entacapone
TRANSCRIPT
AD IS NEW DRUG PROFILE
Entacapone Wendy McNeely and Rick Davis Adis International Limited, Auckland, New Zealand
Contents
Summary ......... . 1. Pharmacodynamic Profile 2. Pharmacokinetic Profile 3. Therapeutic Trials ..... . 4. Tolerability ......... . 5. Entacapone: Current Status
Summary
.&. Entacapone is a potent, orally active, selective inhibitor of peripheral catechol-O-methyltransferase (COMT), which has therapeutic potential as an adjunct to levodopa therapy in patients with Parkinson's disease.
... Entacapone decreases peripheral conversion of levodopa to 3-0-methyldopa and improves central uptake of levodopa.
.&. Addition of entacapone to levodopalcarbidopa or levodopalbenserazide increased the duration of clinical response in patients with Parkinson's disease: the duration of 'on' time was increased and the duration of 'of[ ' time was decreased.
.&. Levodopa requirements were reduced in patients with Parkinson's disease who received adjunctive entacapone therapy.
.&. Entacapone was generally well tolerated, with few reported adverse events.
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eNS Drugs 1997 Jul; 8 (1).79-88 1172-7047/97/fXJJ7-fYJ79/SQ5 00/0
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Features and properties of entacapone (OR-611) .
Indication
Par1<inson's disease Phase III
Mechanism of action
Reversible Increases extracellular
79 80 84 85 86 87
calechol-O-methyltransferase levodopa and consequently inhibitor striatal dopamine
concentrations
Dosage and administration
Usual dosage and frequency in 200mg 2 to 10 times daily cl inical trials coadministered with
levodopaldopa-decarboxylase inhib~or
Route of administration Oral
Pharmacokinetic profile (200mg per dose)
Peak plasma concentration 1 .16 mgIL'
Time to peak plasma concentration
Elimination half·life
Adverse events
Most frequent
1.2ha
Dyskinesias, gastrointestinal disorders
a In patients with Parkinson's disease.
b In healthy male volunteers.
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Entacapone
Parkinson's disease is caused by the loss of dopaminergic neurons in the substantia nigra and subsequent reduction of dopamine levels in the corpus striatum)!) Dopamine itself does not cross the bloodbrain barrier; however, its precursor levodopa does and is the mainstay of pharmacological treatment for the disease.
In the periphery, levodopa is predominantly metabolised by dopa-decarboxylase (aromatic L-arnino acid decarboxylase; DDC) to dopamine (fig. 1).[2]
This can lead to adverse events including vomiting, orthostatic hypotension and cardiac arrythmia. It also reduces the amount of levodopa available for central uptake. Thus, levodopa is usually given in conjunction with a peripheral DDC inhibitor (carbidopa or benserazide). However, inhibition of DDC increases the metabolism of levodopa via catecholO-methyltransferase (COMT) to 3-0-methyldopa (3-0MD).[3] 3-0MD competes with levodopa for uptake into the brain. It has a long half-life (15 hours) compared with that of levodopa (about 1 hour) and therefore plasma concentrations of3-0MD may remain high during repeated administration of levodopaJDDC inhibitor. Accumulation of 3-0MD has been associated with motor fluctuations (also termed the ' wearing off' phenomenon) during long term levodopa therapy in patients with Parkinson's disease)4]
Addition of entacapone, a peripheral COMT inhibitor, to levodopaJDDC inhibitor therapy decreases levodopa degradation to 3-0MD and thus improves central uptake of levodopa and ultimately enhances
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McNeely & Davis
availability of dopamine in the brain (see section 2) .
1. Pharmacodynamic Profile
• In rats with a unilateral lesioned nigrostriatal pathway, a model of Parkinson's disease, entacapone 3 mg/kg increased the incidence (by 4.8-fold; p < 0.001) and duration (by 124 minutes) of levodopa/carbidopa (2/30mg)-induced contralateral turning behaviour)S] Tolcapone (3 mg/kg), another COMT inhibitor, increased the incidence and duration of turning behaviour, respectively, by 3.1-fold (not significant) and by 126 minutes. At a higher dose of levodopa (5 mg/kg), the incidence of turning was increased by 2.3-fold with each agent (p < 0.05 for entacapone; p < 0.01 for toIcapone); corresponding increases in duration of turning were 112 and 150 minutes.
