This site is intended for healthcare professionals
COMT inhibition in Parkinson’s Disease

COMT Inhibitors

Read time: 20 mins

COMT Inhibitors

Do you understand the differences between second and third generation COMT inhibitors? This section of the Learning Zone looks at the mode of action and key efficacy and safety data of the available COMT inhibitors which can be used to treat motor fluctuations. Let’s start with a recap on how COMT inhibitors work. 


Mode of action 

Only 1% of an oral dose of levodopa reaches the brain1. Even when administered with a dopamine decarboxylase (DDC) inhibitor, up to 90% of levodopa is inactivated by catechol-O-methyl transferase (COMT)1. Blocking peripheral conversion of levodopa to the therapeutically inactive metabolite 3-O-methyldopa (3-OMD), adjunctive COMT inhibitors prolong the half-life of levodopa and improve its delivery to the brain which reduces OFF-time and helps control motor symptoms (Figure 1)2.

BIAL_Parkinsons_COMTi_Fig1__9E2DF94B-01BE-4970-8C42C23630BF4150.png

Figure 1. Enhancement of dopamine levels in the brain by adjunctive treatment of levodopa (adapted from Dingemanse1; Zahoor et al2). 
3-OMD, 3-O-methyldopa; COMT, catechol-O-methyl transferase; DDC, DOPA decarboxylase. 


COMT inhibitors also increase the amount of each levodopa dose that reaches the brain, which may amplify dopaminergic-related side effects such as dyskinesia3–6.  

Clinical development of COMT inhibitors  

There are three generations of COMT inhibitors. The first generation were unselective, nonpotent, and considerably toxic7. Second and third generation COMT inhibitors have offered progressive benefits to patients and have been approved as adjunctive therapy to levodopa/DOPA decarboxylase inhibitors in adult patients with Parkinson's disease and end-of-dose motor fluctuations who cannot be stabilised on those combinations3–6

BIAL_Parkinsons_COMTi_FigA__0D831722-E1F2-499F-A1A03CC87697B25E.png

How do the COMT inhibitors differ? 

There are a number of differences between the COMT inhibitors in terms of their site of action, binding affinity for COMT and administration requirements. 

Tolcapone 

Tolcapone acts both centrally and peripherally, with a plasma half-life of 5–8 hours, which necessitates 100–200 mg dosing three times daily7

Entacapone 

Entacapone acts peripherally and has a plasma half-life of 1–2 hours following a 200 mg dose which means administration with each levodopa/DDCI dose7

Opicapone 

Opicapone acts peripherally and while it has an elimination half-life of 0.7–3.2 hours, its high binding affinity for COMT (sub-picomolar Kd) gives a long duration of action requiring only once daily 50 mg dosing (at bedtime at least 1 hour before or after levodopa combinations)6,8. For example, while the reported COMT inhibition half-life for opicapone is >100 hours after multiple doses8, it is 39 hours for tolcapone9

Ask the expert  

What is the current role of COMT inhibitors in terms of MOA and clinical efficacy?

Professor Rascol discusses the properties of the available COMT inhibitors. 

Efficacy of COMT inhibitors 

Let’s now look at the key efficacy data for the COMT inhibitors determined from their phase 3 trials in patients with Parkinson’s disease and motor fluctuations. 

Tolcapone 

Double-blind, placebo-controlled clinical studies of tolcapone in patients with motor fluctuations have shown a significant reduction in OFF time (20–30%), a similar increase in ON time, and reduced severity of symptoms5

Register free for full access to medthority.com

Safety of COMT inhibitors 

As always, selecting the right treatment for your patient involves the balance of efficacy, safety and individual requirements. This section of the Learning Zone describes the safety aspects of COMT inhibitor treatments for motor fluctuations. 

Tolcapone 

Clinical trials of tolcapone showed elevated liver enzymes (> 3 times above the upper limit of normal) in ~1% and ~3% of patients dosed with 100 and 200 mg, respectively17. There were also three deaths from acute liver failure after 60000 patients had received tolcapone for a total of 40000 patient-years17. Because of the concerns for liver toxicity, tolcapone is only used in patients who failed to respond to or are intolerant of other COMT inhibitors5.  

