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Safety, tolerability, and pharmacokinetics of etamicastat, a novel dopamine-β-hydroxylase inhibitor, in a rising multiple-dose study in young healthy subjects.

Nunes T, Rocha JF, Vaz-da-Silva M, Igreja B, Wright LC, Falcão A, Almeida L, Soares-da-Silva P - Drugs R D (2010)

Bottom Line: Urinary excretion of norepinephrine decreased following repeated administration of etamicastat.Etamicastat was generally well tolerated.Etamicastat was well tolerated.

View Article: PubMed Central - PubMed

Affiliation: Department of Research and Development, BIAL-Portela and Co., SA, S. Mamede do Coronado, Portugal.

ABSTRACT

Background: Activation of the sympathetic nervous system is an important feature in hypertension and congestive heart failure. A strategy for directly modulating sympathetic nerve function is to reduce the biosynthesis of norepinephrine (noradrenaline) via inhibition of dopamine-β-hydroxylase (DβH).

Objective: To assess the safety, tolerability, and pharmacokinetics of etamicastat (BIA 5-453), a new DβH inhibitor, following repeated dosing.

Methods: A double-blind, randomized, placebo-controlled study was conducted in healthy young male volunteers. Participants received once-daily doses of placebo or etamicastat 25, 50, 100, 200, 400, or 600 mg, for 10 days.

Results: Etamicastat underwent N-acetylation to its metabolite BIA 5-961. Etamicastat and BIA 5-961 maximum concentrations were achieved at 1-3 and 2-4 hours, respectively, after dosing. Elimination half-lives ranged from 18.1 to 25.7 hours for etamicastat and 6.7 to 22.5 hours for BIA 5-961. Both etamicastat and BIA 5-961 followed linear pharmacokinetics. The extent of systemic exposure to etamicastat and BIA 5-961 increased in an approximately dose-proportional manner, and steady-state plasma concentrations were attained up to 9 days of dosing. Etamicastat accumulated in plasma following repeated administration. The mean observed accumulation ratio was 1.3-1.9 for etamicastat and 1.3-1.6 for BIA 5-961. Approximately 40% of the etamicastat dose was recovered in urine in the form of parent compound and BIA 5-961. There was a high variability in pharmacokinetic parameters, attributable to different N-acetyltransferase-2 (NAT2) phenotype. Urinary excretion of norepinephrine decreased following repeated administration of etamicastat. Etamicastat was generally well tolerated. There was no serious adverse event or clinically significant abnormality in clinical laboratory tests, vital signs, or ECG parameters.

Conclusion: Etamicastat was well tolerated. Etamicastat undergoes N-acetylation, which is markedly influenced by NAT2 phenotype. NAT2 genotyping could be a step toward personalized medicine for etamicastat.

Trial registration: EudraCT No. 2007-004142-33.

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Related in: MedlinePlus

Proportionality of maximum concentration (Cmax) and area under the plasma concentration-time curve from time 0 to 24 hours (AUC24) of etamicastat and BIA 5-961 following the first dose (day 1) and the final dose (day 10) of repeated administration of etamicastat to healthy subjects
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Tab5: Proportionality of maximum concentration (Cmax) and area under the plasma concentration-time curve from time 0 to 24 hours (AUC24) of etamicastat and BIA 5-961 following the first dose (day 1) and the final dose (day 10) of repeated administration of etamicastat to healthy subjects

Mentions: Etamicastat Cmax was reached 1–3 hours post-dose and declined thereafter, with an approximate mean apparent t1/2 of 9–15 hours following the first dose of etamicastat and 18–26 hours following repeated administration. Cmax of BIA 5-961 was reached 2–4 hours post-dose and declined thereafter, with a mean t1/2 of 4–8 hours following the first dose of etamicastat and 7–23 hours following repeated administration. Systemic exposure to etamicastat and BIA 5-961 increased with increasing doses on both day 1 and day 10 (table V and figure 5). The apparent dose-proportional increase in systemic exposure was confirmed by the statistical analysis using an exponential regression model. Also, the comparison of etamicastat and BIA 5-961 pharmacokinetic parameters after log-transformation and dose-normalization showed that Cmax, AUCt and AUC24 following the first dose of etamicastat, and Cmax, AUCt, AUC24, and AUC∞ following the last dose were not significantly different between dose groups.