In a second study, the dose oftoIcapone required to produce a similar increase in the duration of response was 3 times that of entacapone)6] In the presence of entacapone (10 mg/kg) the dosage of levodopa could be reduced by 50% without loss of turning behaviour.
Effect on Soluble COMT
• In vitro, entacapone 0.01 ~mollL inhibited soluble COMT activity in rat duodenal , brain and liver tissue and also in erythrocytes.[7] Concentrations of entacapone producing 50% inhibition of COMT activity (lCso) were 10 nmollL for duodenum and 160 nmol/Lfor liver. In addition, an inhibitory constant (Kj) of 14 nmollL was recorded for the inhibition of soluble rat liver COMT.
• Activity of soluble COMT in peripheral blood cells was significantly (p < 0.001) inhibited by oral entacapone 50 to 800mg compared with placebo in both patients with Parkinson's disease[8] and healthy volunteers;[9,1O] inhibition was dose related, An approximate 40% reduction in activity was observed with oral entacapone 200mg)8,9] In volunteers, maximum inhibition of COMT activity was observed I hour after administration of the agent, with recovery within 8 hours ,[IO]
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Entacapone: New Drug Profile
Periphery (intestinal mucosa & circulation)
LevodopalDDC inhibitor
./ 3-0MD
Levodopa
Dopamine
Blood-brain barrier
Brain
81
____ 3-oMD - ---fT'f----7""'--
~rE-NT-A-CA-P-O-N-E"'T[-
Levodopa r=--------."""'-~-----'LL---L----I
Dopamine
LevodopalDDC inhibitor +
entacapone
Fig. 1. Peripheral and central metabolism and distribution of levodopa. Thickness of arrows indicates relative amounts of particular agent (not to scale). Abbreviations: DOC = dopa-decarboxylase; 3-0MD = 3-D-methyldopa.
Effects on Central Dopamine and Metabolites
• Brain microdialysis studies in rats have shown that entacapone ( I 0 mg/kg) had no effect on baseline striatal levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) or 5-hydroxyindoleacetic acid (5-HIAA), but significantly decreased levels of homovanillic acid (HVA), a centrally formed metabolite of dopamine (p < 0.05 vs baseline))ll) In comparison, tolcapone (10 mg/kg) significantly increased baseline extracellular levels of dopamine
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(p < 0.01) and DOPAC (p < 0.001), decreased HVA (p < 0.001) but had no effect on 5-HIAA.
• After administration of Jevodopa/carbidopa (50/50 mg/kg) or levodopa alone (50 mg/kg) to rats, brain microdialysis showed that baseline dopamine, DOPAC and HVA levels were significantly increased (p < 0.001))11] Peak levels for DOPAC and HVA were significantly higher than controls after levodopa (p ~ 0.001) but there were no significant differences between the area under the plasma concentration-time curve (AUChsomin val-
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ues of control and levodopa groups. Levels of 3-OMD were below the limit of detection. In contrast, after levodopa/carbidopa peak AVC values of dopamine, DOPAC and HVA were significantly higher than controls (p::;; 0.01); 5-HIAA values did not differ between the groups, and previously undetected 3-0MD was apparent after 40 minutes.
Addition of entacapone (10 mg/kg) further increased the AVC values of dopamine (p < 0.05) and DOPAC (p < 0.01) and had no significant effect on HVA or 5-HIAA values, but suppressed 3-0MD production (p < 0.001; all vs carbidopa/levodopa). Tolcapone (10 mg/kg) had a greater effect than entacapone on the AVC of dopamine and DOPAC (p < 0.001) and decreased levels of both HVA (by 77%) and 3-0MD (both p < 0.001 vs levodopa/carbidopa).
• Microdialysis studies in rats revealed no significant interaction between entacapone 10 mg/kg and nomifensine (a dopamine uptake inhibitor), clorgiline (a monoamine oxidase-A inhibitor) or selegiline (deprenyl; a monoamine oxidase-B inhibitor) regarding modulatory effects on striatal efflux of dopamine, DOPAC, 5-HIAA or HVA.[12] In contrast, tolcapone 10 mg/kg, in the presence of nom ifensine, further increased dopamine levels, decreased HVA levels and caused an initial increase in DOPAC levels, followed by a decline to baseline levels. (Nomifensine alone induced a decrease, and tolcapone an increase, in basal DOPAC levels.) Compared with clorgiline alone, the addition of tolcapone increased dopamine and reduced DOPAC and HVA levels (all p < 0.001).