Register free for full access to medthority.com

References

  1. Dingemanse J, Waters, Schapira, Nutt, Obeso, Reichmann, et al. Issues important for rational COMT inhibition. Neurology. 2000;55(11 SUPPL. 4).
  2. Zahoor I, Shafi A, Haq E. Pharmacological Treatment of Parkinson’s Disease. 2018 http://www.ncbi.nlm.nih.gov/pubmed/30702845. Accessed 16 January 2020.
  3. Zahoor I, Shafi A, Haq E. Pharmacological Treatment of Parkinson’s Disease. 2018 http://www.ncbi.nlm.nih.gov/pubmed/30702845. Accessed 16 January 2020.
  4. Comtan® (entacapone). Summary of Product Characteristics. Novartis Europharm Ltd. Available at: https://www.ema.europa.eu/en/documents/product-information/comtan-epar-product-information_en.pdf. Last updated 03 Sep 2018. Accessed 3 February 2020.
  5. Tasmar® (tolcapone) Summary of Product Characteristics. Meda AB. Available at: https://www.ema.europa.eu/en/documents/product-information/tasmar-epar-product-information_en.pdf. Last updated 08 Aug 2018. Accessed 3 February 2020.
  6. Ongentys® (opicapone) Summary of Product Characteristics. Bial - Portela Ca, S.A. Available at: https://www.ema.europa.eu/en/documents/product-information/ongentys-epar-product-information_en.pdf. Last updated 13 Mar 2019. Accessed 3 February 2020.
  7. Gershanik OS. Improving l-dopa therapy: The development of enzyme inhibitors. Movement Disorders. 2015;30(1):103–113.
  8. Rocha JF, Almeida L, Falcão A, Palma PN, Loureiro AI, Pinto R, et al. Opicapone: A short lived and very long acting novel catechol-O-methyltransferase inhibitor following multiple dose administration in healthy subjects. Br J Clin Pharmacol. 2013;76(5):763–775.
  9. Dingemanse J, Jorga K, Zürcher G, Fotteler B, Sedek G, Nielsen T, et al. Multiple-dose clinical pharmacology of the catechol-O-methyl-transferase inhibitor tolcapone in elderly subjects. Eur J Clin Pharmacol. 1996;50(1–2):47–55.
  10. Entacapone to tolcapone switch: Multicenter double-blind, randomized, active-controlled trial in advanced Parkinson’s disease. Mov Disord. 2007;22(1):14–19.
  11. Rinne UK, Larsen JP, Siden Å, Worm-Petersen J. Entacapone enhances the response to levodopa in parkinsonian patients with motor fluctuations. Neurology. 1998;51(5):1309–1314.
  12. Kieburtz. Entacapone improves motor fluctuations in levodopa-treated Parkinson’s disease patients. Ann Neurol. 1997;42(5):747–755.
  13. Larsen JP, Worm-Petersen J, Sidén Å, Gordin A, Reinikainen K, Leinonen M. The tolerability and efficacy of entacapone over 3 years in patients with Parkinson’s disease. Eur J Neurol. 2003;10(2):137–146.
  14. Lees AJ, Ferreira J, Rascol O, Reichmann H, Stocchi F, Tolosa E, et al. Opicapone for the management of end-of-dose motor fluctuations in patients with Parkinson’s disease treated with L-DOPA. Expert Rev Neurother. 2017;17(7):649–659.
  15. Ferreira JJ, Lees A, Rocha JF, Poewe W, Rascol O, Soares-da-Silva P. Opicapone as an adjunct to levodopa in patients with Parkinson’s disease and end-of-dose motor fluctuations: A randomised, double-blind, controlled trial. Lancet Neurol. 2016;15(2):154–165.
  16. Lees AJ, Ferreira J, Rascol O, Poewe W, Rocha JF, McCrory M, et al. Opicapone as adjunct to levodopa therapy in patients with Parkinson disease and motor fluctuations a randomized clinical trial. JAMA Neurol. 2017;74(2):197–206.
  17. Watkins P, Olanow, Rascol, Obeso, Koller, Sage, et al. COMT inhibitors and liver toxicity. Neurology. 2000;55(11 SUPPL. 4).
  18. Lees A, Ferreira JJ, Rocha JF, Rascol O, Poewe W, Gama H, et al. Safety Profile of Opicapone in the Management of Parkinson’s Disease. J Parkinsons Dis. 2019;9(4):733–740.
  19. Ferreira JJ, Lees AJ, Poewe W, Rascol O, Rocha JF, Keller B, et al. Effectiveness of opicapone and switching from entacapone in fluctuating Parkinson disease. Neurology. 2018;90(21):E1849–E1857.
Welcome: