- Top of page
- Competing Interests
- Supporting Information
The non-ergolinic dopamine agonist rotigotine with activity across D1 through D5 receptors as well as select adrenergic and serotoninergic sites was developed as a silicone-based matrix-type transdermal system to provide continuous drug delivery with maintenance of stable plasma concentrations over 24 h . Continuous drug delivery potentially minimizes pulsatile stimulation of striatal dopamine receptors which is implicated in the development of motor fluctuations and dyskinesia . Following patch application, on average approximately half of the administered rotigotine dose (46%) is systemically absorbed . Rotigotine is then rapidly metabolized, mainly by conjugation (sulphation and glucuronidation) . A second pathway is the formation of N-desalkyl metabolites with subsequent conjugation . There is no pharmacokinetic interaction with levodopa/carbidopa  and rotigotine can be co-administered with the anti-emetic domperidone without changes in the pharmacokinetics of rotigotine . Randomized, placebo-controlled studies have demonstrated efficacy in early Parkinson's disease (PD) as monotherapy [7, 8] and in combination with levodopa in advanced patients [9, 10]. Efficacy has also been shown for the treatment of restless legs syndrome (RLS) [11, 12].
Both PD and RLS prevalence increase with age. Overall the prevalence of PD in seven European population-based studies was 1.8% in patients over the age of 65 years, ranging from 0.6% for those aged 65 to 69 years up to 2.6% for the 85 to 89 year age group . The increase in RLS prevalence between young and older age is two to three fold . RLS prevalence is also high in dialysis patients, and patients suffering from both end-stage renal disease (ESRD) and RLS have an increased risk of mortality .
Elderly PD and RLS patients are likely to suffer from other age-related impairments, as most major body systems are affected by advancing age. Changes in renal function and anatomy occur with age  which have important implications for drug therapy in the elderly . This phase I study evaluated the influence of different stages of chronic renal insufficiency on the pharmacokinetics and safety/tolerability of the transdermally applied dopamine agonist rotigotine.
- Top of page
- Competing Interests
- Supporting Information
A total of 32 subjects participated in the study: eight healthy subjects, one subject with mild impairment of renal function, seven patients with moderate impairment of renal function, eight patients with severe impairment of renal function and eight patients with end-stage renal insufficiency requiring haemodialysis. More male subjects (65.6%) were enrolled compared with female subjects (34.4%). Table 1 summarizes the demographic characteristics of the study population. The groups compared well. However, healthy subjects were slightly younger and patients with moderate impairment of renal function older than the other groups. Concomitant diseases reported at study entry for subjects with chronic renal insufficiency were mostly related to their underlying disease. All subjects with impairment of renal function were taking concomitant medication at study entry and throughout the study, primarily for treatment of renal insufficiency and associated diseases. Two healthy subjects received concomitant medication (paracetamol for headache; ascorbic acid + calcium + rutoside for serous nose discharge; ascorbic acid + chlorhexidine for throat reddening) which was not considered to impact on the study objective. All 32 subjects completed the study and were included in the per protocol and safety analysis. Since only one subject with mild impairment of renal function enrolled in the study, an anova was not possible for this group and this group could therefore not be included in comparative pharmacokinetics.
Table 1. Demographic characteristics of the study population
| ||Healthy||Mild impairment of renal function||Moderate impairment of renal function||Severe impairment of renal function||End-stage renal insufficiency requiring haemodialysis|
|Number of patients||8||1||7||8||8|
|Age (years)||37.6 (17.2)||39||55.4 (11.2)||41.5 (13.5)||49.0 (8.7)|
|Bodyweight (kg)||71.0 (9.3)||78.0||77.7 (9.7)||73.8 (12.7)||71.0 (9.0)|
|Height (m)||1.67 (0.09)||1.78||1.71 (0.11)||1.70 (0.03)||1.71 (0.06)|
|Body mass index (kg m−2)||25.5 (3.7)||24.6||26.7 (3.8)||25.6 (4.2)||24.3 (3.4)|
The apparent dose values for rotigotine as an estimate for the amount of drug absorbed within 24 h were similar for all groups (ranging from a mean value of 1.95 mg for patients with end-stage renal insufficiency to a mean value of 2.3 mg for patients with severe impairment of renal function) with a mean value of 2.14 mg which corresponds to 45.2% of the applied dose.
