Manuel Vaz-da-Silva

Pharmacokinetic and safety profile of trans-resveratrol in a rising multiple-dose study in healthy volunteers

This was a double-blind, randomised, placebo-controlled study to investigate the pharmacokinetics and safety of trans-resveratrol. In four groups of ten healthy adult subjects (five males and five females), two subjects were randomized to receive placebo and eight subjects to receive trans-resveratrol 25, 50, 100 or 150 mg, six times/day, for thirteen doses. Peak plasma concentrations of trans-resveratrol were reached at 0.8-1.5 h postdose. Following the 13th dose of trans-resveratrol 25, 50, 100 and 150 mg, mean peak plasma concentration (C(max)) was 3.89, 7.39, 23.1 and 63.8 ng/mL and mean area under the plasma concentration-time curve (AUC(0-tau)) was 3.1, 11.2, 33.0 and 78.9 ng.h/mL. Interindividual variability was high, with coefficients of variation >40%. Trans-resveratrol half-life was 1-3 h following single-doses and 2-5 h following repeated dosing. Trough (C(min)) concentrations were < or = 1 ng/mL following 25 and 50 mg, 3 ng/mL following 100 mg and < 10 ng/mL following 150 mg. Trans-resveratrol pharmacokinetics showed circadian variation. Adverse events were mild in severity and similar between all groups. In conclusion, repeated administration was well-tolerated but produced relatively low plasma concentrations of trans-resveratrol, despite the high doses and short dosing interval used. Bioavailability was higher after morning administration.

Pharmacokinetics of Trans‐resveratrol Following Repeated Administration in Healthy Elderly and Young Subjects

From the Department of Research and Development, S Mamede do Coronado, Portugal (Dr Nunes, Dr Almeida, Mr Rocha, Mr Fernandes-Lopes, Ms Loureiro, Dr Wright, Dr Vaz-da-Silva, Dr Soares-da-Silva); Institute of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal (Dr Almeida, Dr Vaz-da-Silva, Dr Soares-da-Silva); Department of Health Sciences, University of Aveiro, Portugal (Dr Almeida); and 4Health Consulting, BIOCANT, Cantanhede, Portugal (Dr Falcao). Submitted for publication February 27, 2009; revised version accepted May 10, 2009. Address for correspondence: Patricio Soares-da-Silva, MD, PhD, Department of Research & Development, BIAL, A Av da Siderurgia Nacional, 4745-457 S Mamede do Coronado, Portugal; e-mail: psoares.silva@bial.com.DOI: 10.1177/0091270009339191

Effect of food on the pharmacokinetic profile of trans-resveratrol.

OBJECTIVE It has been postulated that trans-resveratrol may act as an antioxidant, cardioprotective, neuroprotective and cancer chemopreventive agent. The objective of this study was to investigate the effect of food on the bioavailability of trans-resveratrol following oral administration. MATERIAL AND METHODS Single-centre, open-label, randomized, 2-way crossover study on 24 healthy subjects. The study consisted of two consecutive treatment periods separated by a washout of 7 days or more. On each of the study periods subjects were administered a single-dose of 400 mg of trans-resveratrol following either a standard high fat content meal or 8 hs of fasting. RESULTS There was a large interindividual variability in the trans-resveratrol pharmacokinetic parameters. Mean +/- SD maximum plasma concentration (Cmax) was 42.2 +/- 36.6 ng/ml in fed and 47.3 +/- 30.0 ng/ml in fasting conditions. Median time to Cmax (tmax) was 2.0 h in fed and 0.5 h in fasting (p < 0.0001). The fed/fasting geometric mean ratio (GMR) and 90% confidence interval (90% CI) were 79.4 and 53.8, 117.0% for Cmax, and 106.0 and 86.8, 128.0% for the area under the plasma concentration-time curve (AUC0- yen). The 90% CI for the GMR of AUC0- yen and Cmax fall outside the usual bioequivalence acceptance range of 80, 125%, but that of AUC0- yen was close to the bioequivalence standard. CONCLUSION The rate of absorption of trans-resveratrol following an oral 400 mg single-dose was significantly delayed by the presence of food, as reflected by Cmax and tmax. However, the extent of absorption, as reflected by AUC- yen, was not affected in a relevant way.

