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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 maximum plasma concentrations (Cmax) and area under the concentration-time curve from time zero to the last sampling time at which concentrations were at or above the limit of quantification (AUCt) of ( and b) etamicastat and (c and d) BIA 5-961 in rapid or poor N-acetyltransferase-2 acetylators following single (day 1) and repeated (day 10) 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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Fig7: Mean maximum plasma concentrations (Cmax) and area under the concentration-time curve from time zero to the last sampling time at which concentrations were at or above the limit of quantification (AUCt) of ( and b) etamicastat and (c and d) BIA 5-961 in rapid or poor N-acetyltransferase-2 acetylators following single (day 1) and repeated (day 10) 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 interindividual variability in the pharmacokinetic parameters was high for both etamicastat and BIA 5-961, with mean CV close to 100% in some parameters. This variability is due to the different subjects’ NAT2 phenotype (fast/slow acetylating ability), which affects the rate of biotransformation of etamicastat into BIA 5-961. Table VI presents the distribution of the different subjects’ NAT1 and NAT2 phenotypes within each etamicastat dose group. No relevant effect of NAT1 phenotype on etamicastat pharmacokinetics was apparent. Etamicastat pharmacokinetics was shown to be markedly affected by the NAT2 status (figure 7). The extent of systemic exposure to etamicastat in NAT2 slow acetylators was 1.5–6.7 times higher than in NAT2 fast acetylators. BIA 5-961 exposure was 1.5–3.5 times higher in rapid NAT2 acetylators. These results explain the high variability observed in the main etamicastat and BIA 5-961 pharmacokinetic parameters.


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 maximum plasma concentrations (Cmax) and area under the concentration-time curve from time zero to the last sampling time at which concentrations were at or above the limit of quantification (AUCt) of ( and b) etamicastat and (c and d) BIA 5-961 in rapid or poor N-acetyltransferase-2 acetylators following single (day 1) and repeated (day 10) 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

Fig7: Mean maximum plasma concentrations (Cmax) and area under the concentration-time curve from time zero to the last sampling time at which concentrations were at or above the limit of quantification (AUCt) of ( and b) etamicastat and (c and d) BIA 5-961 in rapid or poor N-acetyltransferase-2 acetylators following single (day 1) and repeated (day 10) 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 interindividual variability in the pharmacokinetic parameters was high for both etamicastat and BIA 5-961, with mean CV close to 100% in some parameters. This variability is due to the different subjects’ NAT2 phenotype (fast/slow acetylating ability), which affects the rate of biotransformation of etamicastat into BIA 5-961. Table VI presents the distribution of the different subjects’ NAT1 and NAT2 phenotypes within each etamicastat dose group. No relevant effect of NAT1 phenotype on etamicastat pharmacokinetics was apparent. Etamicastat pharmacokinetics was shown to be markedly affected by the NAT2 status (figure 7). The extent of systemic exposure to etamicastat in NAT2 slow acetylators was 1.5–6.7 times higher than in NAT2 fast acetylators. BIA 5-961 exposure was 1.5–3.5 times higher in rapid NAT2 acetylators. These results explain the high variability observed in the main etamicastat and BIA 5-961 pharmacokinetic parameters.

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