sign in sign up
<<
Home , Entacapone, Methyltransferase, Nitecapone

18616ournal ofNeurology, Neurosurgery, and Psychiatry 1994;57:186-189 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.57.2.186 on 1 February 1994. Downloaded from Effect of , a peripherally acting -O-methyltransferase inhibitor, on the motor response to acute treatment with levodopa in patients with Parkinson's disease

Marcelo Merello, Andrew J Lees, Roy Webster, Michael Bovingdon, Ariel Gordin

Abstract treatment.7-'0 The oral of lev- Catechol-O-methyltransferase (COMT) odopa is low due to first pass inhibitors may be useful in the treatment which is at least partly due to the high activity of Parkinson's disease by improving the of COMT in the gut and ." 12 The com- bioavailability of levodopa and by pro- bination of a peripheral COMT inhibitor longing its effects. Entacapone (OR-611), with levodopa/DCI therapy might therefore a novel COMT inhibitor, which does not produce a smoother and more prolonged cross the blood brain barrier, was motor response in patients with Parkinson's assessed in 12 patients with Parkinson's disease."3 14 As early as in 1971 Ericsson'5 disease and motor fluctuations in a reported beneficial effects with a COMT randomised, double-blind, cross-over, inhibitor with concomitant reduction in single dose study. The magnitude and levodopa-induced . More recently, duration of the therapeutic response to a a new generation of COMT inhibitors have single dose of 200 mg levodopa/50 mg been developed, which are much more potent was evaluated after concomi- and specific."'3 1620 Fluorodopa positron tant placebo, or 200 or 800 mg enta- emission tomography (PET) studies in mon- capone. A significant increase in the keys and patients with Parkinson's disease duration of the motor response to lev- have also shown that peripheral COMT odopa was seen when 200 mg entacapone inhibitors increase striatal fluorodopa was given with levodopa/carbidopa. uptake.21-23 Plasma levodopa concentrations were Entacapone (OR-611) is a highly selective increased with both doses of the COMT and potent nitrocatechol-structured COMT inhibitor. The latency to onset of motor inhibitor that penetrates the brain poorly, act- response did not differ significantly ing mainly in the gut. In animal models of between active and placebo. Parkinson's disease, entacapone potentiated Entacapone may prove useful in prolong- and prolonged the therapeutic effect of levo- ing the duration of the benefit obtained dopa in a dose-dependent manner.2425 from individual doses oflevodopa. We have studied the motor response and

