Effects of zamicastat treatment in a genetic model of salt-sensitive hypertension and heart failure.

Hyperactivity of sympathetic nervous system plays an important role in the development and progression of cardiovascular diseases. An approach to mitigate the enhanced sympathetic nervous system drive is restricting the biosynthesis of noradrenaline via inhibition of the enzyme dopamine ß-hydroxylase (DßH), that catalyzes the hydroxylation of dopamine to noradrenaline in sympathetic nerves. The aim of the present study was to evaluate the effects of zamicastat, a novel DßH inhibitor that decreases noradrenaline and increases dopamine levels in peripheral sympathetically innervated tissues, on the hemodynamic and cardiometabolic parameters in salt-induced hypertension and heart failure in the Dahl salt-sensitive (SS) rat. Zamicastat (10, 30 and 100 mg/kg body weight) was tested acutely against salt-induced hypertension in the Dahl SS rat. Chronic zamicastat treatment (30 mg/kg/day) was evaluated against salt-induced cardiac hypertrophy and biomarkers of cardiometabolic risk and inflammation in Dahl SS rats and upon the survival rate in aged Dahl SS rats fed a high-salt diet. The reduction in the sympathetic tone attained with zamicastat shaped a dose- and time-dependent effect on blood pressure. Prolonged treatment with zamicastat ameliorated end-organ damage, metabolic syndrome and inflammation hallmarks in hypertensive Dahl SS rats. Survival rate of Dahl SS rats fed a high-salt diet demonstrated that zamicastat increased median survival of Dahl SS rats fed a high-salt diet. The use of DßH inhibitors, like zamicastat, is a promising approach to treat hypertension, heart failure and cardiovascular diseases where a reduction in the sympathetic tone has beneficial effects.

Sustained high blood pressure reduction with etamicastat, a peripheral selective dopamine ß-hydroxylase inhibitor.

The aim of the present study was to evaluate the influence of chronic inhibition of dopamine ß-hydroxylase by etamicastat on the development of hypertension in the spontaneously hypertensive rat (SHR) and the sustainability of effects on the systolic and diastolic blood pressure in the SHR and the normotensive Wistar-Kyoto rat (WKY). WKY and SHR received etamicastat (10 mg/kg/d) from 5 weeks of age for 35 weeks in drinking water, and cardiovascular assessments were performed on a weekly basis. Etamicastat reduced systolic and diastolic blood pressure when SHRs reached the age of 16 weeks with mean decreases of 37 and 32 mm Hg, respectively, for the subsequent for 24 weeks of treatment, but did not prevent the increase in blood pressure (BP) aged between 5 and 11 week. The BP lowering effect of etamicastat in SHR was reversible on discontinuation and quickly resumed after reinstatement of therapy and was not accompanied by changes in heart rate. Etamicastat affected neither BP nor heart rate in WKY during 36 weeks of treatment. Etamicastat reduced urinary excretion of norepinephrine to a similar extent in WKY and SHR, accompanied by significant increases in urinary dopamine in SHR. Chronic administration of etamicastat did not adversely affected development of animals. Chronic dopamine ß-hydroxylase inhibition with etamicastat effectively decreases BP, although does not prevent the development of hypertension in the SHR.

Eslicarbazepine acetate for the treatment of focal epilepsy: an update on its proposed mechanisms of action.