• Entacapone 30 mg/kg produced a 42% (p < 0.001 vs control) reduction in striatal HVA levels in rats predosed with amphetamine but had no effect on DOPAC or 3-methoxytyramine levels.[l3] In comparison, tolcapone 30 mg/kg reversed the effect of amphetamine on 3-methoxytyramine and DOPAC levels and reduced HVA levels. In addition, pimozide-induced changes (a 54% decrease and a 518% increase, respectively, in striatal levels of 3-methoxytyramine and HVA, centrally formed metabolites of dopamine) were not altered by entacapone (30 mg/kg), but were both decreased (by 99
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McNeely & Davis
and 71%, respectively) by the same dose of tolcapone. These data suggest that the effects of entacapone are mainly peripheral and that tolcapone may have both peripheral and central activity.
Effects on Central (18F)-6-L-Fluorodopa Uptake and Accumulation
• The ratio of (striatum - occipital) : occipital activity of [lsF] represents the specific uptake of [ISF]-6-L-fluorodopa ([ISF]dopa) and its subsequent metabolism to [lsF]dopamine.[l4] This ratio was significantly increased by 38% after administration of entacapone. Figure 2, a positron emission tomography (PET) scan, illustrates the increased central accumulation of [ISF]dopa in a patient with Parkinson's disease after administration of entacapone 800mg.
• In 15 patients with Parkinson's disease and 6 healthy age-matched controls, PET studies showed that entacapone (200 to 800mg) both decreased peripheral O-methylation and increased the central accumulation of administered [ISF]dopa.[l5] Mean increases in the caudate to occipital ratios of radioactivity were 19% (p = 0.0005) for controls and 6% (p = 0.049) for patients. The mean, respective, increases in putamen to occipital ratios were 24% (p = 0.0006) and 2% (not statistically significant) for controls and patients.
• Mean plasma concentrations of unmetabolised [lsF]dopa were measured 94 minutes after administration of the labelled compound in 4 patients with Parkinson's disease and 6 age-matched volunteers.[l4] These concentrations were significantly higher in entacapone than placebo recipients (56 vs 22%; p < 0.0001). However, there were no significant differences in the plasma concentrations measured in volunteers or patients either with or without entacapone. In addition, the effect of entacapone on peripheral metabolism of [ISF]dopa was not related to the dose administered: about 21, 55 and 57% unmetabolised [ISF]dopa was measured, respectively, without entacapone and with entacapone 400 and 800mg.
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Entacapone: New Drug Profile 83
Fig. 2. Positron emission tomography images of central ['8Fl-6-L-fluorodopa accumulation in a patient with Parkinson's disease. Brain scans taken, at a similar anatomical level, pre- and post-treatment with entacapone BOOmg. These images have been scaled to activity in the occipital cortex; the colour scale is arbitrary [reproduced from Orion Pharma (data on file) with permissionl .
• The relationship between [ISF]dopa uptake into the striatum and clinical response to a single 200mg dose of entacapone was examined in patients with Parkinson's disease: 16 patients had levodoparelated motor fluctuations and 4 were de novo patients.l l61 Accumulation of [ISF]dopa in the putamen was increased, respectively, by 30 and 15% in de novo and fluctuating patients. There was a significant inverse correlation between the increased putamen accumulation after entacapone and duration of disease (r = -0.512; P = 0.0075), severity of disease (i.e. Hoehn and Yahr stage) [r = -0.449; P = 0.021] and the motor Unified Parkinson's Disease Rating Scale (UPDRS) score (r = -0.570; p = 0.0036).
Other Effects in Humans
• In 12 healthy men, minimum plasma concentrations (Cmin) for prolactin were 20% lower in entacapone recipients (400mg single dose) than in placebo recipients (78 vs 98 MIU/L; p < 0.05).[171
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However, Cmin values for growth hormone were not significantly different between groups; neither were the AUCs for prolactin or growth hormone. Levodopa/carbidopa-induced increases in secretions of growth hormone and prolactin were not significantly influenced by entacapone.
• Haematological parameters, including heart rate and systolic or diastolic blood pressure were not affected by entacapone 50 to 800mg, either at rest or during exercise, in healthy male vo]unteers.[IS,191 Endogenous catecholamine metabolism, however, was significantly altered:[IS,19] 3,4-dihydroxyphenylglycol
(DHPG) levels were increased and 3-methoxy-4-hydroxyphenylglycol (MHPG) levels decreased at rest and during exercise (p < 0.05).
