RESUMO
INTRODUCTION: The in vitro-in vivo pharmacokinetic correlation models (IVIVC) are a fundamental part of the drug discovery and development process. The ability to accurately predict the in vivo pharmacokinetic profile of a drug based on in vitro observations can have several applications during a successful development process. OBJECTIVE: To develop a comprehensive model to predict the in vivo absorption of antiretroviral drugs based on permeability studies, in vitro and in vivo solubility and demonstrate its correlation with the pharmacokinetic profile in humans. METHODS: Analytical tools to test the biopharmaceutical properties of stavudine, lamivudine y zidovudine were developed. The kinetics of dissolution, permeability in caco-2 cells and pharmacokinetics of absorption in rabbits and healthy volunteers were evaluated. RESULTS: The cumulative areas under the curve (AUC) obtained in the permeability study with Caco-2 cells, the dissolution study and the pharmacokinetics in rabbits correlated with the cumulative AUC values in humans. These results demonstrated a direct relation between in vitro data and absorption, both in humans and in the in vivo model. CONCLUSIONS: The analytical methods and procedures applied to the development of an IVIVC model showed a strong correlation among themselves. These IVIVC models are proposed as alternative and cost/effective methods to evaluate the biopharmaceutical properties that determine the bioavailability of a drug and their application includes the development process, quality assurance, bioequivalence studies and pharmacosurveillance.
INTRODUCCIÓN: Los modelos de correlación In vitro-in vivo (IVIVC) son parte integral del proceso de investigación y desarrollo de fármacos. La capacidad de predecir con exactitud el perfil in vivo a partir de las observaciones in vitro tiene diversas aplicaciones durante el desarrollo exitoso de una formulación. OBJETIVO: Desarrollar un modelo integral para predecir la absorción in vivo de fármacos antirretrovirales con base en estudios de permeabilidad, solubilidad in vitro e in vivo y demostrar su correlación con la farmacocinética en humanos. MÉTODOS: Se desarrollaron y validaron las técnicas bioanalíticas para valorar las propiedades biofarmacéuticas de Estavudina, Lamivudina y Zidovudina. Se evaluó las cineticas de disolución, la permeabilidad en monocapas celulares Caco-2 y la farmacocinética de absorción in vivo en conejos y voluntarios sanos. RESULTADOS: Los valores de AUC acumulados en el sistema de células Caco-2, en la disolución y en el modelo animal, fueron correlacionados con los valores de AUC acumulados en el humano. Con lo anterior se demostró una relación directamente proporcional entre los resultados in vitro con respecto a los obtenidos en la fase de absorción tanto en el humano como en el modelo animal. CONCLUSIONES: Los métodos analíticos y procedimientos aplicados en la IVIVC demostraron las correspondencias directas entre sí, con altos niveles de correlación. Se proponen estos modelos IVIVC como métodos alternativos costo/efectivos para la valoración de las propiedades biofarmacéuticas que determinan la biodisponibilidad, en el desarrollo de productos, en el aseguramiento de la calidad y como pruebas de bioequivalencia en los programas de farmacovigilancia.
Assuntos
Lamivudina/farmacocinética , Modelos Biológicos , Estavudina/farmacocinética , Zidovudina/farmacocinética , Adolescente , Adulto , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacocinética , Área Sob a Curva , Disponibilidade Biológica , Células CACO-2 , Humanos , Lamivudina/química , Masculino , Permeabilidade , Coelhos , Solubilidade , Especificidade da Espécie , Estavudina/química , Adulto Jovem , Zidovudina/químicaRESUMO
Introduction: The in vitro-in vivo pharmacokinetic correlation models (IVIVC) are a fundamental part of the drug discovery and development process. The ability to accurately predict the in vivo pharmacokinetic profile of a drug based on in vitro observations can have several applications during a successful development process. Objective: To develop a comprehensive model to predict the in vivo absorption of antiretroviral drugs based on permeability studies, in vitro and in vivo solubility and demonstrate its correlation with the pharmacokinetic profile in humans. Methods: Analytical tools to test the biopharmaceutical properties of stavudine, lamivudine y zidovudine were developed. The kinetics of dissolution, permeability in caco-2 cells and pharmacokinetics of absorption in rabbits and healthy volunteers were evaluated. Results: The cumulative areas under the curve (AUC) obtained in the permeability study with Caco-2 cells, the dissolution study and the pharmacokinetics in rabbits correlated with the cumulative AUC values in humans. These results demonstrated a direct relation between in vitro data and absorption, both in humans and in the in vivo model. Conclusions: The analytical methods and procedures applied to the development of an IVIVC model showed a strong correlation among themselves. These IVIVC models are proposed as alternative and cost/ effective methods to evaluate the biopharmaceutical properties that determine the bioavailability of a drug and their application includes the development process, quality assurance, bioequivalence studies and pharmacosurveillance.
