Effect of nebicapone on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects

Luis Almeida, Amílcar Falcão, Manuel Vaz-da-Silva, Teresa Nunes, Ana-Teresa Santos, José-Francisco Rocha, Carla Neta, Tice Macedo, C. Fontes-Ribeiro and P. Soares-da-Silva

Abstract

Objective  Nebicapone is a new catechol-O-methyltransferase inhibitor. In vitro, nebicapone has showed an inhibitory effect upon CYP2C9, which is responsible for the metabolism of S-warfarin. The objective of this study was to investigate the effect of nebicapone on warfarin pharmacokinetics and pharmacodynamics in healthy subjects.

Methods  Single-centre, open-label, randomised, two-period crossover study in 16 healthy volunteers. In one period, subjects received nebicapone 200 mg thrice daily for 9 days and a racemic warfarin 25-mg single dose concomitantly with the nebicapone morning dose on day 4 (test). In the other period, subjects received a racemic warfarin 25-mg single dose alone (reference). The treatment periods were separated by a washout of 14 days.

Results  For R-warfarin, mean ± SD Cmax was 1,619 ± 284 ng/mL for test and 1,649 ± 357 ng/mL for reference, while AUC0-t was 92,796 ± 18,976 ng·h/mL (test) and 73,597 ± 11,363 ng·h/mL (reference). The R-warfarin test-to-reference geometric mean ratio (GMR) and 90% confidence interval (90%CI) were 0.973 (0.878–1.077) for Cmax and 1.247 (1.170–1.327) for AUC0-t . For S-warfarin, mean ± SD Cmax was 1,644 ± 331 ng/mL for test and 1,739 ± 392 ng/mL for reference, while AUC0-t was 66,627 ± 41,199 ng·h/mL (test) and 70,178 ± 42,560 ng·h/mL (reference). The S-warfarin test-to-reference GMR and 90%CI were 0.932 (0.845–1.028) for Cmax and 0.914 (0.875–0.954) for AUC0-t . No differences were found for the pharmacodynamic parameter (INR).

Conclusion  Nebicapone showed no significant effect on S-warfarin pharmacokinetics or on the coagulation endpoint (INR). A mild inhibition of the R-warfarin metabolism was found but is unlikely to be of clinical relevance

Eur J Clin Pharmacol(October, 2008-Volume 64, Number 10 )

2008
http://www.springerlink.com/content/m3617087h1347604/

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

José-Francisco Rocha, Amílcar Falcão1, Luis Almeida, Ana-Teresa Santos, Teresa Nunes, Manuel Vaz-da-Silva, Filipe Martins2, C. Fontes-Ribeiro2, Tice Macedo2, P. Soares-da-Silva

ABSTRACT

 

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

2008

Diferenças entre os sexos na distribuição do Omeprazole

C.Neta, F.Martins, J.Silva, T.Morgadinho, T.Macedo, C.Fontes Ribeiro

O sexo é um factor que influencia a distribuição de fármacos. Foi efectuada uma avaliação da distribuição do omeprazol entre os sexos em 2 estudos de bioequivalência.

 

Participaram 68 voluntários (35 homens, 33 mulheres) em 2 estudos abertos, randomizados e cruzados, com 2 sequências, 2 períodos e 2 semanas de intervalo. Foi avaliada a bioequivalência entre 2 formulações com 20mg de omeprazol em jejum em dose única e doses repetidas 10 dias, e após alimentos. O omeprazol foi quantificado por HPLC (UV/VIS). A bioequivalência avaliou-se pelos intervalos de confiança da AUC0-t, AUC0-inf e Cmax, após logaritmização dos dados. As diferenças entre os sexos avaliaram-se através do ANOVA e teste t de Student.

 

As formulações usadas são bioequivalentes (intervalos de confiança das AUCs e Cmax, que definem a bioequivalência, entre 0,80 e 1,25, mas em cada um dos 3 casos estudados os valores do omeprazol foram significativamente superiores no sexo feminino.

Com correcção do peso os valores são ainda mais divergentes, e com valores da depuração total e da constante de eliminação inferiores para o sexo feminino. Os tempos de semi-vida foram idênticos em ambos os sexos.