Safety, tolerability, and pharmacokinetics of etamicastat, a novel dopamine-β-hydroxylase inhibitor, in a rising multiple-dose study in young healthy subjects.

Nunes T, Rocha JF, Vaz-da-Silva M, Igreja B, Wright LC, Falcão A, Almeida L, Soares-da-Silva P - Drugs R D (2010)

Proportionality of maximum concentration (Cmax) and area under the plasma concentration-time curve from time 0 to 24 hours (AUC24) of etamicastat and BIA 5-961 following the first dose (day 1) and the final dose (day 10) of repeated administration of etamicastat to healthy subjects
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585840&req=5

Tab5: Proportionality of maximum concentration (Cmax) and area under the plasma concentration-time curve from time 0 to 24 hours (AUC24) of etamicastat and BIA 5-961 following the first dose (day 1) and the final dose (day 10) of repeated administration of etamicastat to healthy subjects
Mentions: Etamicastat Cmax was reached 1–3 hours post-dose and declined thereafter, with an approximate mean apparent t1/2 of 9–15 hours following the first dose of etamicastat and 18–26 hours following repeated administration. Cmax of BIA 5-961 was reached 2–4 hours post-dose and declined thereafter, with a mean t1/2 of 4–8 hours following the first dose of etamicastat and 7–23 hours following repeated administration. Systemic exposure to etamicastat and BIA 5-961 increased with increasing doses on both day 1 and day 10 (table V and figure 5). The apparent dose-proportional increase in systemic exposure was confirmed by the statistical analysis using an exponential regression model. Also, the comparison of etamicastat and BIA 5-961 pharmacokinetic parameters after log-transformation and dose-normalization showed that Cmax, AUCt and AUC24 following the first dose of etamicastat, and Cmax, AUCt, AUC24, and AUC∞ following the last dose were not significantly different between dose groups.

Bottom Line: Urinary excretion of norepinephrine decreased following repeated administration of etamicastat.Etamicastat was generally well tolerated.Etamicastat was well tolerated.

View Article: PubMed Central - PubMed

Affiliation: Department of Research and Development, BIAL-Portela and Co., SA, S. Mamede do Coronado, Portugal.

ABSTRACT

Background: Activation of the sympathetic nervous system is an important feature in hypertension and congestive heart failure. A strategy for directly modulating sympathetic nerve function is to reduce the biosynthesis of norepinephrine (noradrenaline) via inhibition of dopamine-β-hydroxylase (DβH).

Objective: To assess the safety, tolerability, and pharmacokinetics of etamicastat (BIA 5-453), a new DβH inhibitor, following repeated dosing.

Methods: A double-blind, randomized, placebo-controlled study was conducted in healthy young male volunteers. Participants received once-daily doses of placebo or etamicastat 25, 50, 100, 200, 400, or 600 mg, for 10 days.

Results: Etamicastat underwent N-acetylation to its metabolite BIA 5-961. Etamicastat and BIA 5-961 maximum concentrations were achieved at 1-3 and 2-4 hours, respectively, after dosing. Elimination half-lives ranged from 18.1 to 25.7 hours for etamicastat and 6.7 to 22.5 hours for BIA 5-961. Both etamicastat and BIA 5-961 followed linear pharmacokinetics. The extent of systemic exposure to etamicastat and BIA 5-961 increased in an approximately dose-proportional manner, and steady-state plasma concentrations were attained up to 9 days of dosing. Etamicastat accumulated in plasma following repeated administration. The mean observed accumulation ratio was 1.3-1.9 for etamicastat and 1.3-1.6 for BIA 5-961. Approximately 40% of the etamicastat dose was recovered in urine in the form of parent compound and BIA 5-961. There was a high variability in pharmacokinetic parameters, attributable to different N-acetyltransferase-2 (NAT2) phenotype. Urinary excretion of norepinephrine decreased following repeated administration of etamicastat. Etamicastat was generally well tolerated. There was no serious adverse event or clinically significant abnormality in clinical laboratory tests, vital signs, or ECG parameters.

Conclusion: Etamicastat was well tolerated. Etamicastat undergoes N-acetylation, which is markedly influenced by NAT2 phenotype. NAT2 genotyping could be a step toward personalized medicine for etamicastat.

Trial registration: EudraCT No. 2007-004142-33.

Show MeSH
Related in: MedlinePlus