Eslicarbazepine acetate (ESL) is a once daily antiepileptic drug (AED) approved by the European Medicines Agency (EMA), the Food and Drug Administration (FDA) and Health Canada as an adjunctive therapy in adults with partial-onset seizures (POS). In humans and in relevant animal laboratory species, ESL undergoes extensive first pass hydrolysis to its major active metabolite eslicarbazepine that represents ∼95% of circulating active moieties. ESL and eslicarbazepine showed anticonvulsant activity in animal models. ESL may not only suppress seizure activity but may also inhibit the generation of a hyperexcitable network. Data reviewed here suggest that ESL and eslicarbazepine demonstrated the following in animal models: (1) the selectivity of interaction with the inactive state of the voltage-gated sodium channel (VGSC), (2) reduction in VGSC availability through enhancement of slow inactivation, instead of alteration of fast inactivation of VGSC, (3) the failure to cause a paradoxical upregulation of persistent Na(+) current (I NaP), and (4) the reduction in firing frequencies of excitatory neurons in dissociated hippocampal cells from patients with epilepsy who were pharmacoresistant to carbamazepine (CBZ). In addition, eslicarbazepine effectively inhibited high- and low-affinity hCaV3.2 inward currents with greater affinity than CBZ. These preclinical findings may suggest the potential for antiepileptogenic effects; furthermore, the lack of effect upon KV7.2 outward currents may translate into a reduced potential for eslicarbazepine to facilitate repetitive firing.

Role of P-glycoprotein and permeability upon the brain distribution and pharmacodynamics of etamicastat: a comparison with nepicastat.

1. This study explores the impact of permeability and P-glycoprotein (P-gp) efflux, upon brain exposure to etamicastat, a new dopamine-ß-hydroxylase (DBH) inhibitor and consequently brain levels of catecholamines. 2. Brain exposure to etamicastat (10 mg/kg), following intravenous administration to mice, was residual and upon oral administration of the same dose no compound was detected, concurring with the absence of effects upon brain catecholamines. The intravenous co-administration of elacridar (1.0 mg/kg), a known P-gp/BCRP dual modulator, significantly increased brain etamicastat exposure, but the levels attained were very low when compared to those of nepicastat, a centrally active DBH inhibitor. 3. In vitro permeability studies from apical-to-basal direction conducted in Caco-2 cells and MDCK-II cells showed that etamicastat apparent permeability was 1.2 × 10(-5) and 1.1 × 10(-6 )cm/s, respectively, 5- and 50-fold lower as compared to nepicastat. The secretory efflux ratio in MDCK-II cells overexpressing human P-gp showed an efflux ratio greater than 2, for both compounds, which was significantly decreased by elacridar. Despite its lower bioavailability and higher clearance, as compared to nepicastat, etamicastat showed preferential distribution to peripheral tissues and high plasma free fraction (15.5%), which may explain its effects upon peripheral DBH and catecholamine levels. 4. Though P-gp-mediated efflux may contribute to the limited brain penetration of etamicastat, the low permeability along with the pharmacokinetic properties of etamicastat may be perceived as the main contributors for its peripheral selectivity, which is advantageous for a cardiovascular drug candidate.

Characterization of the interaction of the novel antihypertensive etamicastat with human dopamine-ß-hydroxylase: comparison with nepicastat.

The interaction of etamicastat, a novel peripherally acting dopamine-ß-hydroxylase (DBH) inhibitor, with the enzyme was studied using a classical kinetic approach and the pharmacodynamics effect of the compound upon administration to rats was also evaluated. SK-N-SH cell homogenates convert tyramine into octopamine with a Km value of 9 mM, and a Vmax of 1747 nmol/mg protein/h. The K(m) value for ascorbate was 3 mM. The inhibition of DBH by etamicastat and nepicastat, a known centrally acting DBH inhibitor, with IC50 values of 107 and 40 nM, respectively, was fully reversed by dilution. Non-linear fitting of the velocities, determined at various concentrations of substrate (tyramine) and co-substrate (ascorbic acid), and of etamicastat and nepicastat, indicated that the inhibition of DBH by both compounds follows a mixed-model inhibition mechanism, approaching competitive behavior with regards to the substrate tyramine, with K(i) values of 34 and 11 nM, respectively. Relatively to ascorbate, both compounds followed a mixed-model inhibition mechanism, approaching uncompetitive behavior. Oral administration of both compounds (at 30 mg/kg) inhibited adrenal DBH activity over time and significantly decreased noradrenaline levels in the heart. Nepicastat also decreased noradrenaline levels in the parietal cortex, but not etamicastat. Both compounds significantly decreased systolic and diastolic blood pressure in spontaneously hypertensive rats. In conclusion, etamicastat and nepicastat behave as multisubstrate DBH inhibitors, binding reversibly and preferentially to the reduced form of the enzyme, and simultaneously at the substrate and oxygen binding sites. Etamicastat, in contrast to nepicastat, offers the advantage of peripheral selectivity without central effects.