Unconjugated rotigotine Median plasma concentration–time curves of unconjugated rotigotine are shown in Figure 1.
Figure 1. Median plasma concentration–time profiles of unconjugated rotigotine. ○ group 1 healthy subjects, ● group 3 moderate renal impairment, ▸ group 4 severe renal impairment and group 5 end-stage renal impairment
Download figure to PowerPoint
Curves were similar for all groups with maximum concentrations 16 h after patch application except for patients with end-stage renal insufficiency who showed maximum values at 24 h. Blood sampling times were, however, different for these patients compared with the other groups due to haemodialysis procedures. Rotigotine was eliminated with a terminal half-life of approximately 7 h. Most rotigotine concentrations had reached LOQ 24 h after patch removal in almost all subjects. Patients with end-stage renal insufficiency started dialysis 22 h after patch application. Their rotigotine elimination pattern was not different from the other groups indicating that rotigotine was not removed from plasma by haemodialysis. In accordance, no rotigotine was found in the dialysis fluid.
Table 2 presents the summary for the pharmacokinetic parameters for unconjugated rotigotine. Variability between subjects was high for most parameters. Cmax increased slightly with the degree of renal insufficiency. The same trend was also observed for AUC(0,tlast). Statistical comparison of the primary parameters (Cmax and AUC(0,tlast)) for the different patient populations with renal impairment compared with healthy subjects showed that all point estimates for the ratios were close to 1:0.88 for AUC and 0.93 for Cmax for moderate renal impairment, 1.14 and 1.18 for severe renal impairment and 1.05 and 1.25 for end-stage renal insufficiency requiring haemodialysis (Table S1 in supplementary file). No statistical correlation was observed between either Cmax or AUC(0,tlast) for unconjugated rotigotine and creatinine clearance for healthy subjects and subjects with moderate and severe impairment of renal function (ρSp=−0.045, P= 0.834 for Cmax and ρSp=−0.097, P= 0.654 for AUC(0,tlast)). Median time to reach Cmax was 16 h for healthy subjects and subjects with moderate impairment of renal function and 24 h for more severe renal insufficiency. There was no obvious difference in terminal half-life with mean values in the range of 5–7 h across the four treatment groups. Geometric mean values of 6.99 h and 6.8 h were observed for healthy subjects and end-stage renal insufficiency patients, respectively. The apparent total clearance and volume of distribution were similar across all four groups. On the other hand, Ae and renal clearance decreased with the degree of renal impairment. Statistical correlations with creatinine clearance were observed for Ae (ρSp= 0.433, P= 0.039) and renal clearance (ρSp= 0.416, P= 0.048) but not for CL/F (ρSp= 0.085, P= 0.692). It should be noted, however, that renal clearance of unconjugated rotigotine accounts for only a very small percentage of the administered dose (Ae for healthy subjects was 0.02% of the administered rotigotine dose and ranged between 0.002% and 0.01% for subjects with renal impairment). Changes in renal clearance with increasing renal impairment had no observable effects on the apparent total clearance. Linear regression analysis established a correlation for CLR and CLcr (r2= 0.2864; supplementary Figure S1A) but none for λz with CLcr (r2= 0.0035; supplementary Figure S1B).
