Pharmacokinetics and Tolerability of Etamicastat Following Single and Repeated Administration in Elderly Versus Young Healthy Male Subjects: An Open-Label, Single-Center, Parallel-Group Study
Etamicastat is a new dopamine-β-hydroxylase (DβH) inhibitor currently in clinical development for the treatment of hypertension and heart failure. To evaluate the pharmacokinetics and tolerability of etamicastat after single and repeated administration in elderly subjects (aged ≥65 years) relative t...
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| Published in | Clinical therapeutics Vol. 33; no. 6; pp. 776 - 791 |
|---|---|
| Main Authors | , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Bridgewater, NJ
EM Inc USA
01.06.2011
Elsevier Elsevier Limited |
| Subjects | |
| Online Access | Get full text |
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| Abstract | Etamicastat is a new dopamine-β-hydroxylase (DβH) inhibitor currently in clinical development for the treatment of hypertension and heart failure.
To evaluate the pharmacokinetics and tolerability of etamicastat after single and repeated administration in elderly subjects (aged ≥65 years) relative to young adult healthy controls (aged 18–45 years).
This was a single-center, open-label, parallel-group study in young male adults (n = 13; mean [SD] age 32.6 [16.4] years; range, 18–44 years; weight 79.0 [16.4] kg; systolic blood pressure 117 [12] mm Hg and diastolic blood pressure 61 [7] mm Hg) and 12 elderly male volunteers (n = 12; age 69.3 [3.3] years; weight 69.2 [9.5] kg; systolic blood pressure 115 [13] mm Hg and diastolic blood pressure 64 [4] mm Hg), conducted in 2 consecutive periods. All subjects were white, except for 1 black elderly subject. In Phase A, subjects received a single dose of 100 mg etamicastat. In Phase B, subjects received 100 mg/d etamicastat for 7 days. The pharmacokinetic parameters of etamicastat and its acetylated metabolite BIA 5-961 were calculated after the single dose of Phase A and the last dose of Phase B. Subjects'
N-acetyltransferase type 1 (NAT1) and type 2 (NAT2) genotyping was performed and acetylator status inferred.
After a single dose of etamicastat 100 mg, mean (SD) plasma C
max and plasma AUC
0–∞ were, respectively, 1.3 (0.5) ng/mL/kg and 12.4 (7.8) ng × h/mL/kg in elderly subjects, and 1.3 (0.4) ng/mL/kg and 10.0 (6.6) ng × h/mL/kg in young subjects. At steady-state, C
max and AUC
0–24 were 1.8 (0.5) ng/mL/kg and 15.0 (6.4) ng × h/mL/kg in elderly subjects, and 1.5 (0.7) ng/mL/kg and 12.5 (6.5) ng × h/mL/kg in young subjects. Elderly/young geometric mean ratios and 90% CIs were, respectively, 0.944 (0.788–1.131) and 1.164 (0.730–1.855) for etamicastat C
max and AUC
0–∞ after a single dose, and 1.225 (0.960–1.563) and 1.171 (0.850–1.612) for etamicastat C
max and AUC
0–24 at steady state. Etamicastat steady-state plasma concentrations were reached after 3 to 4 days of dosing. The mean etamicastat accumulation ratio was 1.7 in both age groups. Following etamicastat single dose, mean (SD) BIA 5-961 C
max and AUC
0–∞ were, respectively, 3.5 (2.1) ng/mL/kg and 28.4 (14.7) ng × h/mL/kg in elderly subjects, and 2.5 (1.5) ng/mL/kg and 16.5 (9.7) in young subjects. At steady state, BIA 5-961, C
max, and AUC
0–24 were 4.3 (2.6) ng/mL/kg and 34.6 (17.6) ng × h/mL/kg in elderly subjects, and 3.1 (2.0) ng/mL/kg and 22.2 (11.8) ng × h/mL/kg in young subjects. Large interindividual variability dependent on the NAT2 acetylator status was found in the pharmacokinetic parameters of etamicastat and BIA 5-961. Systemic exposure to etamicastat was higher and systemic exposure to BIA 5-961 was lower in NAT2 poor metabolizers compared with rapid metabolizers. No effect on heart rate and blood pressure was found in the young group. In the elderly, a decrease of supine blood pressure was observed. Postural changes in blood pressure were unaffected. Four adverse events (AEs) were reported by each group: nasopharyngeal pain, sciatica, asthenia, and back pain the elderly group, and headache (2 cases), insomnia, and myopericarditis by the young group. Myopericarditis led to study discontinuation for this subject and was considered to be of probable viral etiology. All other AEs were mild to moderate in intensity.