Effects of eslicarbazepine acetate on acute and chronic latrunculin A-induced seizures and extracellular amino acid levels in the mouse hippocampus.

BACKGROUND: Latrunculin A microperfusion of the hippocampus induces acute epileptic seizures and long-term biochemical changes leading to spontaneous seizures. This study tested the effect of eslicarbazepine acetate (ESL), a novel antiepileptic drug, on latrunculin A-induced acute and chronic seizures, and changes in brain amino acid extracellular levels. Hippocampi of Swiss mice were continuously perfused with a latrunculin A solution (4 µM, 1 µl/min, 7 h/day) with continuous EEG and videotape recording for 3 consecutive days. Microdialysate samples were analyzed by HPLC and fluorescence detection of taurine, glycine, aspartate, glutamate and GABA. Thereafter, mice were continuously video monitored for two months to identify chronic spontaneous seizures or behavioral changes. Control EEG recordings (8 h) were performed in all animals at least once a week for a minimum of one month. RESULTS: Oral administration of ESL (100 mg/kg), previous to latrunculin A microperfusion, completely prevented acute latrunculin A-induced seizures as well as chronic seizures and all EEG chronic signs of paroxysmal activity. Hippocampal extracellular levels of taurine, glycine and aspartate were significantly increased during latrunculin A microperfusion, while GABA and glutamate levels remained unchanged. ESL reversed the increases in extracellular taurine, glycine and aspartate concentrations to basal levels and significantly reduced glutamate levels. Plasma and brain bioanalysis showed that ESL was completely metabolized within 1 h after administration to mainly eslicarbazepine, its major active metabolite. CONCLUSION: ESL treatment prevented acute latrunculin A-induced seizures as well as chronic seizures and all EEG chronic signs of paroxysmal activity, supporting a possible anti-epileptogenic effect of ESL in mice.

Etamicastat, a new dopamine-ß-hydroxylase inhibitor, pharmacodynamics and metabolism in rat.

Despite the importance of sympathetic nervous system in pathophysiological mechanisms of cardiac heart failure and essential hypertension, therapy specifically targeting the sympathetic nervous system is currently underutilized. Etamicastat is a novel dopamine-ß-hydroxylase (DBH) inhibitor that is oxidized into BIA 5-965 and deaminated followed by oxidation to BIA 5-998, which represents 13% of total etamicastat and quantified metabolites. However, the primary metabolic pathway of etamicastat in rats was found to be the N-acetylation (BIA 5-961), which represents 44% of total etamicastat and quantified metabolites. Trace amounts of BIA 5-961 de-sulfated and S-glucuronide were also detected. All the main metabolites of etamicastat inhibited DBH with IC50 values of 306 (228, 409), 629 (534, 741), 427 (350, 522) nM for BIA 5-965, BIA 5-998 and BIA 5-961, respectively. However, only etamicastat (IC50 of 107 (94; 121) nM) was able to reduce catecholamine levels in sympathetic nervous system innervated peripheral tissues, without effect upon brain catecholamines. Quantitative whole body autoradiography revealed a limited transfer of etamicastat related radioactivity to brain tissues and the mean recovery of radioactivity was ~90% of the administered radioactive dose, eliminated primarily via renal excretion over 5 days. The absolute oral bioavailability of etamicastat was 64% of the administered dose. In conclusion, etamicastat is a peripheral selective DBH inhibitor mainly N-acetylated in the aminoethyl moiety and excreted in urine. Etamicastat main metabolites inhibit DBH, but only etamicastat demonstrated unequivocal pharmacological effects as a DBH inhibitor with impact upon the activity of the sympathetic nervous system under in vivo conditions.