Table 2. Pharmacokinetic parameters of unconjugated rotigotine
| ||Healthy||Moderate impairment of renal function||Severe impairment of renal function||End-stage renal insufficiency requiring haemodialysis|
|Apparent dose (mg)†||2.27 (29.5%)||2.04 (23.0%)||2.30 (18.3%)||1.95 (20.4%)|
|Cmax (ng ml−1)||0.199 (56.5%)||0.187 (67.6%)||0.235 (41.6%)||0.249 (52.6%)|
|Cmax,norm (ng ml−1 kg mg−1)||6.4 (37.8%)||7.22 (43.9%)||7.55 (26.3%)||9.21 (48.8%)|
|AUC(0,tlast) (ng ml−1 h)||3.97 (50.9%)||3.48 (61.5%)||4.54 (39.4%)||4.17 (48.8%)|
|AUC(0,tlast)norm (ng ml−1 h kg mg−1)||127.5 (28.4%)||134.6 (40.6%)||146.2 (27.3%)||154.1 (36.3%)|
|AUC(0,∞) (ng ml−1 h)||4.25 (45.8%)||3.64 (57.8%)||4.76 (37.1%)||4.25 (50.7%)|
|Ae (µg)||0.95 (0.55–2.05)||0.45 (0.27–0.89)||0.40 (0–2.47)||0.02 (0–0.18)|
|CLR (l h−1)||0.22 (43.7%)||0.13 (46.3%)||0.11 (104%)||0.018 (139%)|
|CL/F (l h−1)||1058 (45.8%)||1236 (57.8%)||945 (37.1%)||1059 (50.7%)|
|t1/2 (h)||6.99 (55.6%)||5.04 (40.1%)||6.75 (50.8%)||6.8 (34.7%)|
|tmax (h)||16 (12–24)||16 (12–24)||23.8 (16–24)||24 (22–24)|
|Vz/F (l)||10 661 (68.5%)||8991 (97.6%)||9209 (71.3%)||10 381 (75.1%)|
Protein binding could not be evaluated in some samples because rotigotine concentrations were below LOQ in one of the two dialysis chambers. Data above LOQ were available from nine subjects (mainly from the severe and end-stage groups). Median binding was similar in both groups (89% for patients with severe impairment of renal function and 91.9% for patients with end-stage renal insufficiency). Owing to sparse data, a correlation between the unbound fraction and serum albumin concentrations or CLcr could not be determined.
Conjugated rotigotine Median plasma concentration–time curves of conjugated rotigotine are shown in Figure 2. Concentrations are about three-fold higher than for unconjugated rotigotine. Median conjugated rotigotine plasma concentration peaked 16 h after patch application for healthy subjects, 24 h for patients with moderate and with severe impairment of renal function, and 22 h for patients with end-stage renal insufficiency requiring dialysis (Figure 2). Plasma concentrations of conjugated rotigotine were considerably higher for patients with severe impairment of renal function; the peak of median conjugated rotigotine concentrations in this group (0.99 ng ml−1) was more than double the concentration for healthy subjects (0.35 ng ml−1) and for patients with moderate impairment of renal function (0.62 ng ml−1). At the end of the dialysis comparison of median plasma concentrations of conjugated rotigotine measured in samples from the arterial inlet with corresponding concentrations in samples from the venous outlet reflected no extracorporeal extraction, 0.39 ng ml−1vs. 0.43 ng ml−1.
Figure 2. Median plasma concentration–time profiles of conjugated rotigotine. ○ group 1 healthy subjects, ● group 3 moderate renal impairment, ▴ group 4 severe renal impairment and group 5 end-stage renal impairment
Download figure to PowerPoint
Variability between subjects was high for most pharmacokinetic parameters (Table 3). For conjugated rotigotine, Cmax and AUC(0,tlast) and their normalized values increased with decreasing renal function, particularly for the severe impairment group. The mean maximum plasma concentration (Cmax) in this group was higher than for the group on dialysis. Statistical analysis indicated that the exposure to conjugated rotigotine was only slightly increased in subjects with moderate impairment of renal function compared with healthy subjects but Cmax and AUC(0,tlast) doubled in subjects with severe impairment of renal function compared with healthy subjects (Table 3) with point estimates of 2.2 for Cmax and 2.18 for AUC (supplementary Table S1). Intermediate increases in Cmax and AUC(0,tlast) of about 55% and 50% were observed in subjects with end-stage renal insufficiency requiring haemodialysis. However, it should be noted that the 90% CIs were very wide and the variability in the data was high, particularly for the severe renal impairment group.