Effect of Food on the Pharmacokinetic Profile of Eslicarbazepine Acetate (BIA 2-093)

AbstractObjective: To investigate the effect of food on the pharmacokinetics of eslicarbazepine acetate (BIA 2-093), a new voltage-gated sodium channel antagonist. Material and methods: Single-centre, open-label, randomised, two-way crossover study in 12 healthy subjects. The study consisted of two consecutive treatment periods separated by a washout of 14 days or more. In each of the study periods subjects were administered a single dose of eslicarbazepine acetate 800mg following either a standard high-fat content meal or 10 hours of fasting. Results: Eslicarbazepine acetate was rapidly and extensively metabolised to BIA 2-005. Maximum BIA 2-005 plasma concentrations (Cmax) in fed (test) and fasting (reference) conditions were, respectively, 12.8 ± 1.8 μg/mL and 11.3 ± 1.9 μg/mL, and the areas under the plasma concentration time curve from 0 to infinity (AUC∞) were, respectively, 242.5 ± 32.1 μg · h/mL and 243.6 ± 31.1 μg · h/mL (arithmetic mean ± SD). The point estimate (PE) and 90% confidence interval (90% CI) of the test/reference Cmax geometric mean ratio were 1.14 and 1.04, 1.25, respectively; for the AUC∞ ratio, the PE and 90% CI were 1.00 and 0.95, 1.04, respectively. Bioavailability of eslicarbazepine acetate administered in fed and fasting conditions was similar and bioequivalence is accepted for both AUC∞ and Cmax because the 90% CI lies within the acceptance range of 0.80–1.25. No statistically significant differences were found in time of occurrence of Cmax. Conclusion: The presence of food had no significant effect on the pharmacokinetics of eslicarbazepine acetate and therefore this new voltage-gated sodium channel antagonist may be administered without regard to meals.

Pharmacokinetics and tolerability of eslicarbazepine acetate and oxcarbazepine at steady state in healthy volunteers

Investigate the pharmacokinetics of once‐daily (QD; 900 mg) and twice‐daily (BID; 450 mg) regimens of eslicarbazepine acetate (ESL) and BID (450 mg) regimen of oxcarbazepine (OXC) at steady state in healthy volunteers.

Effect of Eslicarbazepine Acetate on the Steady-State Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Subjects During a Three-Stage, Open-Label, Multiple-Dose, Single-Period Study

BACKGROUND The anticoagulant warfarin, which is administered as a racemic mixture of R- and S-enantiomers, has been reported to interact with other drugs, including some antiepileptics. Eslicarbazepine acetate (ESL) is a once-daily voltage-gated sodium channel blocker that has been developed for the treatment of partial epilepsy and other indications. OBJECTIVE The aim of this work was to investigate whether multiple-dose administration of ESL had any effect on the steady-state pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers stabilized on warfarin at a subtherapeutic level. METHODS Subjects received ESL 1200 mg once daily for 8 days concomitantly with racemic warfarin, the dose of which had been individually optimized to a stable prothrombin international normalized ratio (INR) of 1.3 to 1.8 during a previous run-in phase (up to 21 days). Coadministration of ESL and warfarin was followed by a 7-day recovery period when warfarin was again administered alone. The effects of ESL on the steady-state pharmacokinetics of R- and S-warfarin and on the INR were assessed. For the R- and S-warfarin assay, blood sampling was to occur at stage 1 (run-in period), 3 days before starting ESL dosing; stage 2 (combined treatment period), on days 1 and 8 at predose and 0.5, 1, 2, 4, 6, 8, 12, 16, and 24 hours postdose, and on days 4, 6, and 7 at predose; and stage 3 (after the combined treatment period) on days 3, 5, and 7 predose, and on day 8 at 24 hours after the final warfarin dose. For determination of INR, blood sampling was to occur at stage 2 on days 1, 2, 4, 6, 7, and 8 at predose; and at stage 3 on days 1, 3, 5, and 7 at predose and on day 8 at 24 hours after the final warfarin dose. For the assay of the racemic mixture of the S- and the R-enantiomers (eslicarbazepine and R-licarbazepine), blood sampling was to occur at stage 2 on day 8 at predose and 0.5, 1, 2, 4, 6, 8, 12, 16, and 24 hours postdose, and on days 2, 4, 6, and 7 at predose. C(max) and AUC(0-t) were defined as primary pharmacokinetic parameters. Tolerability was evaluated by monitoring adverse events, clinical laboratory safety tests, vital signs, and 12-lead ECG. RESULTS Of the 15 subjects enrolled, 13 (7 men and 6 women) completed the study. The mean (SD) age was 28.1 (7.3) years (range, 20-42 years), mean weight was 67.3 (10.7) kg (range, 54.0-84.4 kg), and 14 subjects (93.3%) were white. Reductions in S-warfarin C(max) (test:reference geometric means ratio [GMR] = 0.81 [90% CI, 0.76 to 0.86] and in S-warfarin AUC(ss) (test:reference GMR = 0.77 [90% CI, 0.72 to 0.82]) were observed, without any clinically relevant changes in the INR. The mean INR was 1.45 (0.10) when warfarin was used alone in stage 1 (control) and 1.51 (0.25) when ESL was added to warfarin in stage 2. In relation to stage 1, a slight mean INR increase of 4.04% [90% CI, 1.03% to 9.12%] was reported in stage 2. In stage 3, following discontinuation of ESL administration, a change of -5.42% in the INR was found [90% CI, -8.85% to -1.98%]. ESL was not associated with any clinically relevant changes in R-warfarin pharmacokinetic parameters. No deaths, serious adverse events, or discontinuations due to adverse events were noted, and no clinically relevant findings were reported for the other safety variables. During the course of the study, 9 subjects (60%) reported a total of 32 adverse events. Catheter-site ecchymosis, venipuncturesite hematoma, dizziness, vasovagal reaction, and adhesive-tape allergy were the most common adverse events reported. During coadministration of ESL and warfarin, 7 subjects reported a total of 17 adverse events, of which 6 (epigastric discomfort, asthenia, dizziness, lipothymia, irritability, and macular rash) were considered possibly related to treatment; only lipothymia reached moderate intensity, and all symptoms subsided without sequelae after ESL was discontinued. CONCLUSIONS In this short-term study in healthy subjects, coadministration of warfarin and ESL 1200 mg once daily was associated with a small, but statistically significant, reduction in systemic exposure to S-warfarin. There was no statistically significant effect on R-warfarin pharmacokinetics or on coagulation as measured by the INR. Protocol identifier: UFH/BIA-2093-108.