• In 8 patients with Parkinson's disease, there was no significant difference between cardiovascular autonomic responses (assessed by deep breathing test, the Valsalva manoeuvre, the tilt test and isometric hand grip test) measured after single-dose
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levodopa/carbidopa (1 00/25mg) with or without entacapone (200mg).f20]
2. Pharmacokinetic Profile
Pharmacokinetic Properties of Entacapone
• In a number of studies, in patients (n = 20)[S] or healthy male volunteers (typically n = 12),[9,10,21] maximum plasma concentrations (Cmax) of entacapone after oral administration increased linearly and dose-dependently over the range 50 to 800mg, After administration of 200mg, the most commonly used dose in clinical trials (section 3), reported Cmax values were 0.88[21] and 1.8 Il'O] mg/L in healthy volunteers and 1.16 mg/L in patients with Parkinson's disease.fS]
• In 1 study, after administration of entacapone 200mg, the absorption half-life (t Y,a) was 0.32 hours.[lO] Absorption slowed slightly, but not significantly, with increased dosage, as indicated by a delay in reaching time to Cmax (tmax) in both volunteers and patients.[S-10.21] Reported values for tmax
were between 0.73 and 2.0 hours in volunteers[9, 1O,21] and about 1.2 hours in patients[S] after a single 200mg dose of entacapone.
• Five metabolites were identified in urine from healthy male volunteers who had received oral entacapone.f22] The majority (95 %) of the metabolites were glucuronides; the most abundant (70%) was the glucuronide of entacapone.
• Biliary excretion is the most probable route of elimination of entacapone.f22] Elimination did not appear to be dose-dependent after oral administration in healthy volunteers.[10,21] After a single 200mg dose of entacapone the plasma terminal elimination half-life (tI/2 ~) was 3.44 hours.f IO]
Effects of Entacapone on the Pharmacokinetic Parameters of Levodopa
• Cmax values of levodopa were not significantly changed by coadministration of entacapone: after a single 200mg dose of the latter drug in patients, the mean Cmax value of levodopa decreased from 2.08 to 1.49 mg/L (fig. 3);[20] furthermore, levo-
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Cma:JC (mg/L)
tmax (h)
AUCs (mg/L' h
1
n I
)
o
McNeely & Davis
I
o Levodopa alone
o With entacapone
I I *
2 3 4 5
Fig. 3. Pharmacokinetic parameters of levodopa after levodopalcarbidopa 100/25mg alone and with entacapone 200mg in 8 patients with Parkinson's disease.[201 Abbreviations and sym
bol: Cmax = maximum plasma concentration; tmax = time to Cmax;
AUC6 = area under the concentration-time curve 6 hours after drug administration; • p < 0.001 .
dopa Cmax values tended to decrease with increasing entacapone dosage.fs,21] However, when administered concomitantly with controlled-release levodopa, entacapone caused a dose-dependent increase in levodopa Cmax values.[9]
With standard levotlopa, there was a trend towards a delay in the tmax of the agent after administration of entacapone (fig. 3): levodopa tmax values (approximately 50 minutes) increased by 12 to 23 minutes after administration of entacapone 200mg to patients and volunteers.[S,20,21 ]
• Eight weeks' treatment with entacapone increased the steady-state peak and trough plasma concentrations of levodopa in patients with Parkinson's disease.[23] There was no indication of levodopa accumulation. • In patients and volunteers who received concomitant standard[21] or controlled-release[9] levodopaIDDC inhibitor (benserazide[S] or carbidopa[21]) and entacapone up to 800mg, the levodopa AUC was increased with increasing doses of entacapone. After 200mg entacap.one, increases in levodopa AUC values at various time points (hours) were reported: 23% (AUC4 ; p < 0.001 vs placebo),[S] 21 % (AUC IO; p < 0.01 vs control)l9] and 42% (AUC=; P < 0.05 vs control).f21]
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Entacapone: New Drug Profile
• A 35% increase in the AUC (no time details available) for levodopa was observed after a single 200mg dose of entacapone in 21 patients with Parkinson's disease; this was significantly and positively correlated with an increase in motor UPDRS scores (r = 0.493; P = 0.038), and a 30-minute increase in 'on' time (r = 0.502; P = 0.034),l24]
• In 15 patients with Parkinson's disease, repeated administration of entacapone compared with control increased the tY2~ of levodopa by about 75 minutes (approximately 60%) after oral or intravenous administration of levodopa.l23] Consequently, levodopa AUC~ values were increased (p < 0.05) from baseline by about 46 or 34% after oral or intravenous levodopa.
