The effect of steady-state ropinirole on plasma concentrations of digoxin in patients with Parkinson’s disease

Abstract

Aims

The aim of this single-blind study was to assess the effect of ropinirole, a novel treatment for Parkinson’s disease, on the steady-state pharmacokinetics and safety of digoxin in 10 patients with Parkinson’s disease.

Methods

There were three parts to the study: digoxin once daily plus placebo three times daily for 1 week; digoxin once daily plus ropinirole three times daily for 6 weeks; and digoxin once daily plus placebo three times daily for 1 week. Serial blood samples were collected over 24 h at the end of each part of the study for pharmacokinetic assessment. Pre-dose blood samples were collected on specific days throughout the study to assess the attainment of steady-state plasma levels of digoxin. The primary endpoints were AUC(0, τ) and C_max for digoxin.

Results

There was a mean decrease of 10% in digoxin AUC (0, τ) (90% CI: 0.79, 1.01) and a 25% decrease in digoxin C_max (90% CI: 0.58, 0.97) when ropinirole was co-administered, compared with digoxin alone. C_min plasma values for digoxin, however, were fairly constant throughout the study (point estimates 0.99, 95% CI: 0.85, 1.15). Changes in trough levels of digoxin are believed to be the most reliable way of assessing steady-state concentrations of digoxin, and therefore the clinical significance of an interaction. Changes in C_max are too readily influenced by other factors.

Conclusions

These results therefore indicate that on pharmacokinetic grounds no dose adjustment is necessary for digoxin co-administered with ropinirole.

Introduction

Ropinirole (4-]2-(dipropylamino)ethyl[-1,3-dihydro-2Hindol-2-one hydrochloride) is a novel, potent and highly selective non-ergoline agonist at dopamine D₂ receptors [1]. Clinical studies have indicated that the efficacy of ropinirole in the oral treatment of Parkinson’s disease is comparable with that of l-dopa in the early stages of the disease [2]. As many of the patients suffering from Parkinson’s disease are elderly, a high proportion would be expected to be receiving concurrent digoxin therapy, used in the treatment of atrial fibrillation and heart failure. Cardiac glycosides have a narrow therapeutic window, and changes in digoxin plasma levels may result in either a loss of therapeutic efficacy or impaired tolerance to the drug. The aim of the present study was therefore to assess the effect of ropinirole (6 weeks’ dosing) on the steady-state pharmacokinetics and safety of digoxin in patients with Parkinson’s disease. A preliminary communication of this work has been published previously [3].

Methods

Patients

The study was carried out at the Casa di Cura ‘Villa Margherita’, Arcugnano (Vicenza), Italy. The ten participating patients (five male, five female) had both idiopathic Parkinson’s disease (modified Hoehn and Yahr Stages I–III) and a cardiac condition requiring treatment with digoxin. Suitability for inclusion in the study was assessed within 15 days prior to its start. This assessment consisted of a medical examination and history, a 12-lead ECG, measurement of pulse and blood pressure, and haematology, clinical chemistry and urinalysis assessments.

Study design and medication

To measure the impact of ropinirole on the steady-state pharmacokinetics and safety of digoxin, this single-blind study was divided into three parts for intra-individual comparison: 1 week’s dosing with digoxin once daily plus placebo three times daily (Part 1); followed by 6 weeks’ dosing with digoxin once daily plus ropinirole three times daily (Part 2); and finally 1 week’s dosing with digoxin once daily plus placebo three times daily as a placebo washout (Part 3). Both drugs and the placebo were administered orally.

All patients had received long-term treatment with oral digoxin and had stable digoxin doses (0.125 or 0.25 mg once daily) prior to entry into the study. Two patients received digoxin, 0.25 mg once daily and the remaining patients received 0.125 mg once daily. No patient received any drugs known to interact with digoxin, and doses of other concomitant medications were held constant during the study. All patients were receiving regular therapy with l-dopa.

Ropinirole, starting at 0.25 mg three times daily for 7 days, was titrated upwards in weekly increments to 2.0 mg three times daily. Doses of ropinirole or placebo were taken with or immediately after a meal, except on the digoxin profile days (24 h serial blood samples taken for pharmacokinetic assessment on days 7, 49 and 56), when the morning dose was administered in the fasting state. The digoxin dose was taken with the morning dose of ropinirole or placebo.