The pharmacokinetic profile of etamicastat was not significantly different in these small groups of healthy young versus elderly adult male volunteers. |
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| AbstractList | Etamicastat is a new dopamine-β-hydroxylase (DβH) inhibitor currently in clinical development for the treatment of hypertension and heart failure.BACKGROUNDEtamicastat is a new dopamine-β-hydroxylase (DβH) inhibitor currently in clinical development for the treatment of hypertension and heart failure.To evaluate the pharmacokinetics and tolerability of etamicastat after single and repeated administration in elderly subjects (aged ≥65 years) relative to young adult healthy controls (aged 18-45 years).OBJECTIVESTo evaluate the pharmacokinetics and tolerability of etamicastat after single and repeated administration in elderly subjects (aged ≥65 years) relative to young adult healthy controls (aged 18-45 years).This was a single-center, open-label, parallel-group study in young male adults (n = 13; mean [SD] age 32.6 [16.4] years; range, 18-44 years; weight 79.0 [16.4] kg; systolic blood pressure 117 [12] mm Hg and diastolic blood pressure 61 [7] mm Hg) and 12 elderly male volunteers (n = 12; age 69.3 [3.3] years; weight 69.2 [9.5] kg; systolic blood pressure 115 [13] mm Hg and diastolic blood pressure 64 [4] mm Hg), conducted in 2 consecutive periods. All subjects were white, except for 1 black elderly subject. In Phase A, subjects received a single dose of 100 mg etamicastat. In Phase B, subjects received 100 mg/d etamicastat for 7 days. The pharmacokinetic parameters of etamicastat and its acetylated metabolite BIA 5-961 were calculated after the single dose of Phase A and the last dose of Phase B. Subjects' N-acetyltransferase type 1 (NAT1) and type 2 (NAT2) genotyping was performed and acetylator status inferred.METHODSThis was a single-center, open-label, parallel-group study in young male adults (n = 13; mean [SD] age 32.6 [16.4] years; range, 18-44 years; weight 79.0 [16.4] kg; systolic blood pressure 117 [12] mm Hg and diastolic blood pressure 61 [7] mm Hg) and 12 elderly male volunteers (n = 12; age 69.3 [3.3] years; weight 69.2 [9.5] kg; systolic blood pressure 115 [13] mm Hg and diastolic blood pressure 64 [4] mm Hg), conducted in 2 consecutive periods. All subjects were white, except for 1 black elderly subject. In Phase A, subjects received a single dose of 100 mg etamicastat. In Phase B, subjects received 100 mg/d etamicastat for 7 days. The pharmacokinetic parameters of etamicastat and its acetylated metabolite BIA 5-961 were calculated after the single dose of Phase A and the last dose of Phase B. Subjects' N-acetyltransferase type 1 (NAT1) and type 2 (NAT2) genotyping was performed and acetylator status inferred.After a single dose of etamicastat 100 mg, mean (SD) plasma C(max) and plasma AUC(0-∞) were, respectively, 1.3 (0.5) ng/mL/kg and 12.4 (7.8) ng × h/mL/kg in elderly subjects, and 1.3 (0.4) ng/mL/kg and 10.0 (6.6) ng × h/mL/kg in young subjects. At steady-state, C(max) and AUC(0-24) were 1.8 (0.5) ng/mL/kg and 15.0 (6.4) ng × h/mL/kg in elderly subjects, and 1.5 (0.7) ng/mL/kg and 12.5 (6.5) ng × h/mL/kg in young subjects. Elderly/young geometric mean ratios and 90% CIs were, respectively, 0.944 (0.788-1.131) and 1.164 (0.730-1.855) for etamicastat C(max) and AUC(0-∞) after a single dose, and 1.225 (0.960-1.563) and 1.171 (0.850-1.612) for etamicastat C(max) and AUC(0-24) at steady state. Etamicastat steady-state plasma concentrations were reached after 3 to 4 days of dosing. The mean etamicastat accumulation ratio was 1.7 in both age groups. Following