Pharmacokinetics, bioavailability, & bioequivalenceOriginal researchPharmacokinetics and Tolerability of Etamicastat Following Single and Repeated Administration in Elderly Versus Young Healthy Male Subjects: An Open-Label, Single-Center, Parallel-Group Study
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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2015, IJC Metabolic and EndocrineCitation Excerpt :Recently, etamicastat demonstrated blood pressure lowering effects in hypertensive patients [20]. In healthy subjects, etamicastat was well tolerated and showed approximate linear pharmacokinetics following single oral doses [21] and multiple once-daily oral doses [22], with no significant differences being observed in elderly versus young healthy subjects [23]. The aim of the present work was to evaluate the effects of etamicastat for cardiac risk both in vitro, testing on the hERG potassium channel of human embryonic kidney (HEK293) cells, and in vivo in the Cynomolgus monkey monitored by telemetry (up to 90 mg/kg etamicastat).
Characterization of the interaction of the novel antihypertensive etamicastat with human dopamine-β-hydroxylase: Comparison with nepicastat
2015, European Journal of PharmacologyCardiovascular safety pharmacology profile of etamicastat, a novel peripheral selective dopamine-ß-hydroxylase inhibitor
2015, European Journal of PharmacologyCitation Excerpt :As such, the observed in vitro effect in the hERG assay is highly unlikely to have any clinical impact and this is supported by the review of Redfern et al. (2003) which concluded that a greater than 30-fold margin between hERG IC50 and unbound clinical Cmax was sufficiently reassuring. Recent studies indicate that the major metabolic pathway of etamicastat in humans is concerned with its N-acetylation to BIA 5-961, mainly by NAT2 (Nunes et al., 2011, , 2010; Rocha et al., 2012; Vaz-da-Silva et al., 2011), which has been described to be responsible for interspecies variability in drug metabolism (Gao et al., 2006; Glinsukon et al., 1975; Sharer et al., 1995). In line with these findings is the observation that dogs, unlike humans, totally lack the enzyme family arylamine N-acetyltransferases (Collins, 2001), which may explain the significant higher exposure to etamicastat observed in the dog, in comparison with humans, and the finding that no N-acetylation of etamicastat to BIA 5-961 was observed.
Etamicastat, a new dopamine-ß-hydroxylase inhibitor, pharmacodynamics and metabolism in rat
2014, European Journal of Pharmacology