Introducción: Los modelos de correlación In vitro-in vivo (IVIVC) son parte integral del proceso de investigación y desarrollo de fármacos. La capacidad de predecir con exactitud el perfil in vivo a partir de las observaciones in vitro tiene diversas aplicaciones durante el desarrollo exitoso de una formulación. Objetivo: Desarrollar un modelo integral para predecir la absorción in vivo de fármacos antirretrovirales con base en estudios de permeabilidad, solubilidad in vitro e in vivo y demostrar su correlación con la farmacocinética en humanos. Métodos: Se desarrollaron y validaron las técnicas bioanalíticas para valorar las propiedades biofarmacéuticas de Estavudina, Lamivudina y Zidovudina. Se evaluó las cineticas de disolución, la permeabilidad en monocapas celulares Caco-2 y la farmacocinética de absorción in vivo en conejos y voluntarios sanos. Resultados: Los valores de AUC acumulados en el sistema de células Caco-2, en la disolución y en el modelo animal, fueron correlacionados con los valores de AUC acumulados en el humano. Con lo anterior se demostró una relación directamente proporcional entre los resultados in vitro con respecto a los obtenidos en la fase de absorción tanto en el humano como en el modelo animal. Conclusiones: Los métodos analíticos y procedimientos aplicados en la IVIVC demostraron las correspondencias directas entre sí, con altos niveles de correlación. Se proponen estos modelos IVIVC como métodos alternativos costo/efectivos para la valoración de las propiedades biofarmacéuticas que determinan la biodisponibilidad, en el desarrollo de productos, en el aseguramiento de la calidad y como pruebas de bioequivalencia en los programas de farmacovigilancia.
Assuntos
Adolescente , Adulto , Animais , Humanos , Masculino , Coelhos , Adulto Jovem , Lamivudina/farmacocinética , Modelos Biológicos , Estavudina/farmacocinética , Zidovudina/farmacocinética , Área Sob a Curva , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacocinética , Disponibilidade Biológica , Lamivudina/química , Permeabilidade , Solubilidade , Especificidade da Espécie , Estavudina/química , Zidovudina/químicaRESUMO
BACKGROUND: The integrase inhibitor dolutegravir and nucleoside analogues abacavir and lamivudine are once-daily treatment options for HIV. This study (NCT01622790) evaluated, first, the bioequivalence (BE) of a fixed-dose combination (FDC) tablet containing dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg (dolutegravir/abacavir/lamivudine FDC) vs coadministered dolutegravir 50 mg and abacavir/lamivudine combination tablets (Epzicom) and, second, the effect of food on the dolutegravir/abacavir/lamivudine FDC tablet. METHODS: Study part A (66 healthy subjects) was a single-dose, open-label, randomized, 2-period crossover study to evaluate the BE of the dolutegravir/abacavir/lamivudine FDC tablet and dolutegravir + abacavir/lamivudine tablets in the fasted state. In study part B, 12 subjects from part A received the dolutegravir/abacavir/lamivudine FDC tablet with a high-fat meal. BE and food effect were assessed by analysis of variance to determine the ratio of geometric least squares means and associated 90% confidence intervals for key pharmacokinetic parameters for each of dolutegravir, abacavir, and lamivudine. RESULTS: Sixty-two subjects completed part A. The dolutegravir/abacavir/lamivudine tablet was bioequivalent to the dolutegravir + abacavir/lamivudine tablets; 90% confidence intervals for the geometric least squares mean ratios fell within the 0.8-1.25 BE criteria. The effect of food on the dolutegravir/abacavir/lamivudine FDC tablet was similar to previous food effects observed with the separate formulations. The safety profile was comparable between treatments, with no observed serious or grade 3/4 adverse events. CONCLUSIONS: The BE of the dolutegravir/abacavir/lamivudine FDC tablet was demonstrated; it may be administered without regard to meals.