Table 3. Pharmacokinetic parameters of conjugated rotigotine
| ||Healthy||Moderate renal impairment||Severe renal impairment||End-stage renal insufficiency requiring haemodialysis|
|Cmax (ng ml−1)||0.492 (46.5%)||0.629 (40.2%)||1.08 (99.1%)||0.663 (75.7%)|
|Cmax,norm (ng ml−1 kg mg−1)||15.8 (52.8%)||24.1 (29.5%)||34.8 (109.4%)||24.5 (55.1%)|
|AUC(0,tlast) (ng ml−1 h)||10.8 (48.0%)||12.0 (32.4%)||23.5 (90.0%)||14.1 (66.4%)|
|AUC(0,tlast)norm (ng ml−1·h·kg mg−1)||347.1 (50.3%)||475.1 (33.4%)||757.0 (96.4%)||520.9 (44.2%)|
|AUC(0,∞) (ng ml−1 h)||11.4 (48.0%)||12.9 (31.7%)||24.6 (88.9%)||14.7 (64.7%)|
|Ae (µg)||148.6 (41.1–395.6)||24.9 (20.3–61.5)||42.2 (11.0–110.6)||2.0 (0.2–8.5)|
|CLR (l h−1)||12.6 (37.2%)||2.14 (46.7%)||1.60 (83.6%)||0.13 (176%)|
|CL/F (l h−1)||394.7 (48.0%)||348.4 (31.7%)||183.0 (88.9%)||306.8 (64.7%)|
|t1/2 (h)||10.2 (33.2%)||8.3 (32.7%)||11.1 (10.4)||9.4 (15.5%)|
|tmax (h)||23.5 (12–26)||23.5 (23.5–24)||24 (16–26)||22 (22–28)|
|λz (1 h−1)||0.068 (33.2%)||0.0836 (32.%)||0.0625 (10.4%)||0.0739 (15.5%)|
Correlations with CLcr were observed for both parameters: ρSp=−0.43, P= 0.036 for Cmax and ρSp=−0.406, P= 0.049 for AUC(0,tlast). Median time to reach Cmax was identical for healthy subjects and subjects with different stages of renal insufficiency. Compared with healthy subjects, terminal half-life was slightly lower in subjects with moderate and end-stage renal insufficiency but higher in subjects with severe impairment of renal function. Hence, there was no obvious difference for terminal half-life with decreasing renal function. There was a general trend for decreasing apparent total clearance and volume of distribution with increasing severity of renal insufficiency; the lowest values were observed in the subjects with severe impairment of renal function. Ae and renal clearance were substantially lower in the groups with impaired renal function compared with healthy subjects: five times lower in the group with moderate impairment of renal function and four times lower for subjects with severe impairment of renal function. Renal clearance of conjugated rotigotine was almost negligible in subjects with end-stage renal insufficiency requiring haemodialysis. The correlation between conjugated rotigotine and creatinine clearance for CLR and Ae was strong: ρSp= 0.863, P < 0.0001 for CLR, and ρSp= 0.629, P= 0.001 for Ae, but not for CL/F: ρSp= 0.376, P= 0.071. Linear regression analysis established a correlation for CLR and CLcr (r2= 0.7592; supplementary Figure S2A) but none for λz with CLcr (r2= 0.0112; supplementary Figure S2B).
N-desalkyl metabolites Total N-desalkyl metabolites of rotigotine (unconjugated N-desalkyl metabolites and conjugates) in plasma were determined 23.5 h after patch application (22 h for the end-stage group) and were higher in all groups with subjects with impaired renal function compared with healthy subjects (supplementary Table S2). Concentrations of unconjugated N-despropyl and N-desthienylethyl metabolites in plasma and urine were below LOQ for the majority of samples across all groups.