 

Concluindo, os níveis de omeprazol no plasma são significativamente superiores no sexo feminino, mas não é relevante para a avaliação da bioequivalência.

V congresso de Investigação e Médica

Congresso
2006

Estudo de Bioequivalência entre comprimidos contendo 875 mg de Amoxicilina e 125 mg de Ácido Clavulânico

C. Neta, F. Martins, J. Silva, H. Marques, T.R.A. Macedo, C.A. Fontes Ribeiro

 

A amoxicilina é um antibiótico de amplo espectro antimicrobiano que, sendo inactivada por b-lactamases, é muitas vezes associada ao ácido clavulânico, um inibidor dessas mesmas enzimas. Para avaliar a bioequivalência entre comprimidos com 875 mg de amoxicilina e 125 mg de ácido clavulânico de duas empresas farmacêuticas diferentes – a formulação teste (T) e a de referência (R) (Augmentin®DUO, da Beecham), realizou-se um ensaio clínico  de fase I, aberto, randomizado e cruzado. Tendo dois princípios activos ou fármacos na sua composição, a bioequivalência das formulações foi determinada após avaliação individual da bioequivalência de cada um dos fármacos.

A cada um dos 36 voluntários participantes foi administrada uma dose única de 875 mg de amoxicilina e 125 mg de ácido clavulânico de cada um dos medicamentos em estudo. Entre as duas fases de administração houve um período de “washout” de, pelo menos, uma semana. Em cada uma das fases foram recolhidas amostras de sangue, uma imediatamente antes da administração e as restantes 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 e 12 h após a toma, para doseamento de amoxicilina e ácido clavulânico; os métodos analíticos foram distintos, tendo sido, cada um deles e antes da sua aplicação em rotina, validados de acordo com procedimento interno do CEB, que contempla as normas em vigor do ICH e da FDA. Foram calculados, após a quantificação de amoxicilina e de ácido clavulânico, os parâmetros Cmax, Tmax, AUC0-n e AUC0-µ (método dos trapézios), e t1/2 para cada um dos indivíduos. A análise da bioequivalência foi feita de acordo com a norma europeia de referência (CPMP//EWP/QWP/1401/98, em vigor desde 2002) [intervalos de confiança (IC) a 90% para as razões T/R antes (para Cmax, Tmax, AUC e t1/2) e após (para Cmax, e AUC) transformação logarítmica dos dados; considerámos ainda a diferença nos Tmax para T e R]. De acordo com a norma, IC a 90% entre 0.80 e 1.25 para Cmax e AUC são indicadores de bioequivalência; relativamente ao Tmax e ao t1/2, apesar de não existirem valores de referência, considerámos apropriados os mesmo intervalos.

Obtiveram-se os resultados apresentados na tabela seguinte.

 

 

Cmax

Tmax

AUC0-n

AUC0-µ

t1/2

 

 

(mg.ml-1)

(h)

(mg.ml-1.h)

(mg.ml-1.h)

(h)

Amoxicilina

T/R

0.96 a 1.16

0.83 a 1.08

0.90 a 1.05

0.90 a 1.04

0.80 a 0.96

ln (T/R)

0.95 a 1.17

—

0.89 a 1.04

0.89 a 1.04

—

Ác.Clavulânico

T/R

0.82 a 1.08

0.95 a 1.09

0.84 a 1.08

0.84 a 1.07

0.91 a 1.01

ln (T/R)

0.86 a 1.20

—

0.85 a 1.22

0.86 a 1.18

—

Em conclusão, tendo-se verificado bioequivalência entre as duas formulações tanto para a amoxicilina como para o ácido clavulânico, pode-se considerar existir bioequivalência entre a formulação teste (T) e a formulação de referência (R) (Augmentin®DUO), que contêm ambos os princípios activos.