Patients attended the clinic on days 1, 6, 7, 8, 15, 22, 29, 36, 43, 48, 49, 50, 55, 56 and 57. Follow-up took place within 15 days of the end of dosing.

The study was conducted in accordance with good clinical practices and the Declaration of Helsinki, as amended in Hong Kong (1989). The protocol and statement of informed consent were approved by the Casa di Cura Ethics Committee prior to the start of the study. Written informed consent was obtained from each patient prior to entry.

Pharmacokinetic and safety assessments

Serial blood samples were collected over 24 h after the morning dose on days 7, 49 and 56 (the end of each part of the study) for pharmacokinetic assessment. Additional pre-dose blood (minimum plasma concentrations, C_min) samples were collected on specific days throughout each part of the study to assess the attainment of steady-state plasma levels of digoxin. Blood samples were centrifuged and the resultant plasma was sent to Phoenix International Life Sciences Inc., Saint-Laurent (Montreal), Quebec, Canada, and analysed for digoxin content by radioimmunoassay. The assay for digoxin was validated and achieved coefficients of variation of less than 20% from known concentrations in quality control samples. The lower limit of quantification of the assay was 0.1 ng ml⁻¹. Vital signs and any adverse experiences were evaluated pre-dose at each visit to the clinic (except on days 1, 6 and 7), and at follow-up. A 12-lead ECG was carried out pre-study and at follow-up, together with laboratory monitoring at pre-study and follow-up, and on days 7 and 57.

Statistical evaluations

Digoxin plasma concentration–time data were subjected to non-compartmental analysis using in-house computer software which incorporates standard algorithms in order to calculate estimates of the area under the individual plasma concentration–time curves over the dosing interval (AUC(0, τ)). Maximum plasma concentrations (C_max) and the time at which C_max occurred (t_max) were determined visually. The primary endpoints for the assessment of any drug interactions between ropinirole and digoxin were AUC (0, τ) and C_max for digoxin. For data interpretation, all derived parameters (C_max, AUC (0, τ) and C_min values) were dose normalized to 0.125 mg digoxin. C_max and AUC (0, τ) were log_e-transformed prior to analysis of variance. Ropinirole was considered to have no effect on the pharmacokinetics of digoxin if the 90% confidence intervals (CIs) for the ratio of the geometric means (digoxin+ropinirole:digoxin alone ]part 2:part 1[) were completely contained within the range 0.80–1.25 for C_max and AUC (0, τ). Parts 1 and 3 were statistically compared for assessment of any period and carryover effects on the pharmacokinetic parameters. Retrospectively, C_min values were also analysed statistically as for C_max values, but 95% CIs were calculated.

Statistical analyses were carried out using an SAS for Windows software package (version 6.08).

Results

The mean age of the 10 patients was 72 years (range 65–74 years); all were Caucasian. A summary of the mean dose-normalized pharmacokinetic parameters for digoxin is given in Table 1. Mean plasma concentration–time profiles are shown in Figure 1. On average, there was a 10% decrease in digoxin AUC (0, τ) when ropinirole was co-administered (Part 2), compared with digoxin alone (Part 1). The 90% CI for this parameter (0.79, 1.01) was just outside the lower range of that defined for a pharmacokinetic interaction (0.80, 1.25). However, one of the patients (number 6) showed very low plasma levels in both Parts 1 and 2 of the study, compared with other patients in the group, though the plasma concentration data for this patient in Part 3 were similar to those of other patients, suggesting an unstable baseline. By re-analysing the data without this patient, the point estimate of 0.90 and associated 90% CI (0.81, 1.00) were completely contained within the acceptance range.

Table 1.

Dose-normalized pharmacokinetic parameters for digoxin.

Figure 1.

Mean plasma concentrations of digoxin following administration of digoxin to steady state with placebo (Parts 1 (○) and 3 (▴)) or with ropinirole (2 mg three times daily; Part 2 (▪)) in patients with Parkinson’s disease.

The peak concentrations of digoxin were on average 25% lower, and median t_max 1 h later, when digoxin was co-administered with ropinirole, compared with the values achieved with digoxin alone (Table 1). Moreover, the ratio for C_max (Part 2:Part 1) of 0.75 and 90% CI (0.58, 0.97) did not support the absence of an interaction between digoxin and ropinirole. C_min plasma values for digoxin, however, were shown to be consistent throughout the study (point estimates 0.99, 95% CI: 0.85, 1.15), supporting the attainment of steady state and the lack of effect of ropinirole on this important pharmacokinetic parameter for digoxin.

