A review of the receptor-binding and pharmacokinetic properties of dopamine agonists

Clinical Therapeutics/Volume 28, Number 8, 2006

A Review of the Receptor-Binding and Pharmacokinetic Properties of Dopamine Agonists Trond Kvernmo, MScl; Sebastian Hartter, PhD2; and Erich B0rger, PhD 2

l Boehringer Ingelheim Norway KS, Asker, Norway; and 2Boehringer Ingelheim Pharma GmbH ~5"Co. KG, Biberach, Germany ABSTRACT Background: Dopamine agonists (DAs), which can be categorized as ergot derived and non-ergot derived, are used in the treatment of Parkinson's disease. Objectives: This review describes the pharmacologic and pharmacokinetic properties of selected DAs and relates these characteristics to clinical outcomes, with an emphasis on adverse events. Methods: Relevant articles were identified through a search of MEDLINE (to May 2006) using the terms dopamine agonists (or each individual drug name) and

pharmacokinetics, metabolism, drug-drug interaction, interactions, CYP450, fibrosis, valvular heart disease, tremor, clinical trials, reviews, and meta-analyses. Abstracts from recent sessions of the International Congress of Parkinson's Disease and Movement Disorders were also examined. Clinical studies with <20 patients overall or <10 patients per treatment group in the final analysis were excluded. All DAs that were graded at least possibly useful with respect to at least 3 of 4 items connected to the treatment/prevention of motor symptoms/complications in the most recent evidence-based medical review update were included. This resulted in a focus on the ergot-derived DAs bromocriptine, cabergoline, and pergolide, and the nonergot-derived DAs pramipexole and ropinirole. Results: Bromocriptine, cabergoline, pergolide, and ropinirole, but not pramipexole, have the potential for drug-drug interactions mediated by the cytochrome P450 (CYP) enzyme system. The occurrence of dyskinesia may be linked to stimulation of the dopamine D 1 receptor, for which cabergoline and pergolide have a similar and relatively high affinity; bromocriptine, pramipexole, and ropinirole have been associated with a lower risk of dyskinesias. The valvular heart disease (VHD) and pulmonary and retroperitoneal fibrosis seen with long-term use appear to represent a class effect of the ergot-derived DAs that may be related to stimulation of serotonin 5-HT2B (and possibly August 2006

5-HT2A ) receptors. The incidence of valvular regurgitation was 31% to 47% with ergot-derived DAs, 10% with non-ergot-derived DAs, and 13% with controls. Conclusions: As reflected in the results of the clinical trials included in this review, dyskinesia associated with DA therapy may be linked to stimulation of the D 1 receptor. Fibrosis (including VHD) seemed to be a class effect of the ergot-derived DAs. Each of the DAs except pramipexole has the potential to interact with other drugs via the CYP enzyme system. (Clin Ther. 2006;28:1065-1078) Copyright © 2006 Excerpta Medica, Inc. Key words: Parkinson's disease, dopamine agonists, bromocriptine, cabergoline, pergolide, pramipexole, ropinirole.

INTRODUCTION

Dopamine agonists (DAs) are used in the treatment of Parkinson's disease (PD) and other disorders involving dopaminergic dysfunction (eg, restless legs syndrome [RLS]). 1 They can be categorized as ergot derived (bromocriptine, cabergoline, and pergolide) and nonergot derived (ropinirole and pramipexole). DAs are considered first-line treatment for functional impairment in PD, 2 with the addition of L-dopa for further symptomatic improvement. The most common adverse effects (AEs) associated with DA therapy are nausea, somnolence, insomnia, dizziness, postural hypotension, anorexia, edema, hallucinations, and dyspepsia, g-5 Because PD and RLS are more prevalent among the elderly, 1,s it may be common for such paAccepted for publication June 27, 2006. ExpressTrack online publication August 9, 2006. doi: 10.1016/j.clinthera.2006.08.004 0149-2918/06/$19.00 Printed in the USA. Reproduction in whole or part is not permitted. Copyright © 2006 Excerpta Medica, Inc.

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tients tO have comorbid conditions (eg, depression in PD 7-9) and take concurrent medications. Therefore, understanding the pharmacologic and pharmacokinetic properties of the DAs is crucial to achieving an optimal outcome and avoiding AEs in this population at risk for potential drug-drug interactions. It must be underscored, however, that clinical outcomes of drug therapy are influenced by many factors other than receptor affinities (eg, age, sex, weight, race, compliance, bioavailability, concomitant diseases, renal/hepatic function). van Camp et al 1° reported a correlation between valvular heart disease (VHD)/fibrosis and high doses of pergolide (_>5 mg/d), as well as a correlation between tenting area of the mitral valve and the cumulative dose of pergolide. Baseman et a111 reported that composite regurgitation was a function of lifetime pergolide use. An association between AEs and high doses of DAs also was seen in the study by Reuter et al, 12 in which 50 PD patients at a rehabilitation unit (mean age, 64 years; Hoehn-Yahr grade, 2-4) were evaluated by echocardiography. A valvular scoring system was used that ranged from 1 (mild valvular disease) to 3 (severe valvular disease). Thirteen patients, 12 of whom had previously been treated with high doses of pergolide, were found to have clinically significant restrictive VHD. There was a correlation between past pergolide treatment and VHD (r = 0.478; P < 0.001), particularly with past receipt of high pergolide doses (r = 0.94; P = 0.001). A recent study by Kim et al, 13 in which 22 patients with PD received bromocriptine (mean dosage, 8.48 mg/d) and 36 patients with PD received pergolide (mean dosage, 1.13 mg/d), failed to find a significant correlation between DA dose and the frequency of valvulopathy. The authors hypothesized that this may have been the result of the relatively low doses used, also suggesting an association between DA dose and AEs. High doses of DAs have been correlated with high plasma concentrations. 14q7 Therefore, drug-drug interactions leading to similar high plasma concentrations may lead to more and/or more severe AEs. On the other hand, lack of drug efficacy due to induction of cytochrome P450 (CYP) enzymes may lead to lack of efficacy. The major aims of this review were to provide a comprehensive overview of the pharmacologic and pharmacokinetic properties of the ergot-derived and non-ergot-derived DAs, to highlight the differences 1066

between DAs, and to discuss the clinical relevance of these differences with respect to AEs and efficacy. MATERIALS A N D M E T H O D S