Effect of opicapone and entacapone upon levodopa pharmacokinetics during three daily levodopa administrations.

BACKGROUND AND OBJECTIVES: Opicapone is a novel third generation catechol-O-methyltransferase (COMT) inhibitor. The purpose of this study was to compare the levodopa pharmacokinetic profile throughout a day driven by the COMT inhibition either following repeated doses of opicapone or concomitant administration with entacapone. METHODS: A randomized, double-blind, gender-balanced, parallel-group study was performed in 4 groups of 20 healthy subjects each. Four subjects in each group received placebo during the entire study. Sixteen subjects in one group received placebo once daily for 11 days and on day 12, 200 mg entacapone concomitantly with each levodopa/carbidopa dose (three times separated by a 5-h interval). Sixteen subjects in each of the remaining three groups received respectively 25, 50, and 75 mg opicapone once daily for 11 days and on day 12, placebo concomitantly with each levodopa/carbidopa dose. RESULTS: Levodopa minimum plasma concentration (Cmin) for each levodopa/carbidopa dose and for the mean of all levodopa/carbidopa doses increased substantially with all active treatments (entacapone and opicapone) when compared to the control group (placebo), with values ranging from 1.7-fold (200 mg entacapone) to 3.3-fold (75 mg opicapone). No statistical difference was found for levodopa peak of systemic exposure (as assessed by maximum observed plasma concentration (Cmax)) between all active treatments and placebo. A significant increase in the levodopa extent of systemic exposure (as assessed by concentration-time curve (AUC)) occurred with all opicapone treatments in relation to placebo. No statistical difference was found for levodopa AUC when entacapone was compared to placebo. When compared to entacapone, both 50 and 75 mg opicapone presented a significant increase for the levodopa AUC. All active treatments significantly inhibited both peak (as assessed by Emax) and extent (as assessed by effect-time curve (AUEC)) of the COMT activity in relation to placebo. When compared to entacapone, all opicapone treatments significantly decreased the extent (AUEC) of the COMT activity due to a long-lasting and sustained effect. The tolerability profile was favorable for all active treatments. CONCLUSION: Opicapone, a novel third generation COMT inhibitor, when compared to entacapone, provides a superior response upon the bioavailability of levodopa associated to more pronounced, long-lasting, and sustained COMT inhibition. The tolerability profile was favorable. On the basis of the results presented in this study and along with the earlier pharmacology studies, it is anticipated that opicapone adjunct therapy at the dosages of 25 and 50 mg will provide an enhancement in levodopa availability that will translate into clinical benefit for Parkinson's disease patients.

Human disposition, metabolism and excretion of etamicastat, a reversible, peripherally selective dopamine ß-hydroxylase inhibitor.

AIMS: Etamicastat is a reversible dopamine-ß-hydroxylase inhibitor that decreases noradrenaline levels in sympathetically innervated tissues and slows down sympathetic nervous system drive. In this study, the disposition, metabolism and excretion of etamicastat were evaluated following [(14)C]-etamicastat dosing. METHODS: Healthy Caucasian males (n = 4) were enrolled in this single-dose, open-label study. Subjects were administered 600 mg of unlabelled etamicastat and 98 µCi weighing 0.623 mg [(14)C]-etamicastat. Blood samples, urine and faeces were collected to characterize the disposition, excretion and metabolites of etamicastat. RESULTS: Eleven days after administration, 94.0% of the administered radioactivity had been excreted; 33.3 and 58.5% of the administered dose was found in the faeces and urine, respectively. Renal excretion of unchanged etamicastat and its N-acetylated metabolite (BIA 5-961) accounted for 20.0 and 10.7% of the dose, respectively. Etamicastat and BIA 5-961 accounted for most of the circulating radioactivity, with a BIA 5-961/etamicastat ratio that was highly variable both for the maximal plasma concentration (19.68-226.28%) and for the area under the plasma concentration-time curve from time zero to the last sampling time at which the concentration was above the limit of quantification (15.82- 281.71%). Alongside N-acetylation, metabolism of etamicastat also occurs through oxidative deamination of the aminoethyl moiety, alkyl oxidation, desulfation and glucuronidation. CONCLUSIONS: Etamicastat is rapidly absorbed, primarily excreted via urine, and its biotransformation occurs mainly via N-acetylation (N-acetyltransferase type 2), although glucuronidation, oxidation, oxidative deamination and desulfation also take place.