Assuntos
Didesoxinucleosídeos/farmacocinética , Interações Alimento-Droga , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Lamivudina/farmacocinética , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/sangue , Fármacos Anti-HIV/farmacocinética , Estudos Cross-Over , Didesoxinucleosídeos/administração & dosagem , Didesoxinucleosídeos/sangue , Gorduras na Dieta , Combinação de Medicamentos , Feminino , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/sangue , Humanos , Lamivudina/administração & dosagem , Lamivudina/sangue , Masculino , Oxazinas , Piperazinas , Piridonas , Equivalência Terapêutica , Cremes, Espumas e Géis Vaginais , Adulto JovemRESUMO
INTRODUCTION: The major processes that control the absorption of orally administered drugs are dissolution and gastrointestinal permeation. These processes depend on two main properties: solubility and permeability. Based on these characteristics, the Biopharmaceutical Classification System (BCS) was proposed as a tool to assist in biowaiver and bioavailability prediction of drugs. METHODS: The purpose of the present study was to evaluate the permeability of lamivudine (3TC) and zidovudine (AZT) using a different ex vivo method in Franz cells. A segment of jejunum was inserted in a Franz cells apparatus, in order to assess drug permeability in the apical-basolateral (A-B) and basolateral-apical (B-A) directions. Each drug was added to the donor chamber, collected from the acceptor chamber and analyzed by HPLC. Fluorescein (FLU) and metoprolol (METO) were used as low and high permeability markers, respectively. RESULTS: The apparent permeability (Papp) results for the A-B direction were: Papp FLU A-B=0.54×10(-4)cm·s(-1), Papp METO A-B=7.99×10(-4)cm·s(-1), Papp 3TC A-B=4.58×10(-4)cm·s(-1) and Papp AZT A-B=5.34×10(-4)cm·s(-1). For the B-A direction, the Papp results were: Papp FLU B-A=0.56×10(-4)cm·s(-1), Papp METO B-A=0.25×10(-4)cm·s(-1), Papp 3TC B-A=0.24×10(-4)cm·s(-1) and Papp AZT B-A=0.19×10(-4)cm·s(-1). DISCUSSION: For the A-B direction, the Papp results of fluorescein and metoprolol show low and high permeability, respectively, indicating that the membranes were appropriate for permeability studies. For the A-B direction, the Papp results of 3TC and AZT suggest that these antiretroviral drugs have permeability values close to metoprolol. Nevertheless, for the B-A direction the Papp results do not suggest efflux mechanism for any of the drugs. Thereby, the different ex vivo methods using Franz cells can be successfully applied in drug permeability studies, in particular for drug biopharmaceutical classification.
Assuntos
Mucosa Intestinal/metabolismo , Lamivudina/farmacocinética , Zidovudina/farmacocinética , Animais , Disponibilidade Biológica , Permeabilidade da Membrana Celular , Absorção Intestinal , Jejuno/metabolismo , Masculino , Ratos , Ratos Wistar , SolubilidadeAssuntos
Fármacos Anti-HIV/uso terapêutico , Doença de Chagas/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Nitroimidazóis/uso terapêutico , Pirrolidinonas/uso terapêutico , Tripanossomicidas/uso terapêutico , Adenina/administração & dosagem , Adenina/análogos & derivados , Adenina/farmacocinética , Adenina/uso terapêutico , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Terapia Antirretroviral de Alta Atividade , Sulfato de Atazanavir , Doença de Chagas/complicações , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Infecções por HIV/complicações , Humanos , Lamivudina/administração & dosagem , Lamivudina/farmacocinética , Lamivudina/uso terapêutico , Nitroimidazóis/administração & dosagem , Nitroimidazóis/farmacocinética , Oligopeptídeos/administração & dosagem , Oligopeptídeos/farmacocinética , Oligopeptídeos/uso terapêutico , Organofosfonatos/administração & dosagem , Organofosfonatos/farmacocinética , Organofosfonatos/uso terapêutico , Paraguai/etnologia , Piridinas/administração & dosagem , Piridinas/farmacocinética , Piridinas/uso terapêutico , Pirrolidinonas/administração & dosagem , Pirrolidinonas/farmacocinética , Raltegravir Potássico , Ritonavir/administração & dosagem , Ritonavir/farmacocinética , Ritonavir/uso terapêutico , Espanha , Tenofovir , Tripanossomicidas/administração & dosagem , Tripanossomicidas/farmacocinética , Zidovudina/administração & dosagem , Zidovudina/farmacocinética , Zidovudina/uso terapêuticoRESUMO
