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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

Mean cumulative urinary excretion of etamicastat following single (day 1 []) and repeated (day 10 [b]), and BIA 5-961 following single (day 1 [c]) and repeated (day 10 [d]) oral once-daily administration of etamicastat in the dose range 25–600 mg (etamicastat 200 mg: n = 12; other dose groups: n = 6 per dose group).
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Fig6: Mean cumulative urinary excretion of etamicastat following single (day 1 []) and repeated (day 10 [b]), and BIA 5-961 following single (day 1 [c]) and repeated (day 10 [d]) oral once-daily administration of etamicastat in the dose range 25–600 mg (etamicastat 200 mg: n = 12; other dose groups: n = 6 per dose group).

Mentions: The cumulative amounts of etamicastat and BIA 5-961 recovered in urine are displayed in figure 6. Urine drug recovery occurred predominantly over the first 12 hours after etamicastat administration. The excretion rate of etamicastat ranged from 0.3 ± 0.1 mg/h (25 mg) to 8.5 ± 3.2 mg/h (600 mg) following the first dose and from 0.4 ± 0.2 mg/h (25 mg) to 10.6 ± 2.8 mg/h (600 mg) following the last dose. For BIA 5-961, the excretion rate ranged from 0.7 ± 0.6 mg/h (25 mg) to 10.4 ± 6.9 mg/h (600 mg) and from 0.753 ± 0.560 mg/h (25 mg) to 15.2 ± 9.8 mg/h (600 mg), respectively. Renal clearance was relatively similar at the different dose levels, ranging from 11.9 to 16.0 L/h for etamicastat and from 11.3 to 14.8 L/h for BIA 5-961.


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)

Mean cumulative urinary excretion of etamicastat following single (day 1 []) and repeated (day 10 [b]), and BIA 5-961 following single (day 1 [c]) and repeated (day 10 [d]) oral once-daily administration of etamicastat in the dose range 25–600 mg (etamicastat 200 mg: n = 12; other dose groups: n = 6 per dose group).
© Copyright Policy
Related In: Results  -  Collection

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

Fig6: Mean cumulative urinary excretion of etamicastat following single (day 1 []) and repeated (day 10 [b]), and BIA 5-961 following single (day 1 [c]) and repeated (day 10 [d]) oral once-daily administration of etamicastat in the dose range 25–600 mg (etamicastat 200 mg: n = 12; other dose groups: n = 6 per dose group).
Mentions: The cumulative amounts of etamicastat and BIA 5-961 recovered in urine are displayed in figure 6. Urine drug recovery occurred predominantly over the first 12 hours after etamicastat administration. The excretion rate of etamicastat ranged from 0.3 ± 0.1 mg/h (25 mg) to 8.5 ± 3.2 mg/h (600 mg) following the first dose and from 0.4 ± 0.2 mg/h (25 mg) to 10.6 ± 2.8 mg/h (600 mg) following the last dose. For BIA 5-961, the excretion rate ranged from 0.7 ± 0.6 mg/h (25 mg) to 10.4 ± 6.9 mg/h (600 mg) and from 0.753 ± 0.560 mg/h (25 mg) to 15.2 ± 9.8 mg/h (600 mg), respectively. Renal clearance was relatively similar at the different dose levels, ranging from 11.9 to 16.0 L/h for etamicastat and from 11.3 to 14.8 L/h for BIA 5-961.

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