Effect of eslicarbazepine acetate on the pharmacokinetics of a combined ethinylestradiol/levonorgestrel oral contraceptive in healthy women

OBJECTIVE To investigate the effect of once-daily (QD) eslicarbazepine acetate (ESL) 800 mg and 1,200 mg administration on pharmacokinetics of a combined ethinylestradiol/levonorgestrel oral contraceptive (OC) in women of childbearing potential. METHODS Two two-way, crossover, two-period, randomized, open-label studies were performed in 20 healthy female subjects, each. In one period (ESL+OC period), subjects received ESL 800 mg QD in one study and ESL 1200 mg QD in the other study, for 15 days; concomitantly with the Day 14 ESL dose, an oral single dose of 30 μg ethinylestradiol and 150 μg levonorgestrel was administered. In the other period (OC alone), a single dose of 30 μg ethinylestradiol and 150 μg levonorgestrel was administered. Three weeks or more separated the periods. An analysis of variance (ANOVA) was used to test for differences between pharmacokinetic parameters of 30 μg ethinylestradiol and 150 μg levonorgestrel following ESL+OC and OC alone, and 90% confidence intervals (90%CI) for the ESL+OC/OC alone geometric mean ratio (GMR) were calculated. RESULTS ESL significantly decreased the systemic exposure to both ethinylestradiol and levonorgestrel. GMR (90%CI) for AUC0-24 of ethinylestradiol were 68% (64%; 71%) following 1,200 mg ESL and 75% (71%; 79%) following 800 mg ESL. GMR (90%CI) for AUC0-24 of levonorgestrel were 76% (68%; 86%) following 1,200 mg ESL and 89% (82%; 97%) following 800 mg ESL. CONCLUSIONS A clinically relevant dose-dependent effect of ESL administration on the pharmacokinetics of ethinylestradiol and levonorgestrel was observed. Therefore, to avoid inadvertent pregnancy, women of childbearing potential should use other adequate methods of contraception during treatment with ESL, and, in case ESL treatment is discontinued, until CYP3A4 activity returns to normal.

Bioavailability and bioequivalence of two enteric-coated formulations of omeprazole in fasting and fed conditions