The amount excreted over 24 h for total N-despropyl and N-desthienylethyl metabolites varied between the groups (supplementary Table S2). There was no obvious trend for a decrease with increasing severity of renal insufficiency.
In total, 13 subjects reported 29 treatment emergent adverse events, most of which were mild or moderate in intensity. None of the AEs occurred in the group with end-stage renal insufficiency. No serious AEs or deaths occurred during the study. Two severe AEs (headache and elevated blood pressure) were reported for a subject with moderate impairment of renal function. Another patient with moderate impairment of renal function had a mild upper respiratory tract infection which deteriorated into an acute bronchitis. The number of adverse events did not increase with the severity of renal insufficiency and all adverse events resolved by the end of the study. Seventy-two percent (72%) of all AEs were considered related to the study medication including all events of nausea (21.9%, two healthy subjects, five subjects with impaired renal function), vomiting (9.4%, one healthy subject, two subjects with impaired renal function) and application site reactions (9.4%, two healthy subjects, one subject with impaired renal function). The latter were described as ‘itching under the patch’ and were mild in intensity. Evaluation of skin tolerability revealed one case of evident and eight cases of slight erythema after 24 h of patch application as well as one slight and two marginal oedemas. Overall patch adhesiveness was good. The majority of patients did not show any patch lift (72%) and only four subjects presented with a 20%–49% lift.
There were no clinically relevant changes in vital signs, physical examination or ECG findings during the study. Laboratory values differed between the groups consistent with the underlying condition of the subjects with impaired renal function compared with healthy subjects but there were no clinically relevant changes in any group.
- Top of page
- Competing Interests
- Supporting Information
Exposure to the active substance, unconjugated rotigotine, was similar in healthy subjects and subjects with different stages of renal insufficiency as indicated by similar plasma concentration–time curves and pharmacokinetic parameters AUC(0,tlast) and Cmax. Bioavailability of unconjugated rotigotine was not affected by renal insufficiency. Point estimates for the ratio between healthy subjects and renal impaired subjects for AUC(0,tlast) and Cmax were near 1. The respective 90% CIs were quite wide owing to the low subject number in each group. The lack of a correlation of these parameters with CLcr supports the findings for unconjugated rotigotine. The terminal half-life of rotigotine was also comparable between the groups. Renal elimination of unconjugated rotigotine decreased with increasing severity of renal insufficiency but had no relevant effect on the total clearance. This can be explained by the extremely low percentage of unconjugated rotigotine (<1% of the administered dose) excreted in urine. Plasma concentrations did not decrease in the central circulation under extracorporeal haemodialysis, indicating that the compound was not extracted by haemodialysis.
Median plasma protein binding data measured in this study are in accordance with the plasma protein binding assessed in vitro (91.6%). The fact that rotigotine is not extracted from plasma by haemodialysis is mainly due to its high protein binding.
Conjugated rotigotine concentrations increased with impairment of renal function but there was no obvious trend for terminal half-life. Statistical comparison with healthy subjects revealed point estimates for the ratio of AUC(0,tz) and Cmax of approximately 1.4 in subjects with moderate impairment of renal function, approximately 1.5 in subjects with end-stage renal insufficiency and 2.2 in subjects with severe impairment of renal function. Both parameters correlated with CLcr. Whereas the renal clearance of conjugated rotigotine showed a correlation with the extent of renal function, the rate constant of elimination showed no influence of renal function on the rate of elimination as a whole. This indicates that biliary excretion is relevant as alternative elimination route for conjugated rotigotine.