N-acetylation of etamicastat, a reversible dopamine-ß-hydroxylase inhibitor.

Etamicastat [(R)-5-(2-aminoethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3H)-thione hydrochloride] is a reversible dopamine-ß-hydroxylase inhibitor that decreases norepinephrine levels in sympathetically innervated tissues. After in vivo administration, N-acetylation of etamicastat was found to be a main metabolic pathway. The purpose of the current study was to characterize the N-acetylation of etamicastat by N-acetyltransferases (NAT1 and NAT2) and evaluate potential species differences in etamicastat N-acetylation using a sensitive and specific liquid chromatography-mass spectrometry assay. Marked differences in etamicastat N-acetylation were observed among the laboratory species and humans. After oral administration, the rat, hamster, and human subjects presented the highest rates of etamicastat N-acetylation, whereas almost no acetylation was observed in the mouse, rabbit, minipig, and monkey and no acetylation was observed in the dog. In in vitro studies, rats and humans showed similar acetylation rates, whereas no acetylation was detected in the dog. Studies performed with human recombinant NAT1 4 and NAT2 4 enzymes revealed that both were able to conjugate etamicastat, although at different rates. NAT1 had lower affinity compared with NAT2 (Km, 124.8 ± 9.031 µM and 17.14 ± 3.577 µM, respectively). A significant correlation (r(2) = 0.65, P < 0.05) was observed in a comparison of etamicastat N-acetylation by human single-donor enzymes and sulfamethazine, a selective substrate to NAT2. No correlation was observed with p-aminosalicylic acid, a NAT1 selective substrate. In conclusion, these results suggest that NAT2 and, to a lesser extent, NAT1 contribute to etamicastat N-acetylation. Furthermore, the high interspecies and intraspecies differences in N-acetylation should be taken into consideration when evaluating the in vivo bioavailability of etamicastat.

Opicapone: a short lived and very long acting novel catechol-O-methyltransferase inhibitor following multiple dose administration in healthy subjects.

AIMS: The aim of this study was to assess the tolerability, pharmacokinetics and inhibitory effect on erythrocyte soluble catechol-O-methyltransferase (S-COMT) activity following repeated doses of opicapone. METHODS: This randomized, placebo-controlled, double-blind study enrolled healthy male subjects who received either once daily placebo or opicapone 5, 10, 20 or 30 mg for 8 days. RESULTS: Opicapone was well tolerated. Its systemic exposure increased in an approximately dose-proportional manner with an apparent terminal half-life of 1.0 to 1.4 h. Sulphation was the main metabolic pathway. Opicapone metabolites recovered in urine accounted for less than 3% of the amount of opicapone administered suggesting that bile is likely the main route of excretion. Maximum S-COMT inhibition (Emax ) ranged from 69.9% to 98.0% following the last dose of opicapone. The opicapone-induced S-COMT inhibition showed a half-life in excess of 100 h, which was dose-independent and much longer than plasma drug exposure. Such a half-life translates into a putative underlying rate constant that is comparable with the estimated dissociation rate constant of the COMT-opicapone complex. CONCLUSION: Despite its short elimination half-life, opicapone markedly and sustainably inhibited erythrocyte S-COMT activity making it suitable for a once daily regimen.