of levodopa in 12 patients http://jnnp.bmj.com/ (7 Neurol Neurosurg Psychiatry 1994;57:186-189) with Parkinson's disease and severe motor fluctuations after acute levodopa challenge alone or in combination with two different Catechol-O-methyltransferase (COMT) is an entacapone doses. important involved in the peripheral and central metabolism of .1 In the Departnent of central nervous system it is believed to exert Materials and methods Neurology in Twelve from the of on September 24, 2021 by guest. Protected copyright. M Merello its major action the synaptic cleft. patients Department A J Lees When decarboxylation of levodopa is Neurology, University College and Middlesex Department of blocked by peripheral dopa decarboxylase Hospitals, London treated with levodopa (I 1 Pharmacology, inhibitors (DCIs), 0- becomes men and one woman, mean age 58 5 (range University College and the most prominent pathway of levodopa 46-71) years), mean duration of disease 14-7 Middlesex Hospitals School ofMedicine, catabolism2 and leads to the accumulation of (range 8-24) years), mean daily levodopa London, UK 3-0-. It has been suggested that dose 1183 (range 300-4250) mg agreed to R Webster 3-0-methyldopa may impair the transport of participate. The patients were informed about M Bovingdon levodopa across the blood brain barrier and the objectives and design of the study, and Research Center, compete with levodopa for decarboxylation informed consent was obtained. The study Orion Pharmaceutica, Espoo, Finland within the brain.'-5 It has also been proposed was approved by the Ethics Committee of the A Gordin that accumulation of 3-0-methyldopa may be Faculty of Clinical Sciences, University Correspondence to: a causal factor in the development of motor College School of Medicine, London. Dr Andrew J Lees, All the United Department of Neurology, fluctuations in Parkinson's disease.6 This the- patients fulfilled Kingdom Middlesex Hospital, ory, however, has been challenged. The Parkinson's Disease Brain Bank clinical Mortimer Street, London for Parkinson's WIP 8AA, UK. plasma concentrations of 3-0-methyldopa diagnostic criteria idiopathic Received 20 January 1993 causing a deleterious effect on the clinical disease26 and had a clear response to an acute and in revised form response to levodopa in parkinsonian patients challenge with levodopa. Patients with secon- 26 April 1993 and are 17 May 1993. much higher than those found during dary , severe dementia, unstable Accepted 21 May 1993 long term levodopa decarboxylase inhibitor cardiac, renal, pulmonary, or gastrointestinal Entacapone and the motor response to levodopa in Parkinson's disease 187 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.57.2.186 on 1 February 1994. Downloaded from disease, and women of childbearing age were the Wilcoxon rank test. Statistical analysis of excluded. Those patients receiving for the plasma concentrations was carried out treating parkinsonism other than levodopa with analysis of variance and the Newman- continued on these unchanged throughout Keuls test. the study. The magnitude and duration of the thera- peutic response of a single dose of 200 mg Results levodopa in combination with 50 mg car- CLINICAL RESPONSE bidopa (two tablets of Sinemet plus, Merck, The latency to peak motor response was not Sharp, and Dohme were evaluated after con- significantly different between the three trial comitant administration of placebo, or 200 or days, but the duration of effect when enta- 800 mg entacapone (Orion Pharmaceutica, capone was administered with levodopa was Espoo, Finland). The pharmacokinetics and increased by a mean of 34 5 minutes (200 metabolism of levodopa were also studied. mg) and 39 minutes (800 mg), respectively, The study followed a double-blind, cross- compared with the placebo day (table). The over design and the order of was difference in the duration between the randomised. placebo and 200 mg days was statistically The single doses of levodopa/carbidopa significant (p < 0 05) by paired t test, but sig- and study drugs (entacapone/placebo),were nificance was not quite reached between the given simultaneously at 8.00 am in the fasting placebo and 800 mg day due to a larger varia- state after an overnight drug holiday. tion in response (table). When 200 mg of Clinical scoring was carried out at 15-30 entacapone was used, the overall scores for minute intervals from 7.30 am to noon. If the tapping (p < 0 05), dyskinesias (p < 0 005), drug effect persisted after the noon rating, and global score (p < 0-05) were significantly assessments were continued at 30-minute higher and the walking time significantly intervals until motor scores had returned to lower (p < 0-05) than on the placebo day baseline. The motor function was assessed (figs la and b). The global score with 200 mg by (1) a tapping test-the number of times of entacapone was also higher (p < 0 05) than the patient could alternately tap two labora- with 800 mg, but no statistically significant tory counters 20 cm apart in 30 s with the differences were found between the placebo more severely affected hand; (2) a walking day and the 800 mg day when maximum test-the time required to rise from an arm- values were compared (fig lb). The 800 mg less chair,.walk 6 m, turn, and sit down (cut dose of entacapone gave a higher peak score off time 30 s); (3) a 5-point scale; for dyskinesias than placebo (p < 0 05). The and (4) an overall global score (-4 = severe, maximum tapping score with 200 mg disabling symptoms to 0 = normal to + 4 = entacapone was significantly higher than with severe disabling dyskinesia). The criteria used 800 mg (p< 005; fig la). to assess the duration of response and the Two patients showed a biphasic motor time to "switch off' have been previously response when they received 800 mg enta- described.27 capone (table). Pronounced waning of the Plasma concentrations of levodopa, 3-0- motor response was followed in these patients methyldopa, and the dopamine metabolites by a second spontaneous motor improvement dihydroxyphenyl acetic acid and homovanillic lasting 45 to 60 minutes. These findings are http://jnnp.bmj.com/ acid were measured by high performance liq- not included in the statistics. Patient 6 did uid chromatography (HPLC).25 not "switch on" at all either with placebo or with 800 mg of entacapone. Patient 7 also STATISTICS failed to "switch on" with 800 mg of enta- For each clinical variable, the mean duration capone. These patients are not included in of the difference of the means and the mean the calculation of the latency and duration of

of the maximum values for each patient in the motor response to levodopa. By contrast, on September 24, 2021 by guest. Protected copyright. each treatment sequence were compared by all the patients on 200 mg entacapone