A search of MEDLINE for relevant English-language publications (to May 2006) was conducted using the terms dopamine agonists (or each individual drug name) and pbarmacokinetics, metabolism, drug-drug

interaction, interactions, CYP450, fibrosis, valvular heart disease, and tremor. Separate searches limited to clinical trials, reviews, and meta-analyses were conducted using the term dopamine agonists (or each individual drug name). Abstracts from the eighth (2004) and ninth (2005) International Congress of Parkinson's Disease and Movement Disorders were searched, and 2 Web sites that provide current information on CYP interactions and metabolism were consulted. 18,19 To find complete receptor-affinity data for DAs from experiments on cloned human dopamine receptors when the receptors were in the "high-affinity state, ''2° a search of Boehringer-Ingelheim publications (including languages other than English) was conducted. Clinical studies enrolling <20 patients overall or including <10 patients per treatment group in the final analysis were excluded from the review. All DAs that were considered at least possibly useful with respect to at least 3 of 4 items connected to the treatment/ prevention of motor symptoms/complications in the most recent evidence-based medical review update 21 were included. This resulted in a focus on the ergot-derived DAs bromocriptine, cabergoline, and pergolide, and the non-ergot-derived DAs pramipexole and ropinirole. PROPOSED MECHANISMS FOR THE EFFICACY A N D ADVERSE EFFECTS O F SELECTED D O P A M I N E A G O N I S T S

It has been suggested that D 3 receptors in the mesolimbic pathway may be involved in behavior and mood, 22 which may be associated with the antidepressive and antianhedonic effects seen with certain D3-receptorselective central nervous system agents. 22,23 It has been proposed that the motor benefits of the DAs (improvements in Unified Parkinson Disease Rating Scale scores, wearing-off effect [end-of-dose deterioration], and/or dyskinesia) are mainly the result of D2-receptor stimulation, as the anatomic distribution of dopamine receptors suggests that areas rich in D 2 sites (caudate and putamen) are involved in motor control. 22 Volume 28 Number 8

T. Kvernmo

On the other hand, it has been suggested that D 3receptor loss may play a greater role than D2-receptor changes in a reduced response to dopaminergic drugs. 24 This possibility was investigated by measuring striatal dopamine loss and changes in striatal D 2 and D 3 receptors in the postmortem striatum of patients with PD (n = 23) and controls (n = 21). Historically, 9 of the PD patients had continued to have a clinical response to dopaminergic drugs, whereas 14 had lost the response to these agents. All PD patients, regardless of responder status, had elevations in D2-receptor concentrations in the rostral striaturn compared with controls (P < 0.005 in the dorsal putamen). In contrast, there were significant differences in D3-receptor concentrations between responders and nonresponders. With respect to the rostral striatum, the responder PD group had 13% elevations in D3-receptor concentrations in the caudate nucleus and 17% elevations in the dorsal putamen compared with controls, whereas the nonresponder PD group had 17% to 28% reductions in D3-receptor concentrations in the caudate nucleus, dorsal putamen, ventral putamen, and nucleus accumbens compared with controls (P < 0.005). With respect to the caudal striatum, the responder PD group had 31% elevations in D3-receptor concentrations in the caudate nucleus,

et

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36% elevations in the dorsal putamen, and 24% elevations in the nucleus accumbens compared with nonresponders (P < 0.005). The control group had elevated D3-receptor concentrations in the caudate nucleus and putamen compared with all PD patients (P < 0.005). The PD responder group had elevations in D3-receptor concentrations in the putamen, globus pallidus interna, and globus pallidus externa compared with nonresponders (P < 0.005), whereas concentrations of D 3 receptors were significantly elevated in the globus pallidus interna and externa in PD responders compared with controls (P < 0.005). The authors concluded that the loss of D 3 receptors was associated with a loss in response to antiparkinson drugs and suggested that stimulation of D 3 receptors by antiparkinson drugs could be considered a potential therapeutic target in PD. The AE profiles of the DAs appear to be related mainly to their individual affinities for dopaminergic 25 and serotonergic (5-HT) receptors, 1°-12,25-29 which are summarized in Table I. All ergot-derived DAs have a high affinity for the 5-HT2A and 5-HT2B receptors. It has been suggested that activation of 5-HT2A receptors 32 and 5-HT2B receptors 1°,11,28,33 may mediate fibrotic reactions, including the VHD that has been associated with ergot-derived DAs. Baseman et

Table I. Binding affinities (inhibition constant [Ki] , in nmol/L) For cloned human receptors o f the dopamine agonists.* Receptor Type/SubWpe

Bromocriptine

Cabergoline

Pergolide

Pramipexole

Ropinirole

D1 D2 D2 D3 D4

1659 12.2 2.5 12.2 59.7

Ds

1691

182 2.1 0.7 1.5 9.0 165 20 478.6 8.7 6.2 1.2 (Ag)

172 0.5 0.2 0.5 1.3 164 1.9 281.8 13.2 8.3 7.1 (Ag) 295.1 337 0.4

>50,000 2.2 3.9 0.5 5.1 >10,000 692 8318 1660 > 10,000 >10,000 > 10,000 25.000 7.8

36,600 4.4 3.7 2.9 7.8 41,211 288 > 10,000 1380 > 10,000 3802 > 10,000 8.375 1.3

5-HT1A 5-HT1B 5-HT1D

5-HT2A 5-HT2B 5-HT2c D2/D1 D3/D 2

12.9 354.8 10.7 107.2 56.2 (PAg) 741.3 136 0.2

692

83 0.5

D = dopamine; 5-HT = serotonin; PAg = partial agonist; Ag = agonist. *The lower the Ki, the greater the receptor binding. Data sources: Millan et al, 2s Brecht,3° and Jahnichen et al.31