Comunicação em poster apresentada no 1º Congresso da Soc. Portuguesa de Ciências Farmacêuticas (Lisboa, 13 a 16 de Abril de 2003) Publicação no livro de resumos da Revista Portuguesa de Farmácia, Volume LII (nº1), pág. 51

Congresso
2003

Estudos de Bioequivalência vs Estudos de Biodisponibilidade e a sua importância quando se fala de medicamentos genéricos

Tice Macedo

Jornal da Qualidade

2003

Effect of nebicapone on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects

Luis Almeida & Amílcar Falcão & Manuel Vaz-da-Silva & Teresa Nunes & Ana-Teresa Santos & José-Francisco Rocha & Carla Neta & Tice Macedo & C. Fontes-Ribeiro & P. Soares-da-Silva

ABSTRACT
Objective: Nebicapone is a new catechol-O-methyltransferase inhibitor. In vitro,
nebicapone showed an inhibitory effect upon CYP2C9, which is responsible for the
metabolism of S-warfarin. The objective of this study was to investigate the effect of
nebicapone on the warfarin pharmacokinetics and pharmacodynamics in healthy
subjects.

Eur J Clin Pharmacol, 64: 961 – 966, 2008.

2008

Eslicarbazepine acetate (BIA 2-093: Relative bioavailability and bioequivalence of 50 mg/mL oral suspensions and 200 mg and 800 mg tablet formulations.

Fontes-Ribeiro, C., Nunes, T., Falcão, A., Neta, C., Lima, R., Tavares, S., Almeida, L., Macedo, T., Soares-da-Silva, P.

Abstract:
Objective: To investigate the dosage form proportionality and food effect of the final tablet formulation of eslicarbazepine acetate (ESL) in healthy volunteers.

Methods: This was a randomized, three-way crossover, single-centre study in 18 healthy volunteers. Subjects received a single dose of oral ESL 800 mg following a standard meal in one period, and following 10 hours of fasting in two separate periods (in the form of one 800 mg tablet [reference] or two 400 mg tablets [test]). The statistical method was based upon the 90% confidence interval (CI) of maximum observed plasma drug concentration (Cmax), area under the plasma concentration time curve (AUC) from time zero to the last sampling time at which concentrations were at or above the lower limit of quantification (AUCt) and AUC from time zero to infinity (AUC[infinity]) geometric means ratios (GMRs) of BIA 2-005, the enantiomeric mixture of the ESL active metabolite eslicarbazepine and its enantiomer R-licarbazepine. Bioequivalence was assumed when the 90% CI of the test/reference GMR fell within the bioequivalence acceptance interval (80.00, 125.00).

Results: Following a single dose of ESL 800 mg in the forms of two 400 mg tablets and one 800 mg tablet, the test/reference GMR (%) and 90% CI for Cmax, AUCt and AUC[infinity] were 100.78% (93.91, 108.16), 100.37% (97.82, 102.99) and 100.48% (97.91, 103.13), respectively. Following administration of one 800 mg tablet in fed (test) and fasting (reference) conditions, the test/reference GMR and 90% CI for Cmax, AUCt and AUC[infinity] were 100.96% (94.08, 108.35), 96.79% (94.34, 99.32) and 96.75% (94.27, 99.29), respectively. Treatments were well tolerated.

Conclusions: The bioequivalence criteria between the ESL 400 mg and 800 mg tablets were met and dosage form proportionality was demonstrated. The presence of food had no influence on ESL pharmacokinetics, indicating that ESL can be administered without regard to meals with no significant effects on drug disposition or extent of systemic exposure.

Drugs R D 2005;6(5):253-60.

2005

Dosage form proportionality and food-effect of the final tablet formulation of eslicarbazepine acetate in healthy volunteers

Carlos Fontes-Ribeiro, Tice Macedo, Teresa Nunes, Carla Neta, Teófilo Vasconcelos, Rui Cerdeira, Ricardo Lima, José-Francisco Rocha, Amílcar Falcão, Luís Almeida, Patrício Soares-da-Silva

Abstract:
Objective: To investigate the dosage form proportionality and food effect of the final tablet formulation of eslicarbazepine acetate (ESL) in healthy volunteers.

Methods: This was a randomized, three-way crossover, single-centre study in 18 healthy volunteers. Subjects received a single dose of oral ESL 800 mg following a standard meal in one period, and following 10 hours of fasting in two separate periods (in the form of one 800 mg tablet [reference] or two 400 mg tablets [test]). The statistical method was based upon the 90% confidence interval (CI) of maximum observed plasma drug concentration (Cmax), area under the plasma concentration time curve (AUC) from time zero to the last sampling time at which concentrations were at or above the lower limit of quantification (AUCt) and AUC from time zero to infinity (AUC[infinity]) geometric means ratios (GMRs) of BIA 2-005, the enantiomeric mixture of the ESL active metabolite eslicarbazepine and its enantiomer R-licarbazepine. Bioequivalence was assumed when the 90% CI of the test/reference GMR fell within the bioequivalence acceptance interval (80.00, 125.00).