Table Motor response (time in minutes) Entacapone Placebo 200 mg 800 mg Patient Latency Duration Latency Duration Latency Duration 1 105 120 45 195 30 360 2 105 105 75 120 60 150 3 60 165 60 240 45 105 4 45 165 45 180 60 270 5 45 165 45 225 90 90 6t NR NR 60 60 NR NR 7t 45 90 120 45 NR NR 8 30 150 45 180 75 210 9 75 105 30 60 120 105 10 30 180 45 225 30 210 11 105 30 90 60 105 60 12 60 105 60 150 90 120 Mean (SD) 66 (30-17) 129 (45-39) 54 (17-61) 163-5 (65 36)* 70 5 (30 86) 168 (93 75) *p < 0-01 v placebo. tfmese patients are not included in the statistical analysis. NR = No response. 188 Merello, Lees, Webster, Bovingdon, Gordin J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.57.2.186 on 1 February 1994. Downloaded from Figure 1 Curves of the 40 PHARMACOKINETIC ANALYSIS means ofdifferent clinical en -A variables in 12 patients Entacapone significantly delayed the fall in after acute administration plasma levodopa concentrations (p < 0 05). oflevodopa plus placebo or 30 * .0@ The higher dose also delayed the attainment 200 or 800 mg entacapone. (A) Number oftaps in of peak plasma levodopa concentrations but 30 s with the more disabled ZL,2 neither 200 nor 800 mg entacapone increased hand; (B) global score. the magnitude of the levodopa peak (fig 2a). (O) placebo; (A) The entacapone 200 mg; 10 plasma dihydroxyphenyl acetic acid con- (0) entacapone 800 mg. 730 830 930 1030 1130 1230 1330 1430 centrations were significantly increased and the concentrations reduced (p < 0-01) with 800 mg of entacapane, but not with 200 mg (fig 2b). Plasma 3-0- 0 U)o- methyldopa concentrations were not signifi- cantly different during the three days of the .0 trial. 0

II 1,w, Discussion 1330 1430 Levodopa pharmacokinetics play an impor- Time (h) tant part in determining the duration of the motor response in Parkinson's disease.292829 Peripherally acting COMT inhibitors, by pre- venting conversion of levodopa to 3-0- methyldopa, might therefore provide a means Figure 2 Means ofthe 12r of extending the duration of motor benefit plasma concentrations for from individual levodopa doses. The two (A) levodopa and (B) homovanilic acid (HVA). novel peripherally acting COMT inhibitors (0) placebo; (U) 9 do not significantly alter striatal COMT entacapone 200 mg; activity in animal studies.'625 They also seem (D) entacapone 800 mg. 0E to be much less toxic than the first generation c COMT inhibitors (Gallates, , U- 6 0521).1"-'- 30 The first studies in normal 0 healthy subjects indicate that and 0 entacapone should be safe.'920 31-34 At the pre- -j 3 sent time it is unclear whether a COMT inhibitor with both peripheral and central effects would confer any greater therapeutic -3---'----4---benefit, or whether it could be safely used in -1 0 1 2 Time (h) combination with inhibitors.35 The mean increase of about 30% in the duration of motor response (129 minutes to 163 and 169 after http://jnnp.bmj.com/ E minutes) entacapone intake is appreciable when compared with that reported for selegiline36 or sustained 1-0 release levodopa formulations in acute dose .0 .5 studies.37 If these findings could be repro- o duced with chronic repeated dosing of enta- cB05 capone, a further 30 minute motor