IMPORTANCE OF THE FIELD: The nucleoside reverse transcriptase inhibitors (NRTIs) are used in antiretroviral therapy worldwide for the treatment of HIV infections. These drugs act by blocking reverse transcriptase enzyme activity, causing pro-viral DNA chain termination. As a consequence, NRTIs could cause genomic instability and loss of heterozygosity. AREAS COVERED IN THIS REVIEW: This review highlights the toxic and genotoxic effects of NRTIs, particularly lamivudine (3TC) and stavudine (d4T) analogues. In addition, a battery of short-term in vitro and in vivo systems are described to explain the potential genotoxic effects of these NRTIs as a single drug or a complexity of highly active antiretroviral therapy. WHAT THE READER WILL GAIN: The readers will gain an understanding of a secondary effect that could be induced by 3TC and d4T treatments. TAKE HOME MESSAGE: Considering that AIDS has become a chronic disease, more comprehensive toxic genetic studies are needed, with particular attention to the genetic alterations induced by NRTIs. These alterations play a primary role in carcinogenesis and are also involved in secondary and subsequent steps of carcinogenesis.
Assuntos
Fármacos Anti-HIV/efeitos adversos , Aberrações Cromossômicas/efeitos dos fármacos , Lamivudina/efeitos adversos , Mutação , Inibidores da Transcriptase Reversa/efeitos adversos , Estavudina/efeitos adversos , Adulto , Animais , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/toxicidade , Criança , Ensaios Clínicos como Assunto , Cricetinae , Drosophila melanogaster/efeitos dos fármacos , Drosophila melanogaster/genética , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Haplorrinos , Humanos , Lamivudina/administração & dosagem , Lamivudina/farmacocinética , Lamivudina/toxicidade , Camundongos , Testes de Mutagenicidade , Ratos , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/farmacocinética , Inibidores da Transcriptase Reversa/toxicidade , Estavudina/administração & dosagem , Estavudina/farmacocinética , Estavudina/toxicidadeRESUMO
Bidirectional transport studies were conducted using Caco-2, MDCK, and MDCK-MDR1 to determine P-gp influences in lamivudine and zidovudine permeability and evaluate if zidovudine permeability changes with the increase of zidovudine concentration and/or by association of lamivudine. Transport of lamivudine and zidovudine separated and coadministrated across monolayers based on these cells were quantified using LC-MS-MS. Drug efflux by P-gp was inhibited using GG918. Bidirectional transport of lamivudine and zidovudine was performed across MDCK-MDR1 and Caco-2 cells. Statistically significant transport decrease in B --> A direction was observed using MDCK-MDR1 for zidovudine and MDCK-MDR1 and Caco-2 for lamivudine. Results show increased transport in B --> A and A --> B directions as concentration increases but data from P(app) increase in both directions for both drugs in Caco-2, decrease in MDCK, and does not change significantly in MDCK-MDR1. Zidovudine transport in A --> B direction increases when coadministrated with increasing lamivudine concentration but does not change significantly in B --> A direction. Zidovudine and lamivudine are P-gp substrates, but results assume that P-gp does not affect significantly lamivudine and zidovudine. Their transport in monolayers based on Caco-2 cells increase proportionally to concentration (in both directions) and zidovudine transport in Caco-2 cell monolayer does not show significant changes with lamivudine increasing concentrations.