Pharmacokinetics, pharmacodynamics and tolerability of opicapone, a novel catechol-O-methyltransferase inhibitor, in healthy subjects: prediction of slow enzyme-inhibitor complex dissociation of a short-living and very long-acting inhibitor.

BACKGROUND AND OBJECTIVES: Opicapone is a novel catechol-O-methyltransferase (COMT) inhibitor. The purpose of this study was to evaluate the tolerability, pharmacokinetics (including the effect of food) and pharmacodynamics (effect on COMT activity) following single oral doses of opicapone in young healthy male volunteers. METHODS: Single rising oral doses of opicapone (10, 25, 50, 100, 200, 400, 800 and 1,200 mg) were administered to eight groups of eight subjects per group (two subjects randomized to placebo and six subjects to opicapone), under a double-blind, randomized, placebo-controlled design. In an additional group of 12 subjects, a 50 mg single dose of opicapone was administered on two occasions, once having fasted overnight and once with a high-fat high-calorie meal. RESULTS: Opicapone was well tolerated at all doses tested. The extent of systemic exposure (area under the plasma concentration-time curve and maximum plasma concentration) to opicapone and metabolites increased in an approximately dose-proportional manner and showed a decrease following concomitant ingestion of a high-fat high-calorie meal. The apparent terminal elimination half-life of opicapone was 0.8-3.2 h. Sulphation appeared to be the main metabolic pathway for opicapone, and both opicapone and the main sulphated metabolite are likely excreted by the biliary route. Maximum COMT inhibition by opicapone was dose dependent, ranged from 36.1% (10 mg) to 100% (200 mg and above), and reached statistical significance at all doses tested. The long duration of COMT inhibition by opicapone, however, tended to be independent from the dose taken. The observed half-life of opicapone-induced COMT inhibition in human erythrocytes was 61.6 h (standard deviation [SD] = 37.6 h), which reflects an underlying dissociative process with a kinetic rate constant of 3.1 × 10(-6) s(-1) (SD = 1.9 × 10(-6) s(-1)). Such a process compares well to the estimated dissociation rate constant (k(off)) of the COMT-opicapone molecular complex (k(off) = 1.9 × 10(-6) s(-1)). CONCLUSIONS: Opicapone was well-tolerated and presented dose-proportional kinetics. Opicapone demonstrated marked and sustained inhibition of erythrocyte soluble COMT activity. Based on the observation that the half-life of COMT inhibition is independent of the dose and that it reflects an underlying kinetic process that is consistent with the k(off) value of the COMT-opicapone complex, we propose that the sustained COMT inhibition, far beyond the observable point of clearance of circulating drug, is due to the long residence time of the reversible complex formed between COMT and opicapone. Globally, these promising results provide a basis for further clinical development of opicapone.

Single-dose tolerability, pharmacokinetics, and pharmacodynamics of etamicastat (BIA 5-453), a new dopamine ß-hydroxylase inhibitor, in healthy subjects.

The safety, tolerability, pharmacokinetics, and pharmacodynamics of etamicastat (BIA 5-453), a novel dopamine ß-hydroxylase (DßH) inhibitor, were investigated in 10 sequential groups of 8 healthy male subjects under a double-blind, randomized, placebo-controlled design. In each group, 6 subjects received a single dose of etamicastat (2, 10, 20, 50, 100, 200, 400, 600, 900, or 1200 mg) and 2 subjects received placebo. Etamicastat was well tolerated at all dose levels tested. Maximum plasma etamicastat concentrations occurred at 1 to 3 hours postdose. Elimination was biphasic, characterized by a first short early elimination half-life followed by a longer elimination phase of 16 to 20 hours for etamicastat doses of 100 mg and above. A high interindividual variability of pharmacokinetic parameters of etamicastat and its acetylated metabolite was observed. Pharmacogenomic data showed that N-acetyltransferase type 2 (NAT2) phenotype (rapid or slow N-acetylating ability) was a major source of variability. In NAT2 poor acetylators, the area under the plasma concentration-time curve from time zero to the last sampling time at which concentrations were at or above the limit of quantification (AUC0-t ) of etamicastat was twice that observed in rapid acetylators. Consistent with that finding, AUC0-t of the acetylated metabolite was markedly higher in NAT2 rapid acetylators compared with poor acetylators. Inhibition of DßH activity was observed, reaching statistical significance for etamicastat doses of 100 mg and above.