improvement from each levodopa dose could on September 24, 2021 by guest. Protected copyright. 0 result in up to two to four hours more waking E 0 mobility each day in parkinsonian patients. This may also permit a reduction in the requirement in the total daily dose of levo- -1 2 3 4 dopa. Time (h) Patients receiving entacapone had some- what more dyskinesias indicating increased bioavailability of levodopa to the brain and showed clinical benefit and 10 out of 12 providing clinical support for the PET stud- patients given 200 mg entacap:one had a ies, which have shown increased striatal duration of motor response longer than that fluorodopa uptake.21-23 found with placebo. In previous studies we have found that patients "switched off" when plasma levo- SAFETY dopa concentrations fell to around half the Routine clinical haematological arnid biochem- peak values in an individual patient.28 If this is ical variables did not change significantly applied to the present study, however, a during the study. No adverse 4events were somewhat greater prolongation of motor reported but a transient str(Dng orange response with entacapone would have been colouration to the urine was seien in many predicted than that found. The recorded patients, probably due to entacap(one. motor response and the plasma levodopa Entacapone and the motor response to levodopa in Parkinson's disease 189 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.57.2.186 on 1 February 1994. Downloaded from concentrations correlated closely. No differ- methyldopa and response to levodopa in Parkinson's disease. Ann Neurol 1987;21:584-8. ence in peak plasma concentrations of 11 Nissinen E, Tuominen T, Perhoniemi V, Kaakkola S. levodopa were found between placebo and Catechol-O-methyltransferase in human and rat small intestine. Life Sci 1988;42:2609-14. entacapone, but the slopes of the curves were 12 Ball P, Knuppen R, Haupt M, Breuer H. Purification and more gradual and at four hours after giving properties of catechol-O-methyltransferase of human liver. EurJBiochem 1971;21,517-25. levodopa plasma concentrations were signifi- 13 Mannist6 PT, Kaakkola S. Rationale for selective COMT cantly higher with 200 and 800 mg of enta- inhibitors as adjuncts in the drug treatment of Parkinson's disease. Pharmacol Toxicol 1990;66:317-23. capone. This is in accordance with results in 14 Mannisto PT, Kaakkola S. New selective COMT animals and healthy volunteers. 5 The inhibitors: useful adjuncts for Parkinson's disease? Trends Pharmacol Sci 1989;10:54-6. delay in the attainment of peak plasma lev- 15 Ericsson AD. Potentiation of the L-dopa effect in man by odopa concentrations with 800 mg enta- the use of catechol-O-methyltransferase inhibitors. J NeurolSci 1971;14:193-7. capone might be explained by interference 16 Nissinen E, Linden I, Schultz E, Kaakkola S, Mannisto with levodopa absorption in the gut. PT, Pohto P. Inhibition of catechol-O-methyltransferase activity by two novel disubstituted in the rat. The two patients who failed to "switch on" EurJPharnacol 1988;153:263-9. with placebo or 800 mg entacapone normally 17 Borgulya J, Bruderer H, Bernauer K, Zurcher G, Da Prada M. Catechol-O-methyltransferase-inhibiting took 500 mg levodopa in the morning instead pyrocatechol derivates-synthesis and structure activity of the standard 200 mg dose used in this studies. Helv Clin Acta 1989;72:952-68. 18 Backstrom R, Honkanen E, Pippuri A, et al. Synthesis of study. The fact that 200 mg entacapone with some novel potent and selective catechol-O-methyl- 200 mg levodopa "switched them on" might (COMT) inhibitors. J Med Chem 1989;32: 841-6. indicate possible levodopa sparing effects. 19 Kaakkola S, Gordin A, Jarvinen N, Wikberg T, Schultz E, Both patients had very high 3-0-methyldopa Nissinen E, et al. Effect of a novel catechol-O-methyl- transferase inhibitor, Nitecapone, on the metabolism of concentrations. L-dopa in healthy volunteers. Clin Neuropharmacol The lower concentrations of the 0-methy- 1990;13:436-47. 20 Keranen T, Gordin A, Karlsson M, et al. Effect of the lated and deaminated catabolite of dopamine, novel catechol-O-methyltransferase inhibitor OR-611 in homovanillic acid, on both entacapone days healthy volunteers. Neurology 1991;41(suppl 1):345P. 21 Leger G, Reches A, Cedarbaum J, et al. PET studies in and the increased production of the deami- Cynomolgus monkeys show that OR-611 increases nated metabolite, dihydroxyphenyl acetic striatal fluorodopa uptake. Neurology 1991;41(suppl 1): 915S. acid, provide confirmatory evidence that 22 Leger G, Reches A, Cedarbaum J, et al. Inhibition of 3-0- entacapone systematically reduces COMT Methylfluorodopa formation with OR-462: Attempts to simplify the Fluorodopa model for PET analysis. activity. The finding that these effects were Neurology 1990;40(suppl 1):152S. greater with 800 than with 200 mg enta- 23 Laihinen A, Rinne JO, Rinne UK, et al. [18 F]-6- Fluorodopa PET scanning in Parkinson's disease after capone implies that COMT inhibition was selective COMT inhibition with nitecapone (OR-462). dose related, even if the improvement in Neurology 1992;42: 199-203. 24 Etemadzadeh E, Koskinen L, Kaakkola S. Computerized motor response to levodopa was not. rotometer apparatus for recording circling behaviour. The plasma concentrations of 3-0-methyl- Methods Find Exp Clin Pharmacol 1989;11:399-407. 25 Nissinen E, !inden I-B, Schultz E, Pohto P. Biochemical dopa in patients on chronic levodopa DCI and pharmacological properties of a peripherally acting therapy are very high and the half life of 3-0- catechol-O-methyltransferase inhibitor Entacapone. Naunyn Schmiedebergs Arch Pharmacol 1992;346:262-6. methyldopa is long (15-16 hours) compared 26 Gibb WR, Lees AJ. The relevance of the Lewy body to the with levodopa (one hour).2 Therefore plasma pathogenesis of idiopathic Parkinson's disease. Y Neurol Neurosurg Psychiatry 1988:51:745-52. concentrations of 3-0-methyldopa should not 27 Hughes AJ, Lees AJ, Stern GM. test to be reduced by a single dose of entacapone. predict responsiveness in parkinsonian syndromes. Lancet 1990;336:32-4. To reduce the plasma concentrations of 3-0- 28 Kempster PA, Frankel JP, Bovingdon M, Webster R, Lees methyldopa chronic COMT inhibition would AJ, Stern GM. Levodopa peripheral pharmacokinetics http://jnnp.bmj.com/ and duration of motor response in Parkinson's disease. be required. Y Neurol Neurosurg Psychiatry 1989;52:718-23. 29 Gancher ST, Nutt JG, Woodward WR. Response to brief We thank Orion Pharmaceutica, Espoo, Finland for the levodopa infusions in Parkinsonian patients with and generous supply of entacapone. without motor fluctuations. Neurology 1988;38:712-6. 30 Reches A, Fahn S. Catechol-O-methyltransferase and Parkinson's disease. Adv Neurol 1984;40:171-9. 31 Sundberg S, Scheinin M, Ojala-Karlsson P, Kaakkola S, Akkila J, Gordin A. Exercise hemodynamics and cate- 1 Carlsson A. Functional significance of drug induced cholamine metabolism after COMT inhibition with