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a111 investigated this association by mailing a survey to all their patients believed to be receiving pergolide treatment. When the 46 responders (mean age, 67 years) who wished to continue pergolide treatment underwent echocardiography, 41 were found to have some degree of valvular regurgitation (VR), with documented valve thickening in 15. Compared with agedmatched controls from the Framingham Heart Study, the odds ratio (OR) for abnormal valves in pergolide recipients was 3 (P < 0.03). The sum of scores for all 4 valves (maximum composite valve score, 16) was a function of lifetime pergolide use. Based on curve data, the mean composite valve score for lifetime use of 100 mg was -2, and the corresponding value for lifetime use of 10,000 mg was -5. van Camp et al 1° performed an echocardiographic evaluation of 78 PD patients treated with pergolide and 18 control patients with PD who had never received ergot-derived DAs, using a scoring system from 1 to 4, with 1 indicating documented restrictive VHD and 4 indicating no restrictive VHD. Restrictive VHD of any type (score 1-3) was found in 33% of the pergolide group and none of the control group (P < 0.003), and clinically significant disease (score 1-2) was found in 19% of the pergolide group and none of the control group (P = NS). Histopathologic data from 1 patient indicated an ergotlike valvular lesion (ie, fibrotic changes in leaflets and subvalvular apparatus). Interestingly, there was a significant correlation between cumulative doses of pergolide and tenting areas in the mitral valves (r = 0.412; P = 0.017). The 2 foregoing studies had several limitations. Neither was prospective. There were no baseline data, even though age-matched controls were used, and only in the study by van Camp et al 1° were the controls PD patients. In the study by Baseman et al, 11 46% of the patients who were eligible for the study terminated pergolide treatment when they were informed about the potential for fibrosis or declined to undergo examination. In addition, 33 pergolide patients in the database were lost to follow-up, van Camp et al provided no information about whether patients declined examination or terminated pergolide treatment when informed about the potential for fibrosis. Horvath et al 2s reported 4 cases of VHD with ergot-derived DAs (1 treated with cabergoline, 3 with pergolide). One of the pergolide patients underwent tricuspid valve replacement surgery, and there was a histopathologic finding of noninflammatory fibrotic 1068

degeneration. Although the sample was small, one possible interpretation of the findings is that VHD is a chronic process taking years to become clinically apparent (1.5-5 years of therapy in these 4 cases). In 2002, the United Kingdom Committee on Safety of Medicines reported 79 cases of fibrotic reactions in patients treated with ergot-derived DAs (3 of whom died). 32 When given written and verbal information about potential AEs, 88 of 99 patients treated with ergot-derived DAs at a regional movement disorder clinic elected to switch to a non-ergot-derived DA. 33 It has been suggested that the occurrence of dyskinesia in patients receiving antiparkinson medication is related to Dl-receptor affinity. 34 Bromocriptine, with a presumed lower risk for dyskinesia, has Dl-antagonistic properties, 35 whereas pergolide and cabergoline, which are associated with a relatively higher risk for dyskinesia, have Dl-agonist properties. 36 The selected DAs are reviewed in detail in the following sections. Their pharmacokinetic properties are summarized in Table II, and their potential for inhibition by or induction of the CYP enzyme system is summarized in Table III. ERGOT-DERIVED D O P A M I N E A G O N I S T S Bromocriptine

Pharmacology and Clinical Effects Bromocriptine is indicated for use in PD and reproductive medicine. 39 In addition to its D2-receptoragonist activity, bromocriptine has Dl-receptor antagonistic properties. 35 It has a relatively high affinity for 5-HT2A receptors (inhibition constant [Ki] = 107 nmol/L) and 5-HT2B receptors (Ki = 56 nmol/L), being a partial agonist of the latter. 31 The incidence of dyskinesia was compared in patients treated with bromocriptine or cabergoline (a Dl-receptor agonist 31) in a meta-analysis by Clarke and Deane. 36 The analysis included a total of 1071 patients from 5 randomized, double-blind, parallelgroup studies, 4 of them short term (12-15 weeks) and 1 of medium duration (36 weeks). The incidence of dyskinesia as an AE was significantly greater for cabergoline compared with bromocriptine (OR = 1.57; P = 0.03). This finding may be associated with bromocriptine's strong Dl-receptor antagonism. 31 A weakness of this meta-analysis was the short duration of the studies. The ergot-derived DAs' relatively high affinity for 5-HT2A and 5-HT2B receptors may be related to reVolume 28 Number 8

T. Kvernmo

et

al.

Table II. P h a r m a c o k i n e t i c p r o p e r t i e s o f the d o p a m i n e agonists. Bromocriptine Total dosage, mg/d

5-40

No. ofdaily doses

3

Cmax, lag/L (for dose, mg)

Cabergoline

Pergolide

2-6

1.5-5

1

Pramipexole

Ropinirole

0.375-4.5 (salE)

3-24

3

3

3

1.3-6.5 (12.5-100)

0.03-0.07 (0.5-1.5)

1.8 (0.14)

0.5-2.5

0.5-4.0

1-3

1-3

1-2

6

50-80

20-60

>90

50

-

7.0

7.5

95-96

15

20-40

T max' h Oral bioavailability, % Vd, L/kg

3.4

Protein binding, %

0.375-4.5 (0.445-6.31)

5.3-26.9 (1-6)

90-96

40

Clearance, L/h

55

192

Unknown

30

47

Elimination tl/2, h

3-7

63-110

27

8-12

6

Unknown

Yes/un known ~

Yesf

Yest

Yes/unknown§

6% (unchanged and metabolites)

20% (mainly metabolites), 4% unchanged

55% (mainly metabolites)

90%

(unchanged)

