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Effect of moderate liver impairment on the pharmacokinetics of opicapone

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Opicapone (OPC) is a novel catechol-O-methyltransferase (COMT) inhibitor to be used as adjunctive therapy in levodopa-treated patients with Parkinson’s disease. The purpose of this study was to evaluate the effect of moderate liver impairment on the pharmacokinetics (PK) and pharmacodynamics (PD; effect on COMT activity) of OPC.

Methods

An open-label, parallel-group study in patients (n = 8) with moderate liver impairment (Child–Pugh category B, score of 7 to 9) and matched healthy subjects (n = 8, control) with normal liver function. All subjects received a single 50-mg oral dose of OPC, with plasma and urine concentrations of opicapone and its metabolites measured up to 72 h post-dose, including soluble COMT (S-COMT) activity. A one-way analysis of variance (ANOVA) was used to compare the main PK and PD parameters between groups. Point estimates (PE) of geometric mean ratios (GMR) and corresponding 90 % confidence intervals (90%CI) for the ratio hepatic/control subjects of each parameter were calculated and compared with the reference interval (80–125 %).

Results

Exposure to opicapone (AUC and Cmax) increased significantly in patients with moderate hepatic impairment (PE [90%CI]: AUC0-∞, 184 % [135–250 %]; Cmax, 189 % [144–249 %]). Although apparent total clearance (CL/F) of opicapone was decreased by ∼35 %, similar elimination half-life and unbound/bound fractions of opicapone were observed between the two groups. Both rate and extent of exposure to BIA 9-1103 were higher in the hepatically impaired group, but not statistically significant compared with the control group. Similar to the parent (opicapone), the observed increase in exposure to BIA 9-1106 was statistically significant in the hepatically impaired group over the control group. BIA 9-1106 was the only metabolite detected in urine and its urine PK parameters were in accordance with plasma data. Maximum S-COMT inhibition (Emax) occurred earlier for the hepatically impaired group with values of 100 % and 91.2 % for the hepatically impaired and control groups respectively. Both Emax and AUEC for the hepatically impaired group reached statistical significance over the control group. OPC was well tolerated in both hepatically impaired and control groups.

Conclusion

The bioavailability of an orally administered single dose of 50 mg OPC was significantly higher in patients with moderate chronic hepatic impairment, perhaps by a reduced first-pass effect. As the tolerability profile of OPC was favourable under the conditions of this study and its exposure is completely purged from systemic circulation before the subsequent dose administration, no OPC dose adjustment is needed in patients with mild to moderate chronic hepatic impairment. However, as OPC is under clinical development for use as adjunctive therapy in levodopa-treated patients with Parkinson’s disease, an adjustment of levodopa and/or OPC regimens in patients should be carefully considered based on a potentially enhanced levodopa dopaminergic response and the associated tolerability.

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Conflict of interest

This study was sponsored by Bial (Portela & Cª, S.A). All authors were involved in the design or conduction of the study, the collection, management or analysis of the data, and the preparation or review of the manuscript. Dr Amílcar Falcão received consultancy honoraria from Bial (Portela & Cª, S.A.). Drs José Francisco Rocha, Ana Santos, Nelson Lopes, Teresa Nunes, Roberto Pinto and Patrício Soares-da-Silva are or were employees of Bial at the time of the study.

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Authors and Affiliations

  1. Department of Research and Development, Bial (Portela and Cª, S.A.), Av. da Siderurgia Nacional, 4745-457, S. Mamede do Coronado, Portugal

    José Francisco Rocha, Ana Santos, Nelson Lopes, Teresa Nunes, Roberto Pinto & Patrício Soares-da-Silva

  2. Laboratory of Pharmacology, Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal

    Amílcar Falcão

  3. Department Pharmacology and Therapeutics, Faculty of Medicine, University Porto, Porto, Portugal

    Roberto Pinto & Patrício Soares-da-Silva

Authors
  1. José Francisco Rocha
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  2. Ana Santos
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  3. Amílcar Falcão
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  4. Nelson Lopes
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  5. Teresa Nunes
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  6. Roberto Pinto
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  7. Patrício Soares-da-Silva
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Corresponding author

Correspondence to Patrício Soares-da-Silva.

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Rocha, J.F., Santos, A., Falcão, A. et al. Effect of moderate liver impairment on the pharmacokinetics of opicapone. Eur J Clin Pharmacol 70, 279–286 (2014). https://doi.org/10.1007/s00228-013-1602-9

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  • DOI: https://doi.org/10.1007/s00228-013-1602-9

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