Spotlight on opicapone as an adjunct to levodopa in Parkinson&amp;rsquo;s disease: design, development and potential place in therapy

Annus, Ádám; Vécsei, László

doi:10.2147/dddt.s104227

Cited by 23 publications

(24 citation statements)

References 48 publications

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“…COMT inhibitors are used in combined therapy for the treatment of Parkinson's disease to improve the bioavailability and efficacy of L-DOPA (Gonçalves et al, 2012;Kiss and Soares-da-Silva, 2014;Silva et al, 2016). Currently, there are three COMT inhibitors available in the market: entacapone; tolcapone, only used in patients unresponsive to other treatments and with monitoring of liver function; and opicapone, since its recent approval by the European Medicines Agency in June 2016 (Kiss and Soares-da-Silva, 2014;Annus and Vécsei, 2017). The peripheral (BIA 9-1059, BIA 9-1079, entacapone, and opicapone) and/or central (nebicapone and tolcapone) enzymatic inhibition displayed by these compounds justify the investigation of the role that P-gp and/or BCRP may have in their access to the CNS (Learmonth et al, 2002;Napolitano et al, 2003;Parada and Soares-da-Silva, 2003;Kiss et al, 2008;Bonifácio et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Elucidation of the Impact of P-glycoprotein and Breast Cancer Resistance Protein on the Brain Distribution of Catechol-O-Methyltransferase Inhibitors

et al. 2017

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P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are clinically important efflux transporters that act cooperatively at the blood-brain barrier, limiting the entry of several drugs into the central nervous system (CNS) and affecting their pharmacokinetics, therapeutic efficacy, and safety. In the present study, the interactions of catechol--methyltransferase (COMT) inhibitors (BIA 9-1059, BIA 9-1079, entacapone, nebicapone, opicapone, and tolcapone) with P-gp and BCRP were investigated to determine the contribution of these transporters in their access to the brain. In vitro cellular accumulation and bidirectional transport assays were conducted in Madin-Darby canine kidney (MDCK) II, MDCK-MDR1, and MDCK-BCRP cells. In vivo pharmacokinetic studies were carried out for tolcapone and BIA 9-1079 in rats, with and without elacridar, a well-known P-gp and BCRP modulator. The results suggest that BIA 9-1079, nebicapone, and tolcapone inhibit BCRP in a concentration-dependent manner. Moreover, with net flux ratios higher than 2 and decreased over 50% in the presence of verapamil or Ko143, BIA 9-1079 was identified as a P-gp substrate while BIA 9-1059, entacapone, opicapone, and nebicapone were revealed to be BCRP substrates. In vivo, brain exposure was limited for tolcapone and BIA 9-1079, although tolcapone crossed the blood-brain barrier at a greater rate and to a greater extent than BIA 9-1079. The extent of brain distribution of both compounds was significantly increased in the presence of elacridar, attesting to the involvement of efflux transporters. These findings provide relevant information and improve the understanding of the mechanisms that govern the access of these COMT inhibitors to the CNS.

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Section: Introductionmentioning

confidence: 99%

Elucidation of the Impact of P-glycoprotein and Breast Cancer Resistance Protein on the Brain Distribution of Catechol-O-Methyltransferase Inhibitors

et al. 2017

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“…(The article also includes the most relevant data before October 2016. For more information see our previous article [10].) The key terms of the search were 'opicapone' and 'BIA 9-1067ʹ.…”

Section: Review Datamentioning

confidence: 99%

“…Currently two COMT inhibitors are in regular use: ENT and TLC [7]. ENT is a safe product to be given several times a day [10]. Although TLC is more potent compared to ENT, TLC requires close monitoring due to the potential risk of hepatotoxicity [13].…”

Section: Overview Of the Marketmentioning

confidence: 99%

“…Dopamine (DA) is not able to cross the blood-brain barrier (BBB), therefore we use its precursor, LD. However, LD is rapidly converted by DOPA decarboxylase (DDC) and catechol-O-methyltransferase (COMT) enzymes to its metabolites in the periphery (Figure 1; [10]). If we administer LD orally, only 1% will penetrate into the central nervous system (CNS [11];).…”

Section: Introductionmentioning

confidence: 99%

“…The function of the COMT enzyme is to transfer a methyl group to catecholamines. During the catalytic process S-adenosyl methionine (SAM) is converted to S-adenosyl homocysteine (SAH) [10]; the detailed metabolism is presented in Figure 1. The most common COMT inhibitors are entacapone (ENT) and tolcapone (TLC) [12].…”