Primarily renal as metabolites

Linear kinetics Renal clearance

*Studied in 12 healthy men at up to 1.5 mg/d (below the therapeutic dosing range for Parkinson's disease [PD]). fStudied in 20 patients (10 men, 10 women) at up to 3 mg/d (60% of the maximum therapeutic dosage for PD). tStudied in 8 healthy men and 8 healthy women over the entire therapeutic dosing range for PD. § Studied at up to 12 mg/d, half the maximum therapeutic dosage for PD. (Four PD patients were studied at 12 mg/d, 2 at 18 mg/d.) Data sources: Kaye and Nicholls, TM Wright et al, is Andreotti et al, 16 Thalamas et al, 17 Stacy, 37 and Deleu et al. 38

Table III. Potential i n t e r a c t i o n s o f d o p a m i n e a g o n i s t s with the c y t o c h r o m e P450 (CYP) system. ~

Isozyme Dopamine Agonist

CYP1A2

CYP2D6

CYP3A4

CYP inhibition Bro mocriptine Cabergoline Pergolide Pramipexole Ropinirole

No U n known No No Yes

No U n known Yes No Yes

Yes Yes Yes No No

CYP metabolism Bro mocriptine Cabergoline Pergolide Pramipexole Ropinirole

No U n known U n known No Yes

No U n known U n known No No

Yes Yes Yes No Yes

*Data are continuously updated at the Web sites listed in references 18 and 19.

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ports of retroperitoneal and pulmonary fibrosis with these agents, 32 as well as to the risk for severe multiVHD. 28 In addition to 246 fibrotic syndromes associated with bromocriptine therapy described by Mtiller and Fritze, 32 there is a published report of fibrotic VHD after bromocriptine treatment. 4° In this case, a 63-year-old man who had been treated with bromocriptine for 5 years (mean dosage, 40 mg/d) experienced anasarca and was admitted to the intensive care unit, where fibrosis was discovered in 3 valves. Bromocriptine treatment was continued for 2 months before being discontinued. Six months after the cessation of bromocriptine, there was no worsening in the valvular fibrosis, and the inflammatory process had resolved.

Metabolism and Drug-Drug Interactions As a result of its low K i (50% inhibitory concentration [ICs0] = 1.69 lamol/L) with respect to inhibition of CYP3A4, 41 which is the most abundant isozyme in the liver and intestine, bromocriptine may inhibit and thus increase plasma concentrations of other CYP3A4 substrates (eg, simvastatin, codeine, zopiclone). Bromocriptine is also metabolized by CYP3A4, 41 which may lead to inhibition of its metabolism. In a study in 5 male volunteers who received a single dose of bromocriptine 5 mg alone and after 4 days of treatment with the CYP3A4 inhibitor erythromycin (250 mg QID), 42 with serial blood sampling over a 12-hour period, the AUC for bromocriptine was increased 268% (ie, increased plasma concentration). Based on the results of in vivo studies of other drugs metabolized by CYP3A4, 43m5 there is a potential for failure of bromocriptine therapy when given with substances such as St. John's wort, which can induce CYP3A4. 44,45 No published data on the linearity of bromocriptine's pharmacokinetics were found. Cabergoline

Pharmacology and Clinical Effects Cabergoline is indicated for use in PD (except in the United States) and reproductive medicine. 46 In addition to its D2-type receptor-agonist activity, cabergoline has a relatively high affinity for Dl-type receptors and high affinity for 5-HT2A (Ki = 6.2 nmol/L) and 5-HT2B (Ki = 1.2 nmol/L) receptors. In the previously mentioned meta-analysis, 36 the incidence of dyskinesia (reported as an AE) was signifi1070

cantly increased with cabergoline compared with bromocriptine (OR = 1.57; P = 0.03), which may be related to Dl-agonist or Dl-antagonist activity on the part of cabergoline. Another meta-analysis included 3 large multicenter, randomized, double-blind studies: one in which 412 patients received either cabergoline, titrated from 0.25 mg/d to a maximum of 4 mg/d, or L-dopa 100 to 600 mg/d for 5 years; a second in which 301 patients received either pramipexole 1.5 to 4.5 mg/d or L-dopa 300 to 600 mg/d for 2 years; and a third in which 268 patients received either ropinirole, titrated from 0.75 mg/d to a maximum of 24 mg/d, or L-dopa 50 to 1200 mg/d for 5 years. 47 All 3 studies allowed the use of rescue L-dopa. The meta-analysis found that the incidence of dyskinesia compared with L-dopa was less likely to be reduced with cabergoline (OR = 0.38; P < 0.008) than with pramipexole (OR = 0.25; P < 0.001) or ropinirole (OR = 0.31; P < 0.001), again suggesting that cabergoline may have some D 1agonist activity. Because there were differences in the definition of dyskinesia used in the individual studies, the authors of the meta-analysis stated that the results should be interpreted with caution. Reports of retroperitoneal and pulmonary fibrosis 32 and a potentially increased risk for VHD 28,29 may be related to cabergoline's high affinity for 5-HT2A and 5-HT2B. Miiller and Fritze 32 reviewed reports of fibrotic syndromes during DA treatment in the database of the World Health Organization Collaborating Centre for International Drug Monitoring in Uppsala, Sweden. The total number of reports for bromocriptine, cabergoline, pergolide, pramipexole, and ropinirole were a respective 246, 13, 131, 0, and 7. The authors suggested that patients receiving long-term DA treatment should be monitored carefully for the development of drug-induced fibrotic syndromes. Weaknesses of reports based on such databases include differences in reporting procedures, defined daily doses, and time since drug launch. As noted by Horvath et al, 28 analyses based on reports in databases may find a lower frequency of fibrotic syndromes for the DAs with the most recent launch dates. In addition, because no information is available on patients' drug history or other variables, some reports may reflect fibrotic syndromes associated with previous rather than current DA treatment. As noted earlier, Horvath et a128 reported 4 new cases of VHD in PD patients treated with ergotderived DAs. In the case involving cabergoline, the paVolume 28 Number 8

T. Kvernmo et al.

tient was a 5g-year-old woman who had received the drug for 20 months. She complained of shortness of breath during effort, which worsened rapidly. She was found to have severe mitral regurgitation, moderate to severe aortic and tricuspid regurgitation, and mild pulmonary regurgitation. Retraction and thickening of the free aspects of these valves were also documented. There was no evidence of infectious or inflammatory heart disease, nor did the medical history suggest congenital heart disease or childhood rheumatic fever. On discontinuation of cabergoline and treatment with pramipexole, the symptoms improved slowly over 23 months of follow-up with no specific therapy. The regression of valvular insufficiency and marked clinical improvement after discontinuation of cabergoline suggests a potential causal relationship. In another case report, 4s a 63-year-old man who had been treated with cabergoline 2 mg/d for 3 years received a diagnosis of constrictive pericarditis. A radical pericardectomy was performed, and florid chronic inflammation was confirmed. Cabergoline treatment was not discontinued. The patient felt unwell after 6 months, and an inflammatory fibrotic reaction caused by cabergoline was diagnosed. Modest improvement was reported 4 months after discontinuation of cabergoline.

