Chronopharmacology of nebicapone, a new catechol-O-methyltransferase inhibitor

Abstract

Objective:

To investigate the chronopharmacology of nebicapone, a new catechol-O-methyltransferase (COMT) inhibitor currently being developed for use as an adjunct to levodopa/carbidopa or levodopa/benserazide in the treatment of Parkinson’s disease.

Methods:

This was a double-blind, randomised, placebo-controlled, parallel-group study. Eighteen Caucasian subjects were randomly assigned to treatment with either nebicapone 100 mg (n = 6), nebicapone 200 mg (n = 6) or placebo (n = 6) at 4-h intervals for 7 days. First dose occurred at 8:00 AM on day 1 and last dose at 8:00 AM on day 8. Blood samples for the determination of plasma drug concentrations of nebicapone and its glucuronidated and methylated metabolites and for the assay of erythrocyte soluble COMT (S-COMT) activity were taken at frequent times following the first and last doses, and before the 8:00 AM and 8:00 PM doses on days 2–7.

Results:

Three men and three women in each group participated in the study. Mean ± SD (range) age of study participants was 23.7 ± 3.1 (21–28) years in the nebicapone 100 mg group, 22.2 ± 0.4 (22–23) years in the nebicapone 200 mg group and 24.3 ± 5.4 (18–32) in the placebo group. A circadian variation in the pre-dose nebicapone and nebicapone-glucuronide plasma concentrations was apparent. Both nebicapone and nebicapone-glucuronide levels were lower before the 8 PM dose in comparison to the 8 AM dose, suggesting that the absorption of nebicapone may follow a circadian variation. S-COMT activity showed no circadian variation in the placebo group. Therefore, the S-COMT activity variation found in nebicapone-treated subjects is considered to be due to changes in plasma concentrations of nebicapone, which is consistent with the fact that the pre-dose S-COMT activity was lower at the time at which nebicapone levels were maximal. Four subjects in the nebicapone 100 mg and placebo groups and six subjects in the nebicapone 200 mg group reported at least one adverse event (AE). All AEs were of mild or moderate intensity. Both nebicapone treatment regimens were subjectively well-tolerated, but a clinically relevant elevation in aspartate transaminase was observed in one subject of each nebicapone group.

Conclusion:

Nebicapone showed chronopharmacology in young Caucasian healthy subjects. The clinical impact of the circadian variation in the nebicapone metabolism and activity in Parkinson’s disease patients deserves evaluation as it may have implications for drug prescription by modulating the distribution of the total daily dose along the 24-h scale.

Key-words::

• Catechol-O-methyltransferase inhibitors
• Chronopharmacokinetics
• Chronopharmacology
• Nebicapone
• Parkinson’s disease

Transparency

Declaration of funding

This trial was funded by Bial (Portela & C^a, SA, S. Mamede do Coronado, Portugal). Bial was responsible for both the design and the conduct of the study. Bial funded the statistical and pharmacokinetic/pharmacodynamic analysis of this manuscript. The first author was responsible for the first and final versions of the manuscript. All authors had full access to the data and substantially contributed to the interpretation of the data and the writing of the manuscript. L.A. and P. Soares-da-Silva were responsible for the study design and study supervision. M. Vaz-da-Silva and J.M. were responsible for the clinical conduct. A.I.L., L.T., C. Fernandes-Lopes, B.I. and L.W. were responsible for the determination of drug plasma concentrations and S-COMT assays. A.F. conducted the pharmacokinetic/pharmacodynamic analysis.

Declaration of financial/other relationships

All authors but A.F. are or were employees of Bial (the sponsor of the study) at the time of the study. A.F. is an employee of 4Health, an independent contract research organisation contracted by the sponsor to conduct the pharmacokinetic/pharmacodynamic analysis.

Peer reviewers may receive honoraria for their review work at CMRO. The peer reviewers have disclosed no relevant financial relationships.

Acknowledgements

This study was sponsored by Bial, Portugal. Data management was carried out by the independent contract research organisation, Eurotrials – scientific consultants (sponsored by Bial). The pharmacokinetic/pharmacodynamic analysis was carried out by the independent contract research organisation, 4Health (sponsored by Bial).

The authors thank the healthy subjects who participated in the study and the clinical and laboratory staff of Bial’s Human Pharmacology Unit.