• In volunteers, levodopa elimination half-life (tY2) values ranged from 1.6 to 1.9 hours and were essentially unaffected by increasing entacapone doses.[9.21] However, in patients, tY2 values for levodopa were significantly higher after 200mg entacapone (1.0 vs 1.4 hours; p < 0.001 vs placebo).l8]
• The AUC values of levodopa metabolites were altered by entacapone in patients and volunteers: values for 3-0MD were significantly decreased and those of DOPAC were significantly increased (p < 0.05 vs placebo);[8.9,21] the AUC of HVA was unchanged[21] or significantly decreased (p < 0.01 vs controJ;[9] p < 0.001 vs placebo[8]).
3. Therapeutic Trials
In the entacapone repeat-dose studies reviewed, patients received the drug with each dose of levodopaJDDC inhibitor, dosage of the latter was titrated to optimum response. In single-dose studies, entacapone was given in the morning with the first dose of levodopa/DDC inhibitor. • In a double-blind crossover study in 12 patients with Parkinson's disease, latency to peak motor response was not significantly affected after a single administration of entacapone 200 or 800mg compared with placeboP51 The mean duration of motor response, however, was significantly increased with entacapone 200mg (by 34.5 minutes) or 800mg (by 39 minutes) compared with placebo (p < 0.01).
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• The most effective single dose of entacapone in 20 patients with Parkinson's disease and Jevodoparelated motor fluctuations was 200mg.l8] Clinical efficacy was assessed, primarily, as the duration of 'on' time and also as the magnitude of motor response and duration of dyskinesias.
• The peak onset latency and magnitude of effect of levodopa were not notably affected by repeatdose entacapone treatment: after 28 days of therapy, mean onset latency was reported as delayed by 30 minutes (p < 0.01) in one study (n = 12),[26] and 4 minutes (not significant) in another.l27 ]
• Data pertaining to the 2 largest clinical trials of entacapone, conducted in North America (US; n = 205) and Scandinavia (n = 171), are currently available only as abstracts.[28-32] Both studies used similar protocols: patients with motor fluctuations associated with levodopa therapy received 200mg entacapone for 24 weeks. The US study included 4-week, staggered, double-blind washout periods (total 28 weeks). The primary efficacy end-point, the change in daily 'on' time during wakefulness, was calculated from patient diary entries. Intentionto-treat analysis revealed that the mean daily proportion of 'on' time increased by 1 hour (p < 0.05) in the US study and by 1.3 hours (p < 0.001) in the Scandinavian study.[30]
30 * D Motor response * .----
C 20 §.
0 Dyskinesias
c: 0
'~ 10 co
"0
.S 0 Q) Cl c: til L
.J:. 0 -10
-
-20 Placebo Entacapone
Fig. 4. Effect of 4 weeks' treatment with entacapone or placebo on duration of motor response and dyskinesias in 23 patients with Parkinson's disease. Entacapone (200mg) or placebo was given 4 to 10 times daily in combination with the patients' established regimen of levodopa/dopa-decarboxylase inhibitor [benserazide (n = 20) or carbidopa (n = 3)].[271 * P < 0.01 vs placebo.
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• Severity of symptoms, assessed by the UPDRS scores, was marginally altered in the US study: a 3 point increase (worsening of symptoms) occurred with placebo and a 0.5 point decrease with entacaponeP9] In this study the mean levodopa dosage increased (3%) in placebo recipients, but decreased (13%) in entacapone recipients during the study period.
• The mean daily 'off' time was decreased by up to 1.2 and 0.2 hours during 24 weeks' administration of entacapone or placebo in 2 large doubleblind studies (data on file, Orion Pharma).
• In a number of small studies (n = 10 to 26 patients), in which entacapone 200mg was given up to 6 times daily, the duration of motor response in the 'levodopa test' (assessed by use of the motor part of the UPDRS) increased by up to 66 minutes [p = 0.001 vs placebo (fig. 4)[27] and p = 0.02 vs
baseline[26]] after 4 weeks' entacapone 800 to 1200 mg/day treatment in patients with Parkinson's disease. Furthermore, quantitative assessment of motor response with use of computerised technology (described by Relja et al.[33]) concurred with qualitative UPDRS assessment of the effect of entacapone on motor response[34] and revealed an increased duration in patients who received entacapone (45 minutes; p < 0.001 vs placebo).