50-

A recent study addressed concerns about valvulopathy by determining the frequency of VR through routine transthoracic echocardiography of 75 PD patients who received DA treatment for a minimum of 12 months (13 cabergoline, 29 pergolide, 33 pramipexole/ ropinirole) and 49 age-matched controls without PD. 29 Patients receiving pergolide had the longest DA exposure (mean duration of therapy, 61.3 months), followed by ropinirole (45.g months), pramipexole (40.2 months), and cabergoline (29.9 months). VR was graded from 1 (mild) to 3 (severe), as described by Baseman et al. u As shown in the figure, the frequency of VR grades 2 and 3 was significantly higher with the ergot-derived DAs compared with the non-ergotderived DAs (cabergoline, P = 0.009; pergolide, P = 0.031) and compared with controls (cabergoline, P = 0.04; pergolide, P = 0.013). The majority (67%-g3%) of patients with grade 2 or 3 VR had muhivalvular involvement. Echocardiographic evidence of restrictive valvular changes with leaflet thickening was observed in 2 patients (1 receiving cabergoline, 1 receiving pergolide), neither of whom had clinical signs of heart failure. Only 1 patient (pergolide) with VR grades 2 or 3 had clinical symptoms of heart failure. Among patients with grade 2 or 3 VR who had been treated with ergot-derived DAs, treatment was discontinued in 4 of

47 t

c~

40-

~ .~ 3o~ ~ C

--

31"

2o13

o o~

// 10

I0-

0-m

T Pergolide

T Cabergoline

F Pramipexole/ Ropinirole

Control

Figure. Incidence o f g r a d e 2 o r 3 v a l v u l a r r e g u r g i t a t i o n in p a t i e n t s t r e a t e d w i t h d o p a m i n e a g o n i s t s . * P = 0.031 versus p r a m i p e x o l e / r o p i n i r o l e , P = 0 . 0 4 versus c o n t r o l s , t p = 0 . 0 0 9 versus p r a m i p e x o l e / r o p i n i r o l e , P = 0 . 0 1 3 versus c o n t r o l s . D a t a source: Peralta et al. 29

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Clinical

Therapeutics

9 receiving pergolide and 4 of 6 receiving cabergoline. Two of the 4 pergolide-treated patients showed improvement 6 to 12 months after discontinuation of therapy: one had a change in mitral regurgitation from grade 2-3 to grade 1, and the other had a change in aortic regurgitation from grade 3 with thickening of the posterior leaflet to grade 2 with normal leaflet morphology. One of the 4 cabergoline-treated patients showed improvement 6 to 10 months after discontinuation of therapy, with a change in mitral regurgitation from grade 2 to grade 1. The authors noted that assessment of VR alone may not be sufficiently sensitive to detect subtle fibrotic changes. They stated that the higher prevalence of VR with the ergot-derived DAs, as well as the partial reversibility of VR on discontinuation of these agents in some cases, suggested a causal relationship. This study was limited by its retrospective design; lack of baseline data; small number of patients, which may have masked a potential rare valvulopathy related to use of non-ergot-derived DAs; and small number of patients treated with cabergoline. In addition, 2 cabergoline patients with a VR grade 2 or 3 had previous short-term exposure (1-6 months), one to pergolide and the other to bromocriptine; this was, however, followed by cabergoline treatment for 4 and 6 years, respectively. A relationship between agonism at 5-HT2B receptors and cardiac valvulopathy was suggested by a recent ex vivo study of 5-HT2B receptor-mediated relaxation in porcine pulmonary arteries with the ergotderived DAs bromocriptine, cabergoline, pergolide, lisuride, and terguride. 31 Like 5-HT, cabergoline (pECs0 [negative logarithm of the molar concentration producing 50% of the response] = 8.72) and pergolide (pECs0 = 8.72) produced a concentration-dependent relaxation in porcine pulmonary arteries. Bromocriptine behaved as a partial agonist. Although studies of this type have limited predictive value, the results did support the previously suggested mechanism for VHD induced by ergot-derived DAs. Dhawan et a149 conducted a retrospective data review that included 234 patients who had participated in >1 trial of cabergoline therapy (mean duration of treatment, 2.9 years; mean dosage, 3.75 mg/d). They reviewed patients' case notes for evidence of symptoms suggesting pleuropulmonary, cardiac, or retroperitoneal fibrosis and identified 15 possible cases. Echocardiography was performed in 8 of these pa1072

tients, 6 of whom were found to have grade 1 or 2 regurgitation in >1 valve (atrial, mitral, or tricuspid). The authors did not find a definitive association between valvular fibrosis and cabergoline therapy, with the possible exceptions of 1 case of probable alveolitis and 1 case of cardiac murmur. This study was limited by its retrospective design and a patient sample restricted to those who had met the inclusion criteria of the clinical trials. The lack of systematic lungfunction and echocardiographic assessments constituted a major limitation. In studies in which all patients were followed regularly by echocardiographic examination, most patients with high VR scores had no clinical symptoms. 2<29 As suggested earlier, valvular fibrosis is likely to be a chronic process that may continue for years before symptoms become manifest. 28 Thus, this study may have underestimated the prevalence of VR and VHD.