Results: Following a single dose of ESL 800 mg in the forms of two 400 mg tablets and one 800 mg tablet, the test/reference GMR (%) and 90% CI for Cmax, AUCt and AUC[infinity] were 100.78% (93.91, 108.16), 100.37% (97.82, 102.99) and 100.48% (97.91, 103.13), respectively. Following administration of one 800 mg tablet in fed (test) and fasting (reference) conditions, the test/reference GMR and 90% CI for Cmax, AUCt and AUC[infinity] were 100.96% (94.08, 108.35), 96.79% (94.34, 99.32) and 96.75% (94.27, 99.29), respectively. Treatments were well tolerated.

Conclusions: The bioequivalence criteria between the ESL 400 mg and 800 mg tablets were met and dosage form proportionality was demonstrated. The presence of food had no influence on ESL pharmacokinetics, indicating that ESL can be administered without regard to meals with no significant effects on drug disposition or extent of systemic exposure.

 

 

Drugs in R&D 2008; 9 (6): 447-454.

2008

Effect of nebicapone on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects.

Luis Almeida, Amílcar Falcão, Manuel Vaz-da-Silva, Teresa Nunes, Ana-Teresa Santos, José-Francisco Rocha, Carla Neta, Tice Macedo, C. Fontes-Ribeiro, P. Soares-da-Silva

Abstract

Objective  Nebicapone is a new catechol-O-methyltransferase inhibitor. In vitro, nebicapone has showed an inhibitory effect upon CYP2C9, which is responsible for the metabolism of S-warfarin. The objective of this study was to investigate the effect of nebicapone on warfarin pharmacokinetics and pharmacodynamics in healthy subjects.

Methods  Single-centre, open-label, randomised, two-period crossover study in 16 healthy volunteers. In one period, subjects received nebicapone 200 mg thrice daily for 9 days and a racemic warfarin 25-mg single dose concomitantly with the nebicapone morning dose on day 4 (test). In the other period, subjects received a racemic warfarin 25-mg single dose alone (reference). The treatment periods were separated by a washout of 14 days.

Results  For R-warfarin, mean ± SD Cmax was 1,619 ± 284 ng/mL for test and 1,649 ± 357 ng/mL for reference, while AUC0-t was 92,796 ± 18,976 ng·h/mL (test) and 73,597 ± 11,363 ng·h/mL (reference). The R-warfarin test-to-reference geometric mean ratio (GMR) and 90% confidence interval (90%CI) were 0.973 (0.878–1.077) for Cmax and 1.247 (1.170–1.327) for AUC0-t . For S-warfarin, mean ± SD Cmax was 1,644 ± 331 ng/mL for test and 1,739 ± 392 ng/mL for reference, while AUC0-t was 66,627 ± 41,199 ng·h/mL (test) and 70,178 ± 42,560 ng·h/mL (reference). The S-warfarin test-to-reference GMR and 90%CI were 0.932 (0.845–1.028) for Cmax and 0.914 (0.875–0.954) for AUC0-t . No differences were found for the pharmacodynamic parameter (INR).

Conclusion  Nebicapone showed no significant effect on S-warfarin pharmacokinetics or on the coagulation endpoint (INR). A mild inhibition of the R-warfarin metabolism was found but is unlikely to be of clinical relevance.

European Journal of Clinical Pharmacology, 2008 Oct; 64 (10): 961-966.

2008
http://www.springerlink.com/content/m3617087h1347604/?p=cbf93c588e5a491e9c51cd20dc82f48d&pi=0

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

J.-F. Rocha, M. Vaz-da-Silva, L. Almeida, A. Falcão, T. Nunes, A.-T. Santos, F. Martins, C. Fontes-Ribeiro, T. Macedo, P. Soaresd-da-Silva

International Journal of Clinical Pharmacology and Therapeutics, Vol. 47 – nº 4/2009 (255-261).

2009