300 0 Standard formulation * 0
- * Controlled-release J--"2
250
:[ -Q) 200 ,§ I---
-c 150 _0
'0 c
100 0 e :::> 0 50
0 Baseline Day 10
Fig. 5. Effect of the addition of entacapone (200mg) to each dose of levodopa/carbidopa (200/50mg) standard or controlledrelease preparation on 'on' time in 12 patients with Parkinson's disease. Medication was given 3 to 4 times daily over a period of 10 days according to an open crossover design [35) • p < 0.05 vs baseline.
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McNeely & Davis
• Duration of dyskinesia was significantly (p = 0.002) increased (indicating increased striatal dopamine concentrations leading to reduced exogenous levodopa requirements) by 39 minutes [37% vs placebo (fig. 4)[27]] and 66 minutes (58% vs baseline[26]) after 28 days' entacapone therapy. In the same 2 studies, levodopa intake was decreased by 16[27] and 11 %.[26]
• Entacapone enhanced the efficacy of both standard and controlled-release levodopa preparations[35,36] even after optimisation of levodopa therapy.[36] In 1 study, duration of 'on' time was increased by 70 minutes with either formulation (fig. 5[35]), and motor scores were significantly (p < 0.001 vs control day) improved by about 25 and 35%, respectively, for the standard and controlled-release formulation,l35] In another study, mean daily 'on' time was increased by 2.5 and 0.4 hours in entacapone and placebo recipients.[27]
• In patients, 'on' time was positively correlated with a 45-minute increase in the duration of dyskinesias (r = 0.571; P = 0.007).l24] Furthermore, there was a trend towards a negative correlation between an increase in 'on' time and the severity of parkinsonian disability (r = -0.383; P = 0.086).
• Withdrawal of treatment resulted in a greater reduction of 'on' time (p < 0.001) and a greater increase in 'off' time (p < 0.01) in entacapone than in placebo recipients (data on file, Orion Pharma). In addition, more patients who had received entacapone than placebo reported a global worsening of symptoms after treatment withdrawal (p < 0.001).
4. Tolerability
• In general, entacapone 600[35,37] to 2000[27] mg/day was well tolerated in patients with Parkinson's disease. The most frequently occurring adverse events in a placebo-controlled crossover study in 26 patients included dyskinesia (26 vs 4% for placebo), abdominal pain or discomfort (22 vs 13%), diarrhoea (17 vs 4%), faintness (13 vs 4%), confusion (9 vs 4%) and anxiety and insomnia (9 vs 0%). The incidence of orthostatic hypotension was similar at
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Entacapone: New Drug Profile
baseline and during placebo or entacapone therapy.[27]
• Diarrhoea has been reported as the most common reason for study withdrawal with to1capone, another COMT inhibitor.[38] In the entacapone studies reviewed, only 1 case of withdrawal because of diarrhoea has been reported.[23]
• The use of controlled-release compared with standard levodopa formulation in combination with entacapone reduced the incidence of nausea from 58% (7 patients) to 8% (1 patient).[35] The frequency of other adverse events reported, which included constipation, fatigue, dizziness and anorexia, was essentially the same for both formulations ($;25%; 3 of 12 patients).
• In approximately 700 patients who received entacapone (dose not stated) for 6 to 12 months, no treatment-related abnormal liver function tests were observed (data on file, Orion Pharma). In contrast, 0.7% of approximately 300 patients who received placebo for 6 months developed abnormal alanine aminotransferase (serum glutamic pyruvic transaminase; SGPT) or aspartate aminotransferase (serum glutamic oxaloacetic transaminase; SGOT) levels.
• There was no interaction between entacapone (200mg) and moclobernide (150mg), an antidepressant agent, in male volunteers (n = 12).£39]
5. Entacapone: Current Status
Entacapone is a selective COMT inhibitor that is in late phase clinical trials. It has shown efficacy in patients with Parkinson's disease and has been well tolerated in short term clinical trials ($;6 months).
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15. Ruottinen HM, Rinne JO, Ruotsalainen UH, et al. Striatal [18F]fluorodopa utilization after COMT inhibition with entacapone studies with PET in advanced Parkinson's disease. J Neural Transm Park Dis Dement Sect 1995; 10 (2-3): 91-106
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Correspondence: Wendy McNeely, Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand. E-mail: [email protected]
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