Metabolism and Drug-Drug Interactions Cabergoline has an elimination tl/2 of 63 to 110 hours16; therefore, achievement of steady state is expected to take >3 weeks after the completion of dose titration. The literature review identified no studies that calculated cabergoline's K i with respect to CYP3A4 inhibition, but it has been suggested that an ability to inhibit this isozyme reflects a catalytic interaction among structurally similar ergot-derived compounds. 41 Like the other ergot-derived DAs bromocriptine and pergolide, cabergoline is a substrate for CYP3A4 and is metabolized primarily by this enzyme, s° There is a report of a 300% increase in plasma levels of cabergoline (administered at 4 mg/d) when coadministered with the potent CYP3A4 inhibitor itraconazole (administered at 200 mg BID for 1 week), sl In 2 patients who served as controls, receiving only PD medication that included cabergoline, plasma cabergoline levels were stable. The Cmax for cabergoline was increased when the drug was coadministered with clarithromycin, another CYP3A4 inhibitor, in 10 healthy male volunteers and 7 PD patients taking stable doses of cabergoline, s° Both volunteers and PD patients received cabergoline and clarithromycin 400 mg/d concomitantly for 6 days. Cabergoline concentrations over 10 hours after dosing increased 2.6-fold (P < 0.01) in healthy volunteers and 1.7-fold in PD patients (P < 0.01). Furthermore, when grapefruit juice was coadministered with cabergoline in 5 PD patients, the mean concentration of cabergoline increased 1.7-fold. s2 As reported in vivo for other Volume 28 Number 8

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CYP3A4-metabolized drugs 4345,53 and as may be the case for bromocriptine, CYP3A4 induction may result in reduced cabergoline concentrations. Cabergoline's pharmacokinetics have been shown to be linear, but only up to 1.5 mg/d, which is below the therapeutic dosing range for PD. According to the summary of product characteristics for cabergoline, 46 coadministration with antibiotics such as clarithromycin should be avoided due to the risk of increased plasma cabergoline concentrations. Pergolide

Pharmacology and Clinical Effects Pergolide is indicated for the treatment of PD. s4 In addition to its D2-type receptor-agonist activity, pergolide has agonist activity at Dl-type receptors 34 and a high affinity for 5-HT2A (Ki = 8.3 nmol/L) and 5-HT2B (Ki = 7.1 nmol/L) receptors. It is a confirmed agonist of the latter. 31 A recent randomized controlled trial compared pergolide with L-dopa for the prevention of motor complications in patients with early PD. ss This study differed from other comparisons of DAs and L-dopa in that L-dopa rescue therapy was prohibited and disease severity was substantially lower (modified Hoehn-Yahr grade, 1-1.5). An inclusion criterion for this study was a positive result on the apomorphine test, which predicted a high responder rate. Two hundred ninety-four L-dopa-naive patients were randomly assigned to receive pergolide (n = 148) or L-dopa (n = 146). At the 3-year end point, daily doses were 3.23 mg and 504 mg, respectively. There was a significantly higher incidence of dyskinesia at 3 years with L-dopa compared with pergolide (P < 0.001), whereas there was no significant difference with respect to motor complications (fluctuations and wearing-off effect). In a 6-month, double-blind, placebo-controlled trial, s6 patients with advanced PD (Hoehn-Yahr grade 2-4; minimum total weighted PD score of 60 for a combination of speech, tremor, rigidity, bradykinesia, postural stability, and gait on the modified Columbia scale; moderately severe dyskinesia [wearing-off effect]) received pergolide added to L-dopa (n = 189) or placebo plus L-dopa (n = 187). At the end of the study, the prevalence and severity of dyskinesia were the same in both groups. The mean dosages in the 2 treatment groups were pergolide 2.94 mg/d + L-dopa 671 mg/d and L-dopa 894 mg/d, respectively. In addition to a significant reduction in L-dopa dosage compared with August 2006

the placebo group (P < 0.001), the pergolide group also had a significant improvement in the total PD score (P < 0.001). Reports of retroperitoneal and pulmonary fibrosis31 and an increased risk for VHD 10-12'26-29may be related to pergolide's high affinity for 5-HT2A and 5-HT2B receptors. The frequency of VR with pergolide (31%) was similar to that with cabergoline (47%) (figure).> The risk for VHD with pergolide appears to be dose dependent. 1°,12 Although the previously described studies 1°-13,2s,29and the preliminary results from van Camp et a126in 10 patients treated with high doses of pergolide (>5 mg) suggest a cumulative dose relationship, this is in contrast to a case report of the development of multivalvular dysfunction in a 63-year-old man treated with low-dose pergolide (titrated from 0.1 to 2.25 mg/d) for 9 years, s7 Histopathologic findings revealed fibromyoid valvulopathy of the mitral, tricuspid, and aortic valves with no calcification.

Metabolism and Drug-Drug Interactions Pergolide is a potent inhibitor of CYP2D6 (ICs0 = 0.08 tlmol/L), comparable to paroxetine (K i = 0.15 tlmol/L) and quinidine (Ki = 0.03 l~mol/L), 41 and may theoretically interact with other CYP2D6 substrates (eg, tricyclic antidepressants, antiarrythmics). Pergolide appears to be metabolized by CYP3A441; thus, coadministration with a CYP3A4 inhibitor may result in increased concentrations of pergolide, as has been noted in vivo for both bromocriptine 42 and cabergoline, s°-s2,ss As with other CYP3A4-metabolized drugs, 434s,s3 subtherapeutic plasma concentrations may result if pergolide is coadministered with CYP3A4 inducers. Pergolide's pharmacokinetics are linear up to 3 mg/d, which is slightly more than half the therapeutic dosing range for PD treatment. N O N - E R G O T - D E R I V E D D O P A M I N E A G O N ISTS Pramipexole

Pharmacology and Clinical Effects Pramipexole is indicated for PD in the United States and the European Union and for RLS in the European Union. s9 In addition to its agonist activity at D 2 receptors, pramipexole has an even higher affinity for D 3 receptors and a very low affinity for 5-HT2A , 5-HT2B receptors, and Dl-type receptors. The previously described meta-analysis found that the likelihood of a reduction in dyskinesia compared 1073

Clinical Therapeutics with L-dopa was greater with pramipexole (OR -0.25; P -- 0.001) than with cabergoline (OR -- 0.38; P < 0.008), which may reflect the different affinities of these 2 DA agonists for the D 1 receptor. 47 In the study by Joyce et al, 24 loss of D 3 receptors was correlated with a loss in response to antiparkinson drugs. Because stimulation of D 3 receptors may be considered a potential therapeutic target in PD, the significant tremorlytic effect observed in 2 studies (both, P < 0.001) 6°,61 may be associated with pramipexole's selectivity for D 3 receptors.