AbstractObjective: To investigate the relative bioavailability and bioequivalence, in fasting and fed conditions, of repeated doses of two omeprazole enteric-coated formulations in healthy volunteers. Material and methods: Open label, single-centre study consisting of two consecutive randomised, two-way crossover trials (a fasting trial and a fed trial). Each trial consisted of two 7-day treatment periods in which subjects received one daily dose of the test (Ompranyt®) or reference (Mopral®) formulations. At day 7 and day 14 (fasting trial), products were administered in fasting conditions and blood samples were taken for omeprazole plasma assay over 12 hours. At day 21 and day 28 (fed trial), products were administered after a standard high-calorie and high-fat meal and 12-hour blood samples taken. Omeprazole plasma concentrations were quantified by a validated method using a reverse-phase high performance liquid chromatography with UV detection (HPLC-UV). Results: Twenty-four subjects were enrolled and 23 completed the study. Under fasting conditions, the mean ± SD maximum omeprazole plasma concentration (Cmax) was 797 ± 471 μg/L for Ompranyt® and 747 ± 313 μg/L for Mopral® with a point estimate (PE) of 1.01 and a 90% confidence interval (CI) of 0.88, 1.16. The mean ± SD area under the plasma concentration curve from administration to last observed concentration (AUC0–12) was 1932 ± 1611 μg · h/L and 1765 ± 1327 μg · h/L for Ompranyt® and Mopral®, respectively (PE = 1.09; 90% CI 0.95, 1.25). In the presence of food, the Cmax was 331 ± 227 μg/L and 275 ± 162 μg/L (PE = 1.21; 90% CI 0.92, 1.59) and AUC0–12 was 1250 ± 966 μg · h/L and 1087 ± 861 μg · h/L (PE = 1.16; 90% CI 0.92, 1.47) for Ompranyt® and Mopral®, respectively. Bioequivalence of the formulations in the fasting condition was demonstrated both for AUC0–12 and for Cmax because the 90% CI lay within the acceptance range of 0.80–1.25. In contrast with the fasting condition, there were significant reductions in rate (Cmax) and extent (AUC0–12) of systemic exposure when test and reference formulations were administered with food. The food effect was more marked with Mopral® than with Ompranyt®, and the bioequivalence criterion was not fulfilled because the 90% CI fell out of the acceptance range of 0.80, 1.25, for both Cmax and AUC0–12. The two formulations were similarly well tolerated. Conclusion: Bioequivalence of Ompranyt® (test formulation) and Mopral® (reference) formulations was demonstrated after repeated dosing in the fasting condition. Following a high-calorie and high-fat meal, there was a significant reduction in rate and extent of systemic exposure for both products, with Ompranyt® being less affected than Mopral® by the presence of food.

Etamicastat, a Novel Dopamine β-Hydroxylase Inhibitor: Tolerability, Pharmacokinetics, and Pharmacodynamics in Patients With Hypertension

BACKGROUND Etamicastat is a dopamine β-hydroxylase (DβH) inhibitor currently in clinical development for the treatment of hypertension and heart failure. OBJECTIVE This study assessed the tolerability, pharmacokinetics, and pharmacodynamics of etamicastat in patients with arterial hypertension. METHODS This randomized, double-blind, placebo-controlled study was conducted in male patients aged between 18 and 65 years with mild to moderate hypertension. Participants received once-daily doses of etamicastat 50, 100, or 200 mg or placebo for 10 days. Antihypertensive effect was assessed by 24-hour ambulatory blood pressure monitoring (ABPM). RESULTS The study enrolled 23 male volunteers, with ages between 49 and 64 years. There were no serious adverse events reported. All adverse events were mild to moderate in intensity and resolved without sequelae. Etamicastat Tmax was 1 hour postdose, and mean t½ was 19 to 28 hours following repeated administration. Etamicastat underwent N-acetylation by N-acetyltransferase 2 (NAT2), forming the metabolite BIA 5-961. Following repeated administration, mean etamicastat AUC was 2- to 3-fold greater in poor acetylators than in rapid acetylators. Approximately 50% of the etamicastat dose was recovered in urine-30% as unchanged etamicastat and 20% as BIA 5-961. Dose-dependent decreases in systolic and diastolic blood pressure were observed after 10 days of treatment. The mean (95% CI) decreases versus placebo in nighttime SBP were statistically significant with all 3 etamicastat doses (50 mg, -11.66 mm Hg [-21.57 to -1.76; P < 0.05]; 100 mg, -14.92 mm Hg [-24.98 to -4.87; P < 0.01]; and 200 mg, -13.62 mm Hg [-22.29 to -3.95; P < 0.01]). CONCLUSIONS Etamicastat was well tolerated and showed a pharmacokinetic profile consistent with a once-daily regimen. NAT2 phenotype markedly affected the pharmacokinetics. The antihypertensive effect of etamicastat, assessed by 24-hour ABPM, was dose dependent up to 100 mg. The assessment of etamicastat as a novel antihypertensive therapy requires further study in broader populations. EudraCT trial registration 2008-002789-09.

Single‐Dose Tolerability, Pharmacokinetics, and Pharmacodynamics of Etamicastat (BIA 5–453), a New Dopamine β‐Hydroxylase Inhibitor, in Healthy Subjects

The safety, tolerability, pharmacokinetics, and pharmacodynamics of etamicastat (BIA 5–453), a novel dopamine β‐hydroxylase (DβH) 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 DβH activity was observed, reaching statistical significance for etamicastat doses of 100 mg and above.