Assuntos
Permeabilidade da Membrana Celular/efeitos dos fármacos , Lamivudina/farmacologia , Lamivudina/farmacocinética , Zidovudina/farmacologia , Zidovudina/farmacocinética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Acridinas/farmacologia , Animais , Disponibilidade Biológica , Transporte Biológico/efeitos dos fármacos , Células CACO-2 , Células Cultivadas , Cães , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Resistência a Múltiplos Medicamentos , Humanos , Tetra-Hidroisoquinolinas/farmacologiaRESUMO
Until recently, the only generally approved treatment for chronic hepatitis B was alpha-interferon; however, it gives only moderate efficacy in terms of sustained response (biochemical, virological and histological). In fact, only 20 percent to 40 percent of treated patients respond to therapy, with lower percentages (~ 10 percent) among patients infected with precore-mutant strains of HBV (HBeAb HBV-DNA positive). The FDA of the USA approved the use of lamivudine in adult patients affected by chronic hepatitis B in 1998. In this review, we focused on the pharmacokinetic and pharmacodynamic properties and efficacy and tolerability of lamivudine in the treatment of chronic hepatitis B cases that are both HBeAg and anti-HBe-positive.
Assuntos
Humanos , Antivirais/uso terapêutico , Hepatite B Crônica/tratamento farmacológico , Lamivudina/uso terapêutico , Antivirais/efeitos adversos , Antivirais/farmacocinética , Vírus da Hepatite B/imunologia , Hepatite B Crônica/sangue , Lamivudina/efeitos adversos , Lamivudina/farmacocinéticaRESUMO
Until recently, the only generally approved treatment for chronic hepatitis B was alpha-interferon; however, it gives only moderate efficacy in terms of sustained response (biochemical, virological and histological). In fact, only 20% to 40% of treated patients respond to therapy, with lower percentages (~ 10%) among patients infected with precore-mutant strains of HBV (HBeAb HBV-DNA positive). The FDA of the USA approved the use of lamivudine in adult patients affected by chronic hepatitis B in 1998. In this review, we focused on the pharmacokinetic and pharmacodynamic properties and efficacy and tolerability of lamivudine in the treatment of chronic hepatitis B cases that are both HBeAg and anti-HBe-positive.
Assuntos
Antivirais/uso terapêutico , Hepatite B Crônica/tratamento farmacológico , Lamivudina/uso terapêutico , Antivirais/efeitos adversos , Antivirais/farmacocinética , Vírus da Hepatite B/imunologia , Hepatite B Crônica/sangue , Humanos , Lamivudina/efeitos adversos , Lamivudina/farmacocinéticaRESUMO
The intracellular triphosphorylation and plasma pharmacokinetics of lamivudine (3TC), stavudine (d4T), and zidovudine (ZDV) were assessed in a pharmacokinetic substudy, in 56 human immunodeficiency virus-hepatitis C virus (HIV-HCV) coinfected patients receiving peginterferon alfa-2a (40KD) 180 microg/week plus either placebo or ribavirin (RBV) 800 mg/day in the AIDS PEGASYS Ribavirin International Coinfection Trial. There were no significant differences between patients treated with RBV and placebo in plasma pharmacokinetics parameters for the nucleoside reverse transcriptase inhibitors (NRTIs) at steady state (weeks 8 to 12): ratios of least squares mean of area under the plasma concentration-time curve (AUC(0-12 h)) were 1.17 (95% confidence interval, 0.91 to 1.51) for 3TC, 1.44 (95% confidence interval, 0.58 to 3.60) for d4T and 0.85 (95% confidence interval, 0.50 to 1.45) for ZDV, and ratios of least squares mean plasma C(max) were 1.33 (95% confidence interval, 0.99 to 1.78), 1.06 (95% confidence interval, 0.68 to 1.65), and 0.84 (95% confidence interval, 0.46 to 1.53), respectively. Concentrations of NRTI triphosphate (TP) metabolites in relation to those of the triphosphates of endogenous deoxythymidine-triphosphate (dTTP) and deoxcytidine-triphosphate (dCTP) were similar in the RBV and placebo groups. Differences (RBV to placebo) in least squares mean ratios of AUC(0-12 h) at steady state were 0.274 (95% confidence interval, -0.37 to 0.91) for 3TC-TP:dCTP, 0.009 (95% confidence interval, -0.06 to 0.08) for d4T-TP:dTTP, and -0.081 (95% confidence interval, -0.40 to 0.24) for ZDV-TP:dTTP. RBV did not adversely affect HIV-1 replication. In summary, RBV 800 mg/day administered in combination with peginterferon alfa-2a (40KD) does not significantly affect the intracellular phosphorylation or plasma pharmacokinetics of 3TC, d4T, and ZDV in HIV-HCV-coinfected patients.