Elsevier

Clinical Therapeutics

Volume 33, Issue 6, June 2011, Pages 776-791
Clinical Therapeutics

Pharmacokinetics, bioavailability, & bioequivalence
Original research
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

https://doi.org/10.1016/j.clinthera.2011.05.048Get rights and content

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.

Introduction

Activation of the sympathetic nervous system is an important feature in hypertension and congestive heart failure.1, 2, 3, 4, 5, 6 This sympathetic activation, in addition to causing blood pressure elevation, most likely also contributes to left ventricular hypertrophy and to the commonly associated metabolic abnormalities of insulin resistance and dyslipidemia.1 Inhibition of sympathetic nerve function with adrenoceptor antagonists is a rational approach, but some patients do not tolerate the immediate hemodynamic deterioration that accompanies adrenoceptor blockade, particularly heart failure patients.7

An alternative strategy for directly modulating sympathetic nerve function is to reduce the biosynthesis of noradrenaline via inhibition of dopamine-β-hydroxylase (DβH),8 the enzyme that catalyzes the conversion of dopamine into noradrenaline in the catecholamine biosynthetic pathway. The inhibition of DβH has several putative advantages over adrenoceptor blockade, such as gradual sympathetic modulation as opposed to abrupt inhibition of the sympathetic system observed with β-blockers.9 In addition, inhibition of DβH increases the release of dopamine,10, 11 which can promote renal vasodilation, diuresis, and natriuresis.9, 12, 13 Therefore, it may be hypothesized that DβH inhibitors could be advantageous over conventional pure β-blockers or mixed α,β-blockers.

Several DβH inhibitors have been described. The early first and second generation DβH inhibitors, such as disulfiram,14 diethyldithiocarbamate15 or fusaric acid,16 and aromatic or alkyl thioureas,17 were devoid of selectivity for DβH and presented a nonsatisfactory tolerability profile. A third generation DβH inhibitor, nepicastat (RS-25560-197, Roche Bioscience, Palo Alto, California),8 was a selective and potent DβH inhibitor that was developed in early clinical trials.18 Although devoid of some of the problems associated with the earlier DβH inhibitors, nepicastat development in congestive heart failure did not progress. Because nepicastat is able to cross the blood–brain barrier and is a central nervous system active DβH inhibitor, its clinical development is in progress for the indication of cocaine addiction (NCT00656357 at www.clinicaltrials.gov) and post-traumatic stress disorder (NCT00641511 and NCT00659230 at www.clinicaltrials.gov). Therefore, there yet remains an unmet clinical need for a potent, safe, and peripherally selective DβH inhibitor.

Etamicastat (development code BIA 5-453) is a potent and reversible inhibitor of peripheral DβH currently under clinical development for the treatment of hypertension and heart failure. Etamicastat is a reversible DβH inhibitor, displaying mixed (noncompetitive) type inhibition with respect to dopamine with a low nanomolar inhibition constant (Ki) value,19 which prevents the conversion of dopamine to noradrenaline in peripheral sympathetically innervated tissues and slows down the drive of the sympathetic nervous system.20 In contrast to that found in peripheral tissues, etamicastat does not affect dopamine and noradrenaline tissue levels in the brain.20

Etamicastat was tested in animal models predictive of efficacy in cardiovascular disorders.21, 22, 23 Etamicastat reduced systolic (SBP) and diastolic blood pressure (DBP) in spontaneously hypertensive rats with no changes in normotensive Wistar-Kyoto rats.21, 22 Etamicastat did not affect heart rate (HR) in both spontaneously hypertensive rats and Wistar-Kyoto (WKY) rats. Etamicastat increased survival rates in male cardiomyopathic hamsters (Bio TO-2 dilated strain) with advanced congestive heart failure.23

The metabolism of etamicastat is species dependent.24 In the rat, N-acetylation is the major metabolic pathway leading to the formation of BIA 5-961. All other metabolites occur in minor amounts and correspond to oxidative deaminated (BIA 5-965), C-oxidated (BIA 5-998), and N-oxidated (BIA 5-1016) derivatives of etamicastat.25 Entry-into-man studies in healthy subjects administered a single oral doses of etamicastat (range, 2–1200 mg) and multiple doses (range, 25–600 mg/d) showed approximately dose-proportional pharmacokinetics.26, 27 In humans, etamicastat is metabolized to the acetylated metabolite BIA 5-961.26, 27 A high interindividual variability of etamicastat and BIA 5-961 pharmacokinetic parameters was observed, and pharmacogenomic data showed that such variability was mainly dependent upon the N-acetyltransferase (NAT) type 2 acetylator status (rapid or slow acetylating ability).26, 27

Hypertension and cardiac heart failure are very common in the elderly population, and etamicastat is in clinical development for the treatment of those conditions. To treat elderly patients, it is necessary to know if any dose adjustment is needed. Most of the recognized important differences between young and elderly patients are pharmacokinetic differences, often related to impaired excretory function or to drug–drug interactions. The present study aimed to provide an initial assessment of the effects of age on the pharmacokinetics of etamicastat and on its clinical tolerability. The influence of NAT1 and NAT2 genotype on etamicastat pharmacokinetics was also explored.

Section snippets

Population

Subjects were drawn from the study center's pool of volunteers. Volunteers eligible for participation were healthy male volunteers aged 18 to 45 years (young group) or ≥65 years (elderly group) and nonsmokers or smokers of <10 cigarettes/d. Healthy status was determined by interview, medical history, physical examination, vital signs, 12-lead electrocardiogram (ECG), and results of clinical laboratory tolerability tests (including hematology, plasma biochemistry), urinalysis, drugs abuse

Subjects

In total, 25 patients (13 young and 12 elderly) were enrolled. Their demographic and main baseline characteristics are summarized in Table I. All subjects were white, except for 1 black subject in the elderly group. One young subject prematurely discontinued the study due to a serious AE and was replaced. Twenty-four subjects (12 in each age group) completed the study. Because acetylation is the most important etamicastat metabolic pathway, genotyping was performed to distinguish between poor

Discussion

The primary objective of the study was to investigate the effect of age on the pharmacokinetics and tolerability of etamicastat in elderly (≥65 years) versus young adult (18–45 years) subjects. Additionally, the influence of NAT1 and NAT2 genotype on etamicastat pharmacokinetics was explored.

The dosage regimen (100 mg/d) adopted in this study was chosen on the basis of preliminary pharmacokinetic and pharmacodynamic data of entry-into-man clinical studies with etamicastat in healthy subjects.26

Conclusion

Etamicastat was generally well tolerated in the population studied and its kinetic profile was not significantly different in these small groups of healthy young versus elderly adult male volunteers.

Acknowledgments

This study was supported by BIAL-Portela & Ca SA. T. Nunes, J. F. Rocha, M. Vaz-da-Silva, L. Almeida, and P. Soares-da-Silva are or were employees of BIAL (the sponsor of the study) at the time of the study. The other author (A. Falcao) is or was an employee of a contract research organization contracted by the sponsor to review the pharmacokinetic data (4Health Consulting). The authors have indicated that they have no other conflicts of interest regarding the content of this article. All

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