Hepatic UDP-glucuronosyltransferase is responsible for eslicarbazepine glucuronidation.

Eslicarbazepine acetate (ESL) is a once-daily novel antiepileptic drug approved in Europe for use as adjunctive therapy for refractory partial-onset seizures with or without secondary generalization. Metabolism of ESL consists primarily of hydrolysis to eslicarbazepine, which is then subject to glucuronidation followed by renal excretion. In this study, we have identified that human liver microsomes (HLM) enriched with uridine 5'-diphosphoglucuronic acid give origin to a single Escherichia coli ß-glucuronidase-sensitive eslicarbazepine glucuronide (most likely the O-glucuronide). The kinetics of eslicarbazepine glucuronidation in HLM was investigated in the presence and absence of bovine serum albumin (BSA). The apparent K(m) were 412.2 ± 63.8 and 349.7 ± 74.3 µM in the presence and absence of BSA, respectively. Incubations with recombinant human UDP glucuronosyltransferases (UGTs) indicated that UGT1A4, UGT1A9, UGT2B4, UGT2B7, and UGT2B17 appear to be involved in eslicarbazepine conjugation. The UGT with the highest affinity for conjugation was UGT2B4 (K(m) = 157.0 ± 31.2 and 28.7 ± 10.1 µM, in the absence and presence of BSA, respectively). There was a significant correlation between eslicarbazepine glucuronidation and trifluoperazine glucuronidation, a typical UGT1A4 substrate; however, no correlation was found with typical substrates for UGT1A1 and UGT1A9. Diclofenac inhibited eslicarbazepine glucuronidation in HLM with an IC(50) value of 17 µM. In conclusion, glucuronidation of eslicarbazepine results from the contribution of UGT1A4, UGT1A9, UGT2B4, UGT2B7, and UGT2B17, but the high-affinity component of the UGT2B4 isozyme may play a major role at therapeutic plasma concentrations of unbound eslicarbazepine.

Safety, tolerability, and pharmacokinetics of etamicastat, a novel dopamine-ß-hydroxylase inhibitor, in a rising multiple-dose study in young healthy subjects.

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-ß-hydroxylase (DßH). OBJECTIVE: To assess the safety, tolerability, and pharmacokinetics of etamicastat (BIA 5-453), a new DßH 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.

Pharmacokinetics, disposition, and metabolism of [14C]-nebicapone in humans.

