José-Francisco Rocha

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.

Opicapone as an adjunct to levodopa in patients with Parkinson's disease and end-of-dose motor fluctuations: a randomised, double-blind, controlled trial

BACKGROUND Opicapone is a novel, once-daily, potent third-generation catechol-O-methyltransferase inhibitor. We aimed to assess the safety and efficacy of opicapone as an adjunct to levodopa compared with placebo or entacapone in patients with Parkinsons disease and motor fluctuations. METHODS We did a randomised, double-blind, placebo-controlled and active-controlled trial of opicapone as an adjunct to levodopa in patients with Parkinsons disease with end-of-dose motor fluctuations. Patients aged 30-83 years were enrolled at 106 specialist centres across 19 European countries and Russia and were randomly assigned (1:1:1:1:1) by a proprietary computer-generated sequence to oral treatment with opicapone (5 mg, 25 mg, or 50 mg once daily), placebo, or entacapone (200 mg with every levodopa intake) for 14-15 weeks. Patients and investigators (ie, outcome assessors) were masked to treatment allocation. The primary endpoint was the change from baseline to end of study treatment in absolute time in the off state, as assessed by daily paper patient diaries; the primary analysis followed a hierarchical procedure for each opicapone dose in which superiority compared with placebo in the full analysis set was first tested and then, if positive, non-inferiority to entacapone was tested in the per-protocol set with a margin of 30 min. This trial is registered with EudraCT, 2010-021860-13, and ClinicalTrials.gov, NCT01568073. FINDINGS Between March 31, 2011, and Nov 30, 2013, of 679 patients screened, 600 were randomly assigned. 590 patients were included in the full analysis set (120 in the placebo group, 120 in the entacapone group, 119 in the opicapone 5 mg group, 116 in the opicapone 25 mg group, and 115 in the opicapone 50 mg group) and 537 in the per-protocol set (112 in the placebo group, 104 in the entacapone group, 110 in the opicapone 5 mg group, 105 in the opicapone 25 mg group, and 106 in the opicapone 50 mg group). The mean change in time in the off state was -56·0 min (SE 13·4; 95% CI -82·3 to -29·7) for placebo, -96·3 min (13·4; -122·6 to -70·0) for entacapone, -91·3 min (13·5; -117·7 to -64·8) for opicapone 5 mg, -85·9 min (13·7; -112·8 to -59·1) for opicapone 25 mg, and -116·8 min (14·0; -144·2 to -89·4) for opicapone 50 mg. Treatment with opicapone 50 mg was superior to placebo (mean difference in change from baseline -60·8 min, 95% CI -97·2 to -24·4; p=0·0015) and non-inferior to entacapone (-26·2 min, -63·8 to 11·4; p=0·0051). Treatment with opicapone 5 mg (p=0·056) or 25 mg (p=0·080) was not significantly different from treatment with placebo. Treatment-emergent adverse events were reported in 60 (50%) of 121 patients in the placebo group, 69 (57%) of 122 in the entacapone group, 63 (52%) of 122 in the opicapone 5 mg group, 65 (55%) of 119 in the opicapone 25 mg group, and 62 (54%) of 115 in the opicapone 50 mg group. The most common adverse events were dyskinesia (in five patients in the placebo group, ten in the entacapone group, 17 in the opicapone 5 mg group, nine in the opicapone 25 mg group, and 18 in the opicapone 50 mg group), insomnia (in one, seven, two, seven, and seven patients, respectively), and constipation (in three, five, four, none, and seven patients, respectively). Serious adverse events were reported in six patients in the placebo group, eight in the entacapone group, four each in the opicapone 5 mg and opicapone 50 mg groups, and one in the opicapone 25 mg group. INTERPRETATION The addition of opicapone 50 mg to levodopa treatment in patients with Parkinsons disease and end-of-dose motor fluctuations could enable a simplified drug regimen that allows physicians to individually tailor the existing levodopa daily regimen, by potentially reducing the total daily levodopa dose, increasing the dosing interval, and ultimately reducing the number of intakes, thereby maximising its benefit. FUNDING BIAL.

Pharmacokinetic interaction study between eslicarbazepine acetate and lamotrigine in healthy subjects

Almeida L, Nunes T, Sicard E, Rocha J‐F, Falcão A, Brunet J‐S, Lefebvre M, Soares‐da‐Silva P. Pharmacokinetic interaction study between eslicarbazepine acetate and lamotrigine in healthy subjects. 
Acta Neurol Scand: 2010: 121: 257–264.
© 2009 The Authors Journal compilation

Effect of opicapone on levodopa pharmacokinetics, catechol‐O‐methyltransferase activity and motor fluctuations in patients with Parkinson's disease

Opicapone (OPC) is a novel third generation catechol‐O‐methyltransferase (COMT) inhibitor that enhances levodopa availability. This study investigated the effects of OPC in comparison with placebo on levodopa pharmacokinetics, tolerability and safety, COMT activity and motor response to levodopa in Parkinsons disease (PD) patients with motor fluctuations.