etamicastat single dose, mean (SD) BIA 5-961 C(max) and AUC(0-∞) were, respectively, 3.5 (2.1) ng/mL/kg and 28.4 (14.7) ng × h/mL/kg in elderly subjects, and 2.5 (1.5) ng/mL/kg and 16.5 (9.7) in young subjects. At steady state, BIA 5-961, C(max), and AUC(0-24) were 4.3 (2.6) ng/mL/kg and 34.6 (17.6) ng × h/mL/kg in elderly subjects, and 3.1 (2.0) ng/mL/kg and 22.2 (11.8) ng × h/mL/kg in young subjects. Large interindividual variability dependent on the NAT2 acetylator status was found in the pharmacokinetic parameters of etamicastat and BIA 5-961. Systemic exposure to etamicastat was higher and systemic exposure to BIA 5-961 was lower in NAT2 poor metabolizers compared with rapid metabolizers. No effect on heart rate and blood pressure was found in the young group. In the elderly, a decrease of supine blood pressure was observed. Postural changes in blood pressure were unaffected. Four adverse events (AEs) were reported by each group: nasopharyngeal pain, sciatica, asthenia, and back pain the elderly group, and headache (2 cases), insomnia, and myopericarditis by the young group. Myopericarditis led to study discontinuation for this subject and was considered to be of probable viral etiology. All other AEs were mild to moderate in intensity.RESULTSAfter a single dose of etamicastat 100 mg, mean (SD) plasma C(max) and plasma AUC(0-∞) were, respectively, 1.3 (0.5) ng/mL/kg and 12.4 (7.8) ng × h/mL/kg in elderly subjects, and 1.3 (0.4) ng/mL/kg and 10.0 (6.6) ng × h/mL/kg in young subjects. At steady-state, C(max) and AUC(0-24) were 1.8 (0.5) ng/mL/kg and 15.0 (6.4) ng × h/mL/kg in elderly subjects, and 1.5 (0.7) ng/mL/kg and 12.5 (6.5) ng × h/mL/kg in young subjects. Elderly/young geometric mean ratios and 90% CIs were, respectively, 0.944 (0.788-1.131) and 1.164 (0.730-1.855) for etamicastat C(max) and AUC(0-∞) after a single dose, and 1.225 (0.960-1.563) and 1.171 (0.850-1.612) for etamicastat C(max) and AUC(0-24) at steady state. Etamicastat steady-state plasma concentrations were reached after 3 to 4 days of dosing. The mean etamicastat accumulation ratio was 1.7 in both age groups. Following etamicastat single dose, mean (SD) BIA 5-961 C(max) and AUC(0-∞) were, respectively, 3.5 (2.1) ng/mL/kg and 28.4 (14.7) ng × h/mL/kg in elderly subjects, and 2.5 (1.5) ng/mL/kg and 16.5 (9.7) in young subjects. At steady state, BIA 5-961, C(max), and AUC(0-24) were 4.3 (2.6) ng/mL/kg and 34.6 (17.6) ng × h/mL/kg in elderly subjects, and 3.1 (2.0) ng/mL/kg and 22.2 (11.8) ng × h/mL/kg in young subjects. Large interindividual variability dependent on the NAT2 acetylator status was found in the pharmacokinetic parameters of etamicastat and BIA 5-961. Systemic exposure to etamicastat was higher and systemic exposure to BIA 5-961 was lower in NAT2 poor metabolizers compared with rapid metabolizers. No effect on heart rate and blood pressure was found in the young group. In the elderly, a decrease of supine blood pressure was observed. Postural changes in blood pressure were unaffected. Four adverse events (AEs) were reported by each group: nasopharyngeal pain, sciatica, asthenia, and back pain the elderly group, and headache (2 cases), insomnia, and myopericarditis by the young group. Myopericarditis led to study discontinuation for this subject and was considered to be of probable viral etiology. All other AEs were mild to moderate in intensity.The pharmacokinetic profile of etamicastat was not significantly different in these small groups of healthy young versus elderly adult male volunteers.CONCLUSIONThe pharmacokinetic profile of etamicastat was not significantly different in these small groups of