changes in brain monoamine levels. In: Himwich HE, nitecapone. Clin Pharmacol Ther 1990;48:356-64. on September 24, 2021 by guest. Protected copyright. Himwich WA, eds. Biogenic amines. Progress in Brain 32 Teravainen H, Kaakkola S, Jarvinen M, Gordin A. Research. Amsterdam: Elsevier, 1964;8:9-27. Selective COMT inhibitor, nitecapone, in Parkinson's 2 Nutt JG, Fellman JH. Pharmacokinetics of L-dopa. Clin disease. Neurology 1990;40(suppl 1):271. Neuropharmacol 1984;7:35-49. 33 Teravainen H, Kaakkola S, Gordin A. Clinical effect of 3 Muenter MD, Dinapoli RP, Sharpless NS, Tyce GM. COMT inhibition in L-dopa-treated patients with 3-0-methyldopa, L-dopa and in the Parkinson's disease. Neurology 1992;42(suppl 3):442. treatment of Parkinson's disease. Mayo Clin Prc 1973; 34 Keranen T, Gordin A, Hariola V-P, et al. The effect of 48:173-83. catechol-O-methyltransferase inhibition by entacapone 4 Wade LA, Katzman R. 3-0-methyldopa uptake and on the pharmacokinetics and metabolism of levodopa in inhibition of L-dopa at the blood-brain barrier. Life Sci healthy volunteers. Clin Neuropharnacol 16:145-50. 1975;17:131-6. 35 Mannisto PT, Ulmanen I, Lundstrom K, et al. 5 Gervas J, Muradas B, Bazan E, Aguado E, de Yebenes J. Characteristics of catechol-0-methyltransferase (COMT) Effects of 3-OM-dopa on monoamine metabolism in rat and properties of selective COMT inhibitors. Prog Drug brain. Neurology 1983;33:278-82. Res 1992; 39:291-350. 6 Calne DB, Reid JL, Vakil SD. Parkinsonism treated with 36 Lees AJ, Shaw KM, Kohout L, et al. Deprenyl in 3-0-methyldopa. CGn Pharmacol Ther 1972;14:386-9. Parkinson's disease. Lancet 1977;2:791-3. 7 Cedarbaum JM, Kutt H, McDowell FH. Clinical signifi- 37 Poewe WH, Lees AJ, Stem GM. Treatment of motor cance of the relationship between 0-methyldopa levels fluctuations in Parkinson's disease with an oral and levodopa intake. Neurology 1988;38:533-6. sustained release preparation of L-dopa. Clinical and 8 Fabbrini G, Juncos JL, Mouradian MM, Serrati S, Chase pharmacokinetic observations. Clin Neuropharmacol TN. 3-0-methyldopa and motor fluctuations in 1986;9:430-9. Parkinson's disease. Neurology 1987;37:856-9. 38 Cedarbaum JM, Leger G, Guttman M. Reduction of 9 Gancher ST, Nutt JG, Woodward WR. Peripheral circulating 3-0-methyldopa by inhibition of catechol-O- phannacokinetics of levodopa in untreated, stable and methyltransferase with OR-611 and OR-462 in fluctuating Parkinsonian patients. Neurology 1987;37: cynomolgus monkeys: Implications for the treatmnent of 940-4. Parkinson's disease. Clin Neuropharnacol 1991;14: 10 NuttJG, Woodward WR, Gancher ST, Merrick D. 3-0- 330-42.