Metabolism and Drug-Drug Interactions Pramipexole undergoes almost no hepatic biotransformation (90% is excreted unchanged in the urine) 15 and was found to exert no potent CYP inhibition in vitro (Ki >10 tlmol/L).41 Coadministration of pramipexole with other drugs that are renally secreted by the cationic transport system decreased the clearance of pramipexole by 9.0% to 17.7%, which was not felt to warrant a priori dose adjustment. 62 The presence of reduced creatinine clearance may require dose adjustment. 56 Pramipexole has linear pharmacokinetics over its entire therapeutic range, and its AUC is 35% to 43% higher in women than in men. 62

Ropinirole

Pharmacology and Clinical Effects Ropinirole is indicated for the treatment of PD; in the United States and some members of the European Union, it is also indicated for RLS. 63 In addition to agonist activity at D2-type receptors, ropinirole has a very low affinity for 5-HT2A, 5-HT2B, and Dl-type receptors. The previously described meta-analysis found that a reduction in dyskinesia compared with L-dopa was more likely with ropinirole (OR = 0.31; P < 0.001) than with cabergoline (OR = 0.38; P < 0.008), 47 which may reflect the different Dl-receptor affinities of the 2 DA agonists.

Metabolism and Drug-Drug Interactions Ropinirole is extensively cleared by hepatic metabolism, with only 10% excreted as unchanged ropinirole. The main enzyme responsible for its metabolism is CYP1A2, along with CYP3A4.14 An in vitro study found ropinirole to be a potent inhibitor of CYP2D6 (IC50 -- 0.54 l~mol/L)41 and a less potent inhibitor of CYP1A2 (10 tlmol/L of ropinirole reduced activity

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by 36%). As a strong inhibitor of CYP2D6, ropinirole may interact with other CYP2D6 substrates, 41 although no in vivo studies of CYP2D6 inhibition by ropinirole were identified in the literature search. With respect to its potential interaction via CYP1A2, ropinirole did not interact with the CYP1A2 substrate theophylline in a study in 12 patients with PD. 64 Patients received oral ropinirole titrated to 6 mg/d over 4 weeks and then continued at this dosage for 4 weeks. Oral theophylline was coadministered at doses up to 600 mg/d from day 28 to day 40 of ropinirole treatment without significantly altering the pharmacokinetics of ropinirole. When a single 30-minute infusion of aminophylline 5 mg/kg was given on days 0 and 27 of the same study, ropinirole did not alter the pharmacokinetics of intravenous theophylline. When the CYP1A2 inhibitor ciprofloxacin 500 mg BID was coadministered with ropinirole titrated to 6 mg/d in 12 patients with PD, 14 the ropinirole AUC increased by 84%. The clearance of ropinirole was decreased by -33% in female PD patients taking estrogens (n = 16) compared with female PD patients not taking estrogens (n = 56) (P < 0.005). 14 This accords with the results of the study by Laine et al, 65 who found that estrogens had an inhibitory effect on the metabolism of tacrine, another CYP1A2 substrate. There is also a case report of an increase from a previously stable international normalized ratio for warfarin when ropinirole was added to the warfarin regimen. 66 Because of ropinirole's extensive metabolism via CYP3A4 and CYP1A2, its metabolism is potentially inducible by several common substances, including St. John's wort (CYP1A2, CYP3A4). 45 The pharmacokinetics of ropinirole have been shown to be linear up to 12 mg/d, which is half the therapeutic dosing range for PD. According to the summary of product characteristics, 63 use of ropinirole is contraindicated in patients with a creatinine clearance <30 mL/min. Dose adjustment of ropinirole may be necessary when introducing or discontinuing a potent CYP1A2 inhibitor.

DISCUSSION Receptor Profiles The lack of clinical studies powered to compare DAs with respect to efficacy and AEs, as well as the high incidence of AEs in the L-dopa and/or placebo arms as well as the DA group, 3-5,39,46,49,59,63 make it difficult to link the receptor profiles of individual DAs with their effects on motor symptoms. One exception is dyskineVolume 28 Number 8

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sia, as some of the data support an increased risk for dyskinesia as a result of Dl-receptor stimulation. Fici et a134 used primary cerebellar granule cell cultures from 7-day-old Sprague-Dawley rats as a model for measuring Dl-receptor-mediated changes in cellular cyclic adenosine monophosphate (cAMP). They reported that nonselective DA-receptor compounds such as pergolide (P < 0.01), dopamine (P < 0.01), and bromocriptine (P < 0.05) increased cAMP formation, whereas the D 3selective compound pramipexole slightly decreased cAMP formation and the D2-selective compound U-95666A had no significant effect on cAMP formation. The intrinsic activity of DA and pergolide was 100%, whereas that of bromocriptine was 20%. Dyskinesia may be linked to stimulation of the D 1 receptor, for which the ergot-derived DAs cabergoline and pergolide have a similar and relatively high affinity. Clinical studies have reported a lower risk for dyskinesias with bromocriptine and the non-ergotderived DAs pramipexole and ropinirole. 3<47 An increased risk for VHD is becoming recognized as a class effect of ergot-derived DAs. 28 This is consistent with reports of valvular lesions similar to those associated with ergot alkaloids such as ergotamine and methysergide, n which, like the ergot-derived DAs, have a high affinity for the 5-HT2B receptor. 28 A potential role for the 5-HT receptor is supported by the correlation between high 5-HT levels and valvular lesions in patients with carcinoid heart disease, n The suggested mechanism for VHD and pulmonary hypertension is stimulation of 5-HT2B, 10,28 which has recently been reported to induce fibroblast mitogenesis. 28 This mechanism, which links all DA-related fibrotic disorders to stimulation of the 5-HT2B receptor, may also be the result of stimulation of the 5-HT2A receptor. 32 A recent study comparing ergot-derived DAs, nonergot-derived DAs, and age-matched controls with respect to the occurrence of grade 2 or 3 VR found a significantly higher incidence of VR with the ergot-derived DAs compared with non-ergot-derived DAs (31%47% vs 10%, respectively; P = 0.009 for cabergoline; P = 0.031 for pergolide) and compared with controls (13%; P = 0.013 for cabergoline; P = 0.004 for pergolide). 29 There was no significant difference between the control group (13%) and the group treated with non-ergot-derived DAs (10%) (figure). These results are consistent with those of Baseman et al, n who found a 2- to 3-fold increased risk of valve abnormalities in pergolide-treated patients compared with controls. August 2006