healthy young versus elderly adult male volunteers. Etamicastat is a new dopamine-β-hydroxylase (DβH) inhibitor currently in clinical development for the treatment of hypertension and heart failure. To evaluate the pharmacokinetics and tolerability of etamicastat after single and repeated administration in elderly subjects (aged ≥65 years) relative to young adult healthy controls (aged 18–45 years). This was a single-center, open-label, parallel-group study in young male adults (n = 13; mean [SD] age 32.6 [16.4] years; range, 18–44 years; weight 79.0 [16.4] kg; systolic blood pressure 117 [12] mm Hg and diastolic blood pressure 61 [7] mm Hg) and 12 elderly male volunteers (n = 12; age 69.3 [3.3] years; weight 69.2 [9.5] kg; systolic blood pressure 115 [13] mm Hg and diastolic blood pressure 64 [4] mm Hg), conducted in 2 consecutive periods. All subjects were white, except for 1 black elderly subject. In Phase A, subjects received a single dose of 100 mg etamicastat. In Phase B, subjects received 100 mg/d etamicastat for 7 days. The pharmacokinetic parameters of etamicastat and its acetylated metabolite BIA 5-961 were calculated after the single dose of Phase A and the last dose of Phase B. Subjects' N-acetyltransferase type 1 (NAT1) and type 2 (NAT2) genotyping was performed and acetylator status inferred. After a single dose of etamicastat 100 mg, mean (SD) plasma C max and plasma AUC 0–∞ were, respectively, 1.3 (0.5) ng/mL/kg and 12.4 (7.8) ng × h/mL/kg in elderly subjects, and 1.3 (0.4) ng/mL/kg and 10.0 (6.6) ng × h/mL/kg in young subjects. At steady-state, C max and AUC 0–24 were 1.8 (0.5) ng/mL/kg and 15.0 (6.4) ng × h/mL/kg in elderly subjects, and 1.5 (0.7) ng/mL/kg and 12.5 (6.5) ng × h/mL/kg in young subjects. Elderly/young geometric mean ratios and 90% CIs were, respectively, 0.944 (0.788–1.131) and 1.164 (0.730–1.855) for etamicastat C max and AUC 0–∞ after a single dose, and 1.225 (0.960–1.563) and 1.171 (0.850–1.612) for etamicastat C max and AUC 0–24 at steady state. Etamicastat steady-state plasma concentrations were reached after 3 to 4 days of dosing. The mean etamicastat accumulation ratio was 1.7 in both age groups. Following etamicastat single dose, mean (SD) BIA 5-961 C max and AUC 0–∞ were, respectively, 3.5 (2.1) ng/mL/kg and 28.4 (14.7) ng × h/mL/kg in elderly subjects, and 2.5 (1.5) ng/mL/kg and 16.5 (9.7) in young subjects. At steady state, BIA 5-961, C max, and AUC 0–24 were 4.3 (2.6) ng/mL/kg and 34.6 (17.6) ng × h/mL/kg in elderly subjects, and 3.1 (2.0) ng/mL/kg and 22.2 (11.8) ng × h/mL/kg in young subjects. Large interindividual variability dependent on the NAT2 acetylator status was found in the pharmacokinetic parameters of etamicastat and BIA 5-961. Systemic exposure to etamicastat was higher and systemic exposure to BIA 5-961 was lower in NAT2 poor metabolizers compared with rapid metabolizers. No effect on heart rate and blood pressure was found in the young group. In the elderly, a decrease of supine blood pressure was observed. Postural changes in blood pressure were unaffected. Four adverse events (AEs) were reported by each group: nasopharyngeal pain, sciatica, asthenia, and back pain the elderly group, and headache (2 cases), insomnia, and myopericarditis by the young group. Myopericarditis led to study discontinuation for this subject and was considered to be of probable viral etiology. All other AEs were mild to moderate in intensity. The pharmacokinetic profile of etamicastat was not significantly different in these small groups of healthy young versus elderly adult male volunteers. Etamicastat is a new dopamine-β-hydroxylase (DβH) inhibitor currently in clinical development for the treatment of hypertension and heart failure. To evaluate the pharmacokinetics and tolerability of etamicastat after single and repeated administration in elderly subjects (aged ≥65 years) relative to young adult healthy controls (aged 18-45 years). This was a single-center, open-label, parallel-group study in young male adults (n = 13; mean [SD] age 32.6 [16.4] years; range, 18-44 years; weight 79.0 [16.4] kg; systolic blood pressure 117 [12] mm Hg and diastolic blood pressure 61 [7] mm Hg) and 12 elderly male volunteers (n = 12; age 69.3 [3.3] years; weight 69.2 [9.5] kg; systolic blood pressure 115 [13] mm Hg and diastolic blood pressure 64 [4] mm Hg), conducted in 2 consecutive periods. All subjects were white, except for 1 black elderly subject. In Phase A, subjects received a single dose of 100 mg etamicastat. In Phase B, subjects received 100 mg/d etamicastat for 7 days. The pharmacokinetic parameters of etamicastat and its acetylated metabolite BIA 5-961 were calculated after the single dose of Phase A and the last dose of Phase B. Subjects' N -acetyltransferase type 1 (NAT1) and type 2 (NAT2) genotyping was performed and acetylator status inferred. After a single dose of etamicastat 100 mg, mean (SD) plasma Cmax and plasma AUC0-∞ were, respectively, 1.3 (0.5) ng/mL/kg and 12.4 (7.8) ng × h/mL/kg in elderly subjects, and 1.3 (0.4) ng/mL/kg and 10.0 (6.6) ng × h/mL/kg in young subjects. At steady-state, Cmax and AUC0-24 were 1.8 (0.5) ng/mL/kg and 15.0 (6.4) ng × h/mL/kg in elderly subjects, and 1.5 (0.7) ng/mL/kg and 12.5 (6.5) ng × h/mL/kg in young subjects. Elderly/young geometric mean ratios and 90% CIs were, respectively, 0.944 (0.788-1.131) and 1.164 (0.730-1.855) for etamicastat Cmax and AUC0-∞ after a single dose, and 1.225 (0.960-1.563) and 1.171 (0.850-1.612) for etamicastat Cmax and AUC0-24 at steady state. Etamicastat steady-state plasma concentrations were reached after 3 to 4 days of dosing. The mean etamicastat accumulation ratio was 1.7 in both age groups. Following etamicastat single dose, mean (SD) BIA 5-961 Cmax and AUC0-∞ were, respectively, 3.5 (2.1) ng/mL/kg and 28.4 (14.7) ng × h/mL/kg in elderly subjects, and 2.5 (1.5) ng/mL/kg and 16.5 (9.7) in young subjects. At steady state, BIA 5-961, Cmax, and AUC0-24 were 4.3 (2.6) ng/mL/kg and 34.6 (17.6) ng × h/mL/kg in elderly subjects, and 3.1 (2.0) ng/mL/kg and 22.2 (11.8) ng × h/mL/kg in young subjects. Large interindividual variability dependent on the NAT2 acetylator status was found in the pharmacokinetic parameters of etamicastat and BIA 5-961. Systemic exposure to etamicastat was higher and systemic exposure to BIA 5-961 was lower in NAT2 poor metabolizers compared with rapid metabolizers. No effect on heart rate and blood pressure was found in the young group. In the elderly, a decrease of supine blood pressure was observed. Postural changes in blood pressure were unaffected. Four adverse events (AEs) were reported by each group: nasopharyngeal pain, sciatica, asthenia, and back pain the elderly group, and headache (2 cases), insomnia, and myopericarditis by the young group. Myopericarditis led to study discontinuation for this subject and was considered to be of probable viral etiology. All other AEs were mild to moderate in intensity. The pharmacokinetic profile of etamicastat was not significantly different in these small groups of healthy young versus elderly adult male volunteers. Abstract Background Etamicastat is a new dopamine-β-hydroxylase (DβH) inhibitor currently in clinical development for the treatment of hypertension and heart failure. Objectives To evaluate the pharmacokinetics and tolerability of etamicastat after single and repeated administration in elderly subjects (aged ≥65 years) relative to young adult healthy controls (aged 18–45 years). Methods This was a single-center, open-label, parallel-group study in young male adults (n = 13; mean [SD] age 32.6 [16.4] years; range, 18–44 years; weight 79.0 [16.4] kg; systolic blood pressure 117 [12] mm Hg and diastolic blood pressure 61 [7] mm Hg) and 12 elderly male volunteers (n = 12; age 69.3 [3.3] years; weight 69.2 [9.5] kg; systolic blood pressure 115 [13] mm Hg and diastolic blood pressure 64 [4] mm Hg), conducted in 2 consecutive periods. All subjects were white, except for 1 black elderly subject. In Phase A, subjects received a single dose of 100 mg etamicastat. In Phase B, subjects received 100 mg/d etamicastat for 7 days. The pharmacokinetic parameters of etamicastat and its acetylated metabolite BIA 5-961 were calculated after the single dose of Phase A and the last dose of Phase B. Subjects' N -acetyltransferase type 1 (NAT1) and type 2 (NAT2) genotyping was performed and acetylator status inferred. Results After a single dose of etamicastat 100 mg, mean (SD) plasma Cmax and plasma AUC0–∞ were, respectively, 1.3 (0.5) ng/mL/kg and 12.4 (7.8) ng × h/mL/kg in elderly subjects, and 1.3 (0.4) ng/mL/kg and 10.0 (6.6) ng × h/mL/kg in young subjects. At steady-state, Cmax and AUC0–24 were 1.8 (0.5) ng/mL/kg and 15.0 (6.4) ng × h/mL/kg in elderly subjects, and 1.5 (0.7) ng/mL/kg and 12.5 (6.5) ng × h/mL/kg in young subjects. Elderly/young geometric mean ratios and 90% CIs were, respectively, 0.944 (0.788–1.131) and 1.164 (0.730–1.855) for etamicastat Cmax and AUC0–∞ after a single dose, and 1.225 (0.960–1.563) and 1.171 (0.850–1.612) for etamicastat Cmax and AUC0–24 at steady state. Etamicastat steady-state plasma concentrations were reached after 3 to 4 days of dosing. The mean etamicastat accumulation ratio was 1.7 in both age groups. Following etamicastat single dose, mean (SD) BIA 5-961 Cmax and AUC0–∞ were, respectively, 3.5 (2.1) ng/mL/kg and 28.4 (14.7) ng × h/mL/kg in elderly subjects, and 2.5 (1.5) ng/mL/kg and 16.5 (9.7) in young subjects. At steady state, BIA 5-961, Cmax , and AUC0–24 were 4.3 (2.6) ng/mL/kg and 34.6 (17.6) ng × h/mL/kg in elderly subjects, and 3.1 (2.0) ng/mL/kg and 22.2 (11.8) ng × h/mL/kg in young subjects. Large interindividual variability dependent on the NAT2 acetylator status was found in the pharmacokinetic parameters of etamicastat and BIA 5-961. Systemic exposure to etamicastat was higher and systemic exposure to BIA 5-961 was lower in NAT2 poor metabolizers compared with rapid metabolizers. No effect on heart rate and blood pressure was found in the young group. In the elderly, a decrease of supine blood pressure was observed. Postural changes in blood pressure were unaffected. Four adverse events (AEs) were reported by each group: nasopharyngeal pain, sciatica, asthenia, and back pain the elderly group, and headache (2 cases), insomnia, and myopericarditis by the young group. Myopericarditis led to study discontinuation for this subject and was considered to be of probable viral etiology. All other AEs were mild to moderate in intensity. Conclusion The pharmacokinetic profile of etamicastat was not significantly different in these small groups of healthy young versus elderly adult male volunteers. Etamicastat is a new dopamine-β-hydroxylase (DβH) inhibitor currently in clinical development for the treatment of hypertension and heart failure. To evaluate the pharmacokinetics and tolerability of etamicastat after single and repeated administration