The pharmacological activity of rotigotine and its metabolites has been tested in in vitro receptor binding assays with human receptor subtypes expressed in cell lines. Whereas rotigotine exhibits its high affinity for the dopamine receptors, in particular for the D3 receptor, the phase 2 conjugates have practically no affinity (data on file). Therefore, the increase in exposure to conjugated rotigotine observed in subjects with impaired renal function (up to approximately two-fold in subjects with severe impairment of renal function) is considered not relevant for biological activity of rotigotine.
In vitro, unconjugated N-desalkyl metabolites also have a high affinity to some of the dopamine receptors. However, unconjugated N-desalkyl metabolites are hardly detectable in plasma in healthy subjects as well as in subjects with different stages of renal insufficiency. Plasma concentrations of total N-desalkyl metabolites are increased in subjects with impaired renal function compared with healthy subjects. This reflects mainly an increase in conjugates of N-desalkyl metabolites which are also considered biologically inactive.
Taking into consideration all the pharmacokinetic assessments in this study, dose adjustment is not needed for rotigotine treatment in patients with different stages of renal insufficiency including patients requiring haemodialysis.
End-stage renal disease is often associated with RLS. In a recent cross-sectional study of ESRD patients requiring haemodialysis, one fifth of all patients (21.5%) were affected by RLS, with negative impact on quality of sleep, including higher risk of sleep apnoea and more depressive symptoms than in patients without RLS . The incidence of new cardiovascular events was also higher in ESRD patients with RLS, with a significantly higher risk of mortality .
Overall prevalence of PD increases with age . Also, impairment of renal function increases with age , having important implications for drug therapy in the elderly . Hence, the availability of a dopaminergic treatment option without the need for dose adjustment due to a decrease in renal function may be an advantage in patients suffering from PD or RLS.
The influence of renal insufficiency on the pharmacokinetic profile of other dopamine agonists administered for PD and RLS treatment has been investigated. Oral pramipexole is almost completely eliminated by renal tubular secretion  and therefore dose adjustments are needed for patients with moderate to severe impairment of renal function. Oral clearance values of ropinirole were not different in patients with moderate impairment of renal function compared with patients with mild or no impairment of renal function . The effect of haemodialysis on ropinirole removal is not known but considered unlikely because of the relatively high apparent volume of distribution of this dopamine agonist . Data for patients with severe renal insufficiency are not available. The pharmacokinetics of cabergoline were not altered in 12 patients with moderate-to-severe renal insufficiency . The probable reason for this finding is the same as for rotigotine: a very low renal elimination of 1% for the active compound .
Application of the rotigotine patch was well tolerated in both healthy subjects and subjects with impaired renal function. The most frequently reported adverse events were nausea and vomiting, common dopaminergic side effects which were mild to moderate in intensity and resolved by the end of the study. Both skin tolerability and adhesiveness of the transdermal rotigotine patch were good.
In conclusion, no dose adjustment for transdermal rotigotine is required in subjects with different stages of impaired renal function including subjects with end-stage renal insufficiency requiring haemodialysis. This may be of advantage in the chronic treatment of an older patient population, e.g. patients with PD or RLS.
- Top of page
- Competing Interests
- Supporting Information
Figure S1 (A) Correlation of renal clearance of unconjugated rotigotine with creatinine clearance; (•) individual estimations, (—) result of linear regression. (B) Correlation of rate constant of unconjugated rotigotine elimination with creatinine clearance; (•) individual estimations, (—) result of linear regression
Figure S2 (A) Correlation of renal clearance of conjugated rotigotine with creatinine clearance; (•) individual estimations, (—) result of linear regression. (B) Correlation of rate constant of conjugated rotigotine elimination with creatinine clearance; (•) individual estimations, (—) result of linear regression
Table S1 Statistical comparison of Cmax and AUC(0,tlast) between patient groups with different stages of renal insufficiency and healthy subjects (point estimates [least squares means] and 90% confidence interval)
Table S2 Pharmacokinetic parameters of total N-desalkyl metabolites of rotigotine
Please note: Wiley Blackwell is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.