et

al.

Fibrotic reactions have been reported in up to 20% of patients treated with ergot-derived DAs. 39,46,49 This is in contrast to the findings for pramipexole and ropinirole, which have no affinity for 5-HT receptors. Nonetheless, there have been 7 cases of fibrotic syndromes in patients treated with ropinirole (4 pleural effusion, 2 pericardial effusion, 1 pericarditis). 32 The currently available safety data for pramipexole do not suggest a causal relationship between use of pramipexole and the occurrence of fibrotic reactions. The VHD and pulmonary and retroperitoneal fibrosis seen with long-term use appear to represent a class effect of the ergot-derived DAs (bromocriptine, cabergoline, and pergolide) that may be related to stimulation of 5-HT2B 10-12,26-29 (and possibly 5-HT2A32), which induces fibroblast mitogenesis (of which regurgitation may be an early clinical symptom). 28 As the incidence of VHD appears to be dose dependent, 1°,12,26,32 the risk theoretically may be increased by concomitant administration of drugs that are inhibitors of the main metabolic pathway (CYP3A4). D r u g - D r u g Interactions

Bromocriptine, cabergoline, pergolide, and ropinirole have the potential for drug-drug interactions mediated by the CYP enzyme system in at least 3 ways: they may inhibit the metabolism of other drugs, 41,66 their own metabolism may be inhibited, 14,42,5°-53,58,66 or they may be induced by _>1 CYP isozyme involved in their metabolism, with a significant decrease in bioavailability. 18,19,43-45,62 CYP-catalyzed biotransformation is affected by numerous xenobiotics and may be dependent on individual genetic disposition. 67 Bromocriptine, cabergoline, pergolide, and ropinirole may interact with other drugs as a result of their ability to inhibit CYP isozymes and thus the metabolism of other drugs. 41 There is some evidence that the etiology of PD may be related to a lack of CYP2D6 function. 68-72 Use of drugs such as pergolide and ropinirole, which are strong inhibitors of CYP2D6 in vitro, 41 may thus be counterproductive in some instances. Inhibition of DA metabolism may result in increased bioavailability of the DA, as has been reported in vivo for bromocriptine, cabergoline, and ropinirole 14,42,5°-53,58,64 and might be expected in theory for pergolide, potentially giving rise to dopaminergic AEs such as hallucinations and dyskinesia. 33 Furthermore, fibrosis associated with ergot-derived DAs appears to be dose related and 1075

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thus plasma-concentration related. 12,26,32 Although it may not result in acute AEs, even a moderate increase in the bioavailability of ergot-derived DAs over time as a result of chronic interaction with comedication may contribute to an increased risk for AEs such as fibrosis. A recent report found a greater correlation between VHD and high doses of pergolide in the past (r = 0.94; P = 0.001) compared with all doses of pergolide in the past (r = 0.478; P < 0.001). 12 Based on in vivo findings for other drugs metabolized by CYP3A443,44 and/or CYP1A2, 45 it is reasonable to assume that induction of the CYP isozymes involved in DA metabolism may significantly decrease the bioavailability of the drug in question and may result in drug failure. Because bromocriptine, cabergoline, pergolide, and ropinirole are metabolized by CYP1A2 and/or CYP3A4, concomitant administration of drugs that induce CYP may result in drug failure and the possible return of parkinsonian symptoms. Several limitations of this review should be noted. The literature search was limited to MEDLINE, and no government agencies that monitor drug safety were contacted. Thus, the selection of publications and the resulting conclusions may have been biased. Finally, in addition to a drug's pharmacokinetics and receptor-binding properties, it is necessary to consider its efficacy, onset of action, tolerability, convenience, cost, quality-of-life effects, and risk-benefit ratio when selecting a drug for an individual patient. Monitoring signs and symptoms and AEs related to treatment, as well as drug interactions, is warranted in patients treated with DAs. CONCLUSIONS

Dyskinesia as an AE of DA therapy may be related to Dl-receptor stimulation. Fibrosis (including VHD) appears to be a class effect of ergot-derived DAs, all of which have been associated with confirmed valvular lesions in at least 1 study or case report. Bromocriptine, cabergoline, pergolide, and ropinirole have the potential for drug-drug interactions mediated through the CYP enzyme system. REFERENCES 1. Allen RP, Wakers AS, MontplaisirJ, et al. Restless legs syndrome prevalence and impact: REST general population study. Arch Intern Med. 2005;165:1286-1292. 2. Olanow CW, Watts RL, Koller WC. An algorithm (decision tree) for the management of Parkinson's disease

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A d d r e s s c o r r e s p o n d e n c e to: T r o n d K v e r n m o , MSc, B o e h r i n g e r I n g e l h e i m N o r w a y KS, D r e n g s r u d b e k k e n 25, B o x 405, N - 1 3 7 3 Asker, N o r w a y . E-mail: t k v e r n m ° @ ° s l ' b ° e h r i n g e r - i n g e l h e i m ' c ° m

Volume 28 Number 8