in elderly subjects (aged ≥65 years) relative to young adult healthy controls (aged 18-45 years). This was a single-center, open-label, parallel-group study in young male adults (n = 13; mean [SD] age 32.6 [16.4] years; range, 18-44 years; weight 79.0 [16.4] kg; systolic blood pressure 117 [12] mm Hg and diastolic blood pressure 61 [7] mm Hg) and 12 elderly male volunteers (n = 12; age 69.3 [3.3] years; weight 69.2 [9.5] kg; systolic blood pressure 115 [13] mm Hg and diastolic blood pressure 64 [4] mm Hg), conducted in 2 consecutive periods. All subjects were white, except for 1 black elderly subject. In Phase A, subjects received a single dose of 100 mg etamicastat. In Phase B, subjects received 100 mg/d etamicastat for 7 days. The pharmacokinetic parameters of etamicastat and its acetylated metabolite BIA 5-961 were calculated after the single dose of Phase A and the last dose of Phase B. Subjects' N-acetyltransferase type 1 (NAT1) and type 2 (NAT2) genotyping was performed and acetylator status inferred. After a single dose of etamicastat 100 mg, mean (SD) plasma C(max) and plasma AUC(0-∞) were, respectively, 1.3 (0.5) ng/mL/kg and 12.4 (7.8) ng × h/mL/kg in elderly subjects, and 1.3 (0.4) ng/mL/kg and 10.0 (6.6) ng × h/mL/kg in young subjects. At steady-state, C(max) and AUC(0-24) were 1.8 (0.5) ng/mL/kg and 15.0 (6.4) ng × h/mL/kg in elderly subjects, and 1.5 (0.7) ng/mL/kg and 12.5 (6.5) ng × h/mL/kg in young subjects. Elderly/young geometric mean ratios and 90% CIs were, respectively, 0.944 (0.788-1.131) and 1.164 (0.730-1.855) for etamicastat C(max) and AUC(0-∞) after a single dose, and 1.225 (0.960-1.563) and 1.171 (0.850-1.612) for etamicastat C(max) and AUC(0-24) at steady state. Etamicastat steady-state plasma concentrations were reached after 3 to 4 days of dosing. The mean etamicastat accumulation ratio was 1.7 in both age groups. Following etamicastat single dose, mean (SD) BIA 5-961 C(max) and AUC(0-∞) were, respectively, 3.5 (2.1) ng/mL/kg and 28.4 (14.7) ng × h/mL/kg in elderly subjects, and 2.5 (1.5) ng/mL/kg and 16.5 (9.7) in young subjects. At steady state, BIA 5-961, C(max), and AUC(0-24) were 4.3 (2.6) ng/mL/kg and 34.6 (17.6) ng × h/mL/kg in elderly subjects, and 3.1 (2.0) ng/mL/kg and 22.2 (11.8) ng × h/mL/kg in young subjects. Large interindividual variability dependent on the NAT2 acetylator status was found in the pharmacokinetic parameters of etamicastat and BIA 5-961. Systemic exposure to etamicastat was higher and systemic exposure to BIA 5-961 was lower in NAT2 poor metabolizers compared with rapid metabolizers. No effect on heart rate and blood pressure was found in the young group. In the elderly, a decrease of supine blood pressure was observed. Postural changes in blood pressure were unaffected. Four adverse events (AEs) were reported by each group: nasopharyngeal pain, sciatica, asthenia, and back pain the elderly group, and headache (2 cases), insomnia, and myopericarditis by the young group. Myopericarditis led to study discontinuation for this subject and was considered to be of probable viral etiology. All other AEs were mild to moderate in intensity. The pharmacokinetic profile of etamicastat was not significantly different in these small groups of healthy young versus elderly adult male volunteers. |
| Author | Rocha, José Francisco Vaz-da-Silva, Manuel Almeida, Luis Nunes, Teresa Soares-da-Silva, Patricio Falcão, Amilcar |