Section: Introductionmentioning

confidence: 99%

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Opicapone for the treatment of Parkinson’s disease: an update

Salamon

Zádori

Szpisjak

et al. 2019

Expert Opinion on Pharmacotherapy

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Introduction: Parkinson's disease is a neurodegenerative disorder which is characterized by the combination of motor and non-motor symptoms. As yet, there is no curative treatment. The gold standard for symptom control is levodopa. Two years after the start of substitution therapy, around 50% of patients experience some degree of fluctuation in motor performance. Catechol-O-methyltransferase (COMT) inhibitors are important agents in treating these fluctuations. Areas covered: This article summarizes our knowledge about a new third-generation COMT inhibitor, namely opicapone (OPC) (Search period: 2016-2019). The authors detail the pharmacological profile of OPC and summarize the results of completed clinical trials. In addition, they briefly summarize the achievements of the past few years. Expert opinion: Based on clinical trials conducted so far, OPC is an effective and safe new drug. In comparison to entacapone and tolcapone, it does not require close laboratory monitoring or multiple oral administrations, which may result in better adherence. No serious adverse event was reported during the drug development phases. Dyskinesia was the most common complaint. Further comparative studies and broader trial inclusion criteria are needed to help the decision between COMT inhibitors and to expand the patient spectrum where this drug can be applied.

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Effect of Opicapone Tablets on Levodopa and 3‐O‐Methyldopa Pharmacokinetics in Healthy Japanese Subjects: Phase 1 Study

Nomoto

Takeda

Iwai

et al. 2020

Clinical Pharm in Drug Dev

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This study evaluated the effect of a small‐tablet formulation of opicapone for use in clinical trials in Japan on the pharmacokinetics of levodopa (l‐dopa) and 3‐O‐methyldopa (3‐OMD). In an open‐label, 3‐period, single‐sequence crossover phase 1 study in 80 healthy Japanese males (aged 20‐45 years; body mass index, 18.5 to <30.0 kg/m2), 10 mg of l‐dopa/carbidopa 100 was administered 3 times daily on day 0 (period 1) and day 12 (period 3), and opicapone tablets (5, 10, 25, or 50 mg; n = 20 each group) were administered once daily for 11 days (period 2). During periods 1 and 3, plasma concentrations of l‐dopa and 3‐OMD were measured and pharmacokinetic parameters (maximum observed plasma concentration, time at which maximum concentration was observed, area under the plasma concentration–time curve from time 0 to 5 hours [AUC5h] and from time 0 to 24 hours [AUC24h] following each dose, terminal half‐life) of plasma l‐dopa and 3‐OMD were determined along with the geometric mean ratio (period 3/period 1) of AUC24h for l‐dopa and 3‐OMD. Maximum concentration of l‐dopa for the first, second, or third doses of l‐dopa/carbidopa did not significantly increase with increasing opicapone dose. The AUC of l‐dopa increased with increasing opicapone dose but tended toward a peak plateau with opicapone doses of 25 mg and higher. Geometric mean ratios (90% confidence intervals) of AUC24h were 5 mg, 1.16 (1.10‐1.21); 10 mg, 1.26 (1.23‐1.30); 25 mg, 1.51 (1.44‐1.57); 50 mg, 1.60 (1.54‐1.66). Opicapone tablets were well tolerated. In Japanese healthy subjects, increases in plasma exposure to l‐dopa appear to level off with opicapone doses of 25 mg and higher, which may be relevant for optimal dosing among Japanese patients with Parkinson disease.

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Spotlight on opicapone as an adjunct to levodopa in Parkinson’s disease: design, development and potential place in therapy

Cited by 23 publications

References 48 publications

Elucidation of the Impact of P-glycoprotein and Breast Cancer Resistance Protein on the Brain Distribution of Catechol-O-Methyltransferase Inhibitors

Elucidation of the Impact of P-glycoprotein and Breast Cancer Resistance Protein on the Brain Distribution of Catechol-O-Methyltransferase Inhibitors

Opicapone for the treatment of Parkinson’s disease: an update

Effect of Opicapone Tablets on Levodopa and 3‐O‐Methyldopa Pharmacokinetics in Healthy Japanese Subjects: Phase 1 Study

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