Opicapone as Adjunct to Levodopa Therapy in Patients With Parkinson Disease and Motor Fluctuations: A Randomized Clinical Trial

Importance Catechol O-methyltransferase (COMT) inhibitors are an established treatment for end-of-dose motor fluctuations associated with levodopa therapy in patients with Parkinson disease (PD). Current COMT inhibitors carry a high risk for toxic effects to hepatic cells or show moderate improvement. Opicapone was designed to be effective without the adverse effects. Objective To evaluate the efficacy and safety of 25- and 50-mg/d dosages of opicapone compared with placebo as adjunct to levodopa therapy in patients with PD experiencing end-of-dose motor fluctuations. Design This phase 3 international, multicenter outpatient study evaluated a 25- and a 50-mg/d dosage of opicapone in a randomized, double-blind, 14- to 15-week, placebo-controlled clinical trial, followed by a 1-year open-label phase during which all patients received active treatment with opicapone. Patients with PD who experienced signs of end-of-dose deterioration and had a mean total awake off-time (state of akinesia or decreased mobility) of at least 1.5 hours, not including morning akinesia, were enrolled. Data were collected from March 18, 2011, through June 25, 2013. Data from the evaluable population were analyzed from July 31, 2013, to July 31, 2014. Main Outcomes and Measures The primary efficacy outcome of the double-blind phase was the change from baseline in absolute off-time vs placebo based on patient diaries. The open-label phase focused on maintenance of treatment effect in off-time. Results A total of 427 patients (258 men [60.4%] and 169 women [39.6%]; mean [SD] age, 63.1 [8.8] years) were randomized to a 25-mg/d (n = 129) or a 50-mg/d (n = 154) dosage of opicapone or to placebo (n = 144). Of these, 376 patients completed the double-blind phase and entered the open-label phase, of whom 286 completed 1 year of open-label treatment. At the end of the double-blind phase, the least squares mean change (SE) in off-time was −64.5 (14.4) minutes for the placebo group, −101.7 (14.9) minutes for the 25-mg/d opicapone group, and −118.8 (13.8) minutes for the 50-mg/d opicapone group. The adjusted treatment difference vs placebo was significant for the 50-mg/d opicapone group (treatment effect, −54.3 [95% CI, −96.2 to −12.4] minutes; P = .008), but not for the 25-mg/d opicapone group (treatment effect, −37.2 [95% CI, −80.8 to 6.4] minutes; P = .11). The off-time reduction was sustained throughout the open-label phase (−126.3 minutes at 1-year open-label end point). The most common adverse events in the opicapone vs placebo groups were dyskinesia, constipation, and dry mouth. Fifty-one patients (11.9%) discontinued from the study during the double-blind phase. Conclusions and Relevance Treatment with a 50-mg once-daily dose of opicapone was associated with a significant reduction in mean daily off-time in levodopa-treated patients with PD and motor fluctuations, and this effect is maintained for at least 1 year. Opicapone was safe and well tolerated. Trial Registration clinicaltrials.gov Identifier: NCT01227655

Pharmacokinetic interaction study between eslicarbazepine acetate and topiramate in healthy subjects