OBJECTIVE: This study investigated the absorption, distribution, metabolism and excretion (ADME) of nebicapone [BIA 3-202; 1-(3,4-dihydroxy-5-nitrophenyl)-2-phenyl-ethanone], a reversible catechol-O-methyltransferase (COMT) inhibitor, in 4 healthy male subjects. METHODS: This was a single center, open, non-placebo-controlled, single-group, and a single 200 mg dose study of [(14)C]-nebicapone (2.5 MBq). Blood, urine and faeces were collected up to 264 hours post-dose. RESULTS: Collectively more than 22 metabolites were identified in plasma, urine and faeces, with 3-O-nebicapone-glucuronide (BIA 3-476) identified as the major metabolite. Plasma concentration-time profiles of [(14)C]-nebicapone demonstrated T(max) (h) 1.25+/-0.65, t(1/2) (h) 134.55+/-25.67, C(max) (ng-eq/g) 19647.02+/-4930.20, AUC(0-t) (h.ng-eq/g) 161735.51+/-9224.66, AUC(0-infinity) (h.ng-eq/g) 199603.30+/-16854.08, and for whole blood T(max) 1.00+/-0.41, t(1/2) 32.98+/-22.82, AUC(0-t) 35539.23+/-13664.87, AUC(0-infinity) 36970.64+/-14559.17. Plasma pharmacokinetics of nebicapone demonstrated T(max) (h) 1.00+/-0.41, t(1/2) (h) 2.34+/-0.51; C(max) (ng-eq/g) 12650.00+/-2898.85, AUC(0-t) (h.ng-eq/g) 18719.96+/-734.18, AUC(0-infinity) (h.ng-eq/g) 18392.12+/-753.81; BIA 3-476 demonstrated T(max) 1.25+/-0.50, t(1/2) 3.47+/-0.68; C(max) 15250+/-2563.20, AUC(0-t) 53810.61+/-7358.81, AUC(0-infinity) 54541.21+/-7135.70; 3-O-methyl-nebicapone (BIA 3-270) demonstrated T(max) 21.01+/-6.01, t(1/2) 103.43+/-6.01; C(max) 286.25+/-20.48, AUC(0-t) 27641.89+/-4569.99, AUC(0-infinity) 36968.12+/-4294.42. CONCLUSIONS: Nebicapone and BIA 3-476 accounted for most early phase circulating nebicapone-derived moieties, have limited circulating cell association, peak concentrations shortly after dosing, and short body residence. In longer terminal half-life phases low concentrations of BIA 3-270 predominate. While about 70% of the dose was eliminated in the urine as BIA 3-476, < 1% of the dose was excreted as unchanged nebicapone. Faecal excretion accounted for 17.3% administered dose. On average, the total recovery of 88.6% of the radioactivity suggested no worrisome retention of drug derived material following a single 200 mg administration of nebicapone to healthy volunteers. The treatment was very well tolerated with no reported adverse events.

Effects of nebicapone on levodopa pharmacokinetics, catechol-O-methyltransferase activity, and motor fluctuations in patients with Parkinson disease.

OBJECTIVE: To investigate the effects of nebicapone, a new catechol-O-methyltransferase (COMT) inhibitor, on levodopa pharmacokinetics, COMT activity, and motor fluctuations in Parkinson disease in comparison to placebo and entacapone. METHODS: Randomized, double-blind, placebo-controlled, 4-way crossover study consisting of 4 treatment periods (6-9 days duration each) in 19 patients (65.3 +/- 8.5 years) treated with carbidopa/levodopa 3 to 7 times per day. Nebicapone/entacapone/placebo and carbidopa/levodopa doses were administered concomitantly. At the end of each period, a levodopa test was performed, and levodopa and 3-O-methyldopa levels and COMT activity were assayed. RESULTS: After 75 mg nebicapone, 150 mg nebicapone, and 200 mg entacapone, levodopa area under the plasma concentration time curve significantly increased 28.1, 48.4, and 33.3%, and 3-O-methyldopa area under the plasma concentration time curve significantly decreased 59.2, 70.8, and 59.1%, respectively. Peak COMT inhibition was similar between active treatments, but extent of COMT inhibition was more sustained with 75 and 150 mg nebicapone than with 200 mg entacapone. After the levodopa test doses, ON time significantly increased 29 minutes with 75 mg nebicapone, 45 minutes with 150 mg nebicapone, and 16 minutes with 200 mg entacapone. Patients' diaries showed a decrease in daily OFF time of 109 minutes with 75 mg nebicapone, 103 minutes with 150 mg nebicapone, and 71 minutes with 200 mg entacapone, and an increase in daily ON time of 74, 101, and 74 minutes, respectively. Treatments were generally well tolerated and safe; no relevant changes in liver function tests were reported. CONCLUSIONS: Nebicapone, a new COMT inhibitor, significantly decreased COMT activity, increased systemic exposure to levodopa, and improved motor response. Nebicapone deserves further evaluation in larger samples of patients.