| Author_xml | – sequence: 1 givenname: Teresa surname: Nunes fullname: Nunes, Teresa organization: Department of Research and Development, BIAL-Portela & Co., S Mamede do Coronado, Portugal – sequence: 2 givenname: José Francisco surname: Rocha fullname: Rocha, José Francisco organization: Department of Research and Development, BIAL-Portela & Co., S Mamede do Coronado, Portugal – sequence: 3 givenname: Manuel surname: Vaz-da-Silva fullname: Vaz-da-Silva, Manuel organization: Department of Research and Development, BIAL-Portela & Co., S Mamede do Coronado, Portugal – sequence: 4 givenname: Amilcar surname: Falcão fullname: Falcão, Amilcar organization: Faculty of Pharmacy & CNC, University of Coimbra, Coimbra, Portugal – sequence: 5 givenname: Luis surname: Almeida fullname: Almeida, Luis organization: Health Sciences Section, University of Aveiro, Aveiro, Portugal – sequence: 6 givenname: Patricio surname: Soares-da-Silva fullname: Soares-da-Silva, Patricio email: psoares.silva@bial.com organization: Department of Research and Development, BIAL-Portela & Co., S Mamede do Coronado, Portugal |
| BackLink | http://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=24314311$$DView record in Pascal Francis https://www.ncbi.nlm.nih.gov/pubmed/21704242$$D View this record in MEDLINE/PubMed |
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| Keywords | heart failure dopamine-β-hydroxylase age effect dopamine-β-hydroxylase inhibition pharmacokinetics etamicastat hypertension Human Hypertension Heart failure Imidazole derivatives Dopamine β-monooxygenase Healthy subject Etamicastat Enzyme Toxicity Single dose Cardiovascular disease Multiple dose Heart disease Oxidoreductases Pharmacokinetics Elderly Age Comparative study |
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| Snippet | Etamicastat is a new dopamine-β-hydroxylase (DβH) inhibitor currently in clinical development for the treatment of hypertension and heart failure.
To evaluate... Abstract Background Etamicastat is a new dopamine-β-hydroxylase (DβH) inhibitor currently in clinical development for the treatment of hypertension and heart... Etamicastat is a new dopamine-β-hydroxylase (DβH) inhibitor currently in clinical development for the treatment of hypertension and heart failure. To evaluate... Etamicastat is a new dopamine-β-hydroxylase (DβH) inhibitor currently in clinical development for the treatment of hypertension and heart... |
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| SubjectTerms | Adolescent Adult age effect Age Factors Aged Area Under Curve Arterial hypertension. Arterial hypotension Arylamine N-Acetyltransferase - genetics Benzopyrans - administration & dosage Benzopyrans - adverse effects Benzopyrans - pharmacokinetics Biological and medical sciences Blood and lymphatic vessels Cardiology. Vascular system Clinical trials Dopamine Dopamine beta-Hydroxylase - antagonists & inhibitors dopamine-β-hydroxylase dopamine-β-hydroxylase inhibition Drug Administration Schedule Drug dosages Drug therapy Enzyme Inhibitors - administration & dosage Enzyme Inhibitors - adverse effects Enzyme Inhibitors - pharmacokinetics etamicastat Genotype Heart heart failure Heart failure, cardiogenic pulmonary edema, cardiac enlargement Humans Hypertension Imidazoles - administration & dosage Imidazoles - adverse effects Imidazoles - pharmacokinetics Infections Internal Medicine Isoenzymes - genetics Male Medical Education Medical sciences Metabolites Older people pharmacokinetics Pharmacology. Drug treatments Rodents Time Factors Young Adult |
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| Title | Pharmacokinetics and Tolerability of Etamicastat Following Single and Repeated Administration in Elderly Versus Young Healthy Male Subjects: An Open-Label, Single-Center, Parallel-Group Study |
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