Abstract Objective: Combination therapy is frequently required in the management of epilepsy. The primary objective of this study was to investigate the pharmacokinetic interaction between eslicarbazepine acetate (ESL) 1200 mg once daily and topiramate (TPM) 200 mg once daily in healthy subjects. Methods: Multiple-dose, open-label, one-sequence study in two parallel groups of 16 healthy male volunteers. After an 8-day treatment with ESL (Group A) or TPM (Group B), ESL and TPM were co-administered for 19 days. A bioequivalence approach based on a within-subject comparison was used to investigate a potential drug–drug interaction. End/start of treatment geometric mean ratios (GMR, %) and 90% confidence intervals (90% CI) were calculated for maximum plasma concentration (Cmax) and area under the plasma concentration–time curve over the dosing interval at steady-state (AUCss) of eslicarbazepine (ESL major active metabolite), R-licarbazepine (ESL minor active metabolite) and TPM at Day 8 and Day 27. Results: In Group A, eslicarbazepine GMR (90% CI) was 86.79% (81.06%; 92.94%) for Cmax and 92.70% (89.21%; 96.32%) for AUCss. In Group B, TPM GMR (90% CI) was 81.50% (77.48%; 85.89%) for Cmax and 81.81% (79.69%; 84.00%) for AUCss. The 90% CI of eslicarbazepine Cmax and AUCss fell within the pre-specified bioequivalence range (80.00%; 125.00%), allowing it to be concluded that the extent of systemic exposure to eslicarbazepine was unaffected by the concomitant administration of TPM. The 90% CI for topiramate AUCss was borderline in relation to the pre-specified bioequivalence range and topiramate Cmax fell outside the pre-specified bioequivalence range. Therefore, the extent of systemic exposure to TPM following co-administration with ESL was not formally bioequivalent to the extent of systemic exposure to TPM when TPM was administered alone. However, there was no difference between TPM elimination half-life following TPM co-administered with ESL and TPM administered alone (24.0 and 24.3 h, respectively). The bioavailability of R-licarbazepine was essentially bioequivalent. Two subjects discontinued due to adverse events. No clinical interaction appeared to be present in terms of adverse events when both drugs were given concomitantly. Conclusion: Concomitant administration of eslicarbazepine acetate 1200 mg once daily and topiramate 200 mg once daily showed no significant change in exposure to eslicarbazepine but an 18% decrease in exposure to topiramate, most likely caused by a reduced bioavailability of topiramate. No dose adjustment is required.

A Double-Blind, Randomized, Placebo and Active-Controlled Study of Nebicapone for the Treatment of Motor Fluctuations in Parkinson's Disease

To determine the efficacy, safety and tolerability of nebicapone, a new catechol‐O‐methyltransferase inhibitor for the treatment of motor fluctuations in Parkinsons disease (PD), we conducted a multicenter, randomized, 8‐week double‐blind, placebo‐ and active‐controlled, parallel‐group study comparing nebicapone 50 mg, 100 mg, or 150 mg, entacapone 200 mg (active control) or placebo administered concomitantly with levodopa/carbidopa or levodopa/benserazide. Two hundred and fifty‐two PD patients with motor fluctuations treated with levodopa/carbidopa or levodopa/benserazide (4–8 daily doses) were enrolled and 250 patients were eligible for intention‐to‐treat (ITT) analysis on the basis of having at least one efficacy assessment. The primary endpoint was 8‐week change from baseline in absolute “Off” time duration noted in self‐scoring diaries. At 8 weeks of treatment the mean daily “Off” time decreased significantly compared to placebo for nebicapone 150 mg (−106 min; 95%CI: −192; −21) and entacapone 200 mg (−81 min; 95%CI: −142; −19). The decrease in “Off” time with nebicapone 50 mg or 100 mg did not reach statistical significance. Treatment‐emergent adverse events were reported by 32% to 49% of patients in any treatment group, with no observed dose relationship in the nebicapone groups. Clinically relevant elevations in aspartate transaminase (AST) and/or alanine transaminase (ALT) were observed in 4 of 46 patients with the nebicapone 150 mg dose. The results of this study show that nebicapone 150 mg is efficacious for the treatment of motor fluctuations in PD patients. However, the risk of increasing liver transaminases and its clinically relevance deserves further evaluation.

Effect of eslicarbazepine acetate on the pharmacokinetics of metformin in healthy subjects.

PURPOSE Eslicarbazepine acetate (ESL) is a new voltage-gated sodium channel blocker currently in development for the treatment of neuropathic pain, including that of diabetic origin. The primary objective was to investigate the effect of ESL on the pharmacokinetics of metformin, a commonly used oral antidiabetic drug. METHODS Randomized, open-label, two-way crossover study in 20 healthy subjects. The volunteers received an 850 mg single-dose of metformin hydrochloride on two occasions - once as such and once after pre-treatment with an oral once-daily dose of ESL 1200 mg for 6 days - separated by a washout period of at least 2 weeks. The bioequivalence approach was used for assessing the effect of ESL on the pharmacokinetics of metformin. Test/Reference geometric mean ratios (GMR) and 90% confidence intervals (90% CI) were calculated for AUC0- yen, AUC0-12 and Cmax of metformin. RESULTS Test/Reference metformin GMR (90% CI) was 0.95 (0.86; 1.05) for AUC0- yen, 0.95 (0.88; 1.06) for AUC0-12, and 0.88 (0.77; 1.00) for Cmax. Formal bioequivalence could not be demonstrated for metformin Cmax. However, the extent of exposure to metformin, as reflected by AUC0-12 and AUC0- yen, allows the claim of bioequivalence since the 90% CI of the GMR fall within the pre-specified bioequivalence acceptance interval (0.80; 1.25). CONCLUSION Once-daily administration of ESL 1,200 mg had no relevant effect on the systemic exposure to metformin pharmacokinetics in healthy subjects.