No significant period or carryover effect was noted between Parts 1 and 3 of the study for AUC (0, τ). However, such effects cannot be excluded for C_max, as the upper confidence limit was above the stated range of acceptability. This was because the within-subject coefficient of variability for C_max was considerably higher than expected. Whereas the within-subject coefficient of variation was 15.9% for AUC (0, τ), it was 34.2% for C_max. Inter-subject variability for C_max was also high, with coefficients of variation of 46.2%, 52.6% and 37.6% for Parts 1, 2 and 3, respectively. Corresponding values for AUC (0, τ) were 29.4%, 34.6% and 22.2%. From the analysis, patient number 6 was identified as an outlier. When the data for this patient were excluded, the within-subject coefficient of variation was reduced to 12.9% for AUC (0, τ) and 20.1% for C_max, resulting in tighter confidence intervals for both parameters.

No adverse experiences were reported by any of the patients, and there were no withdrawals from the study. There were also no clinically significant findings in the vital signs, ECG or laboratory parameters measured.

Discussion

With respect to the extent of availability of digoxin at steady state, there was, on average, a 10% decrease in AUC (0, τ) and the 90% CI of 0.79, 1.01 narrowly missed the low range of the accepted CI. However, on exclusion of one patient (number 6) whose pharmacokinetic values could be considered outliers, the point estimate (0.90) and 90% CI of 0.81, 1.00 were completely contained within the acceptance range. Small daily fluctuations in digoxin AUC are expected, and not considered to be of any clinical consequence.

With respect to C_max, the average ratio (Part 2:Part 1) of 0.75 and 90% CI (0.58, 0.97) does not support an absence of drug interaction between digoxin and ropinirole. Examination of individual C_max values for Part 2, however, showed high intra-individual variability, which cannot be explained. The higher than expected within-patient variance in the pharmacokinetic parameters of digoxin would also suggest some inadequacy in terms of the sample size. However, this is unlikely to have materially affected the overall conclusions except with respect to contributing to the wide CIs. In addition, it has been suggested that a wider confidence interval of 70–143% is more suitable for C_max [4], in which case the present study meets this criterion and would indicate no important effect of ropinirole on digoxin C_max.

It is possible that the rate of absorption of digoxin was slowed by co-administration with ropinirole, leading to the decrease in C_max, but with no marked effect on the availability of digoxin. Few compounds have been shown to reduce the rate and extent of availability of digoxin through decreased absorption. In a study by Brown et al. [5], cholestyramine, dietary fibre and p-aminosalicylic acid all interfered with the oral absorption of digoxin, and Kirch et al. [6], found that the gastrointestinal absorption of digoxin was reduced by both cisapride and metoclopramide. However, the decrease in C_max for digoxin cannot be predicted from the pharmacological activity of ropinirole. In vivo studies in rats given a ropinirole dose of up to 10 mg kg⁻¹ did not show any marked change in their gastrointestinal function (data on file, SmithKline Beecham Pharmaceuticals).

The lack of any significant period effect for AUC between the two treatment phases of digoxin with placebo (Parts 1 and 3) and fairly consistent within- and between-patient trough values of digoxin throughout the three parts of the study further support the maintenance of steady-state digoxin exposure during the pharmacokinetic assessment. Mean C_min values of digoxin, when administered with ropinirole (at steady state), were essentially similar to those observed with digoxin alone (Parts 1 and 3). It should also be noted that the trough plasma levels of digoxin after repeated once-daily oral dosing in patients with Parkinson’s disease with 0.125 mg digoxin obtained in this study are within the same range quoted for patients in the literature [7]. Changes in trough levels of digoxin are believed to be the most reliable way of assessing steady-state concentrations of digoxin [8, 9], and therefore the clinical significance of an interaction. Changes in C_max are too readily influenced by other factors.

In conclusion, the ropinirole dosing regimen was well tolerated by patients with Parkinson’s disease receiving concurrent digoxin therapy. Although decreases were observed in both C_max and AUC (0, τ), the C_min plasma levels were comparable in each part of the study. The decreases are not considered to be clinically significant, and no dose adjustment on pharmacokinetic grounds is indicated when digoxin is co-administered with ropinirole.