibited by, for example, fluvoxamine, mexiletine, and the older fluoroquinolones, such as ciprofloxacin and norfioxacin. The N-despropyl metabolite is converted to carbamyl glucuronide carboxylic acid, and N-despropyl hydroxy metabolites. The hydroxy metabolite of ropinirole is rapidly glucuronidated. Less than 10% of the administered dose is excreted as unchanged drug in urine. N-despropyl ropinirole is the predominant metabolite found in urine (40%), followed by the carboxylic acid metabolite (10%), and the glucuronide of the hydroxy metabolite (10%).

P450 Interaction: In vitro metabolism studies showed that CYP1A2 was the major enzyme responsible for the metabolism of ropinirole. There is thus the potential for inhibitors or substrates of this enzyme to alter its clearance when coadministered with ropinirole. Therefore, if therapy with a drug known to be a potent inhibitor of CYP1A2 is stopped or started during treatment with Requip, adjustment of the Requip^TM dose may be required.

Population Subgroups

Because therapy with Requip^TM is initiated at a subtherapeutic dosage and gradually titrated upward according to clinical tolerability to obtain the optimum therapeutic effect, adjustment of the initial dose based on gender, weight or age is not necessary.

Age: Oral clearance of ropinirole is reduced by 30% in patients above 65 years of age compared to younger patients. Dosage adjustment is not necessary in the elderly (above 65 years) as the dose of ropinirole is to be individually titrated to clinical response.

Gender: Female and male patients showed similar oral clearance.

Race: The influence of race on the pharmacokinetics of ropinirole has not been evaluated.

Cigarette Smoking: The effect of smoking on the oral clearance of ropinirole has not been evaluated. Smoking is expected to increase the clearance of ropinirole since CYP1A2 is known to be induced by smoking.

Renal Impairment: Based on population pharmacokinetic analysis, no difference was observed in the pharmacokinetics of ropinirole in patients with moderate renal impairment (creatinine clearance between 30 to 50 mL/min.) compared to an age-matched population with creatinine clearance above 50 mL/min. Therefore, no dosage adjustment is necessary in moderately renally impaired patients. The use of Requip^TM (ropinirole hydrochloride) in patients with severe renal impairment has not been studied. The effect of hemodialysis on drug removal is not known, but because of the relatively high apparent volume of distribution of ropinirole (525 L), the removal of the drug by hemodialysis is unlikely.

Hepatic Impairment: The pharmacokinetics of ropinirole have not been studied in hepatically impaired patients. These patients may have higher plasma levels and lower clearance of the drug than patients with normal hepatic function. The drug should be titrated with caution in this population.

Other Diseases: Population pharmacokinetic analysis revealed no change in the oral clearance of ropinirole in patients with concomitant diseases, such as hypertension, depression, osteoporosis/arthritis, and insomnia, compared to patients with Parkinson's disease only.

Clinical Trials

The effectiveness of Requip^TM in the treatment of Parkinson's disease was evaluated in a multi-national drug development program consisting of 11 randomized, controlled trials. Four were conducted in patients with early Parkinson's disease and no concomitant L-dopa and 7 were conducted in patients with advanced Parkinson's disease with concomitant L-dopa.

Among these 11 studies, three placebo-controlled studies provide the most persuasive evidence of ropinirole's effectiveness in the management of patients with Parkinson's disease who were and were not receiving concomitant L-dopa. Two of these three trials enrolled patients with early Parkinson's disease (without L-dopa) and one enrolled patients receiving L-dopa.

In these studies a variety of measures were used to assess the effects of treatment (e.g., the Unified Parkinson's Disease Rating Scale (UPDRS), Clinical Global Impression scores, patient diaries recording time "on" and "off", and tolerability of L-dopa dose reductions). In both studies of early Parkinson's disease (without L-dopa) patients, the motor component (Part III) of the UPDRS was the primary outcome assessment. The UPDRS is a four-part multi-item rating scale intended to evaluate mentation (Part I), activities of daily living (Part II), motor items designed to assess the severity of the cardinal motor findings in patients with Parkinson's disease (e.g. tremor, rigidity, bradykinesia, postural instability,etc.) scored for different body regions and has a maximum (worst) score of 108. Respondents were defined as patients with at least a 30% reductions in the Part III score.

In the study of advanced Parkinson's disease (with L-dopa) patients, both reduction in percent awake time spent "off" and the ability to reduce the daily use of L-dopa were assessed as a combined endpoint and individually.

Studies in Patients with Early Parkinson's Disease (without L-dopa)

One early therapy study was a 12-week multicenter study in which 63 patients (41 on Requip) with idiopathic Parkinson's disease receiving concomitant anti-Parkinson medication (but not L-dopa) were randomized to either Requip^TM or placebo. Patients had a mean disease duration of approximately 2 years. Patients were eligible for enrollment if they presented with bradykinesia and as least tremor, rigidity, or postural instability. In addition, they must have been classified as Hoehn & Yahr Stage I-IV. This scale, ranging from I=unilateral involvement with minimal impairment to V=confined to wheelchair or bed, is a standard instrument used for staging patients with Parkinson's disease. The primary outcome measure in this trial was the proportion of patients experiencing a decrease (compared to baseline)of at least 30% in the UPDRS motor score.

Patients were titrated for up to 10 weeks, starting at 0.5mg b.i.d., with weekly increments of 0.5 mg b.i.d. to a maximum to 5 mg b.i.d. Once patients reached their maximally tolerated dose (or 5 mg b.i.d.), they were maintained on that dose through 12 weeks. The mean dose achieved by patients at study endpoint was 7.4 mg/day. At the end of 12 weeks, 71% of Requip^TM treated patients were responders, compared with 41% of patients in the placebo group (P=0.021).

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