In vitro-in vivo Pharmacokinetic correlation model for quality assurance of antiretroviral drugs / Modelo de correlación farmacocinético in vitro-in vivo para el aseguramiento de la calidad de medicamentos antirretrovirales

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.

Sleep Respiratory Disorders and Clinical Profile in Patients with Type 2 Diabetes Mellitus

Introduction Sleep respiratory disorders (SRDs) are often found in patients with type 2 diabetes mellitus (T2DM). Objective The aim was to establish the prevalence of risk to develop an SRD using the Clinical Berlin Questionnaire (CBQ) and Epworth Sleepiness Scale (ESS) in patients with T2DM and verifying the correlation of anthropometric measurements and life quality (LQ) with ESS. Methods A descriptive and analytical study of a case series evaluating 208 patients with T2DM, submitted to clinical and biochemical evaluation and implementation of CBQ, ESS, and WHOQOL-bref to evaluate LQ. Results Mean age was 60.8 8.8 years, and 65.4% were women. Most diabetics were overweight (36.1%), and 29.8% were class I obese. One-third had positive risk signals for a SRD, with 87.0 and 34.1% having high risk in CBQ and sleep disorders in ESS, respectively. There was a significant difference in the general LQ between the low- and high-risk groups in the CBQ. Conclusion In this scenario, it is noteworthy that the active search for sleep disorders must start from simple methods, such as application of protocols. .

Efeito dos alimentos na biodisponibilidade de medicamentos antirretrovirais: uma revisão sistemática da literatura / Effect of food on the bioavailability of antiretroviral drugs: a systematic review of literature

Objetivo: O objetivo do presente estudo foi identificar as intera��es medicamentoalimento em pacientes em uso de terapia antirretroviral descritas na literatura. Fonte de dados: Trata-se de uma revis�o sistem�tica utilizando os bancos de dados Medline e LILACS, no per�odo de 1998 at� 2012, com os seguintes descritores: food and bioavailability of antiretroviral drugs, food and antiretroviral failure and food and antiretroviral pharmacokinetic. A busca foi restrita aos idiomas ingl�s, portugu�s e espanhol. S�ntese dos dados: Foram selecionados 11 artigos, tendo como desenho estudos de coorte. Destes, seis estudos foram realizados nos Estados Unidos, dois na Espanha, um na Austr�lia, um na Alemanha e um na Su��a. A avalia��o da concord�ncia entre os avaliadores na classifica��o da qualidade dos artigos demonstrou boa concord�ncia (k=0,74), sendo este dado significativo (p<0,05). Do total de estudos analisados, nenhum foi considerado de qualidade A, sete (59,0%) foram de qualidade B e cinco (41,0%) de qualidade C. Todos os estudos consideram os efeitos da intera��o entre o alimento e o medicamento que possam resultar em aumento, decr�scimo, atraso ou que n�o afetem a absor��o do medicamento. Certos componentes dos alimentos, principalmente a gordura, s�o conhecidos por afetar significativamente a absor��o de medicamentos antirretrovirais e efeitos adversos proporcionados pelo medicamento podem acarretar piora na ades�o ao tratamento. Conclus�es: Escassos s�o os estudos prospectivos de qualidade que tenham descrito a associa��o entre a interfer�ncia dos alimentos na biodisponibilidade dos medicamentos antirretrovirais, sendo, os que investigaram esta associa��o, contradit�rios. N�o foram encontrados estudos que atendam a mais de 80% dos crit�rios de qualidade estabelecidos pelo Cochrane.

Objective: The objective of the present study was to identify drug-food interactions in patients on antiretroviral therapy reported in the literature. Data source: It is a systematic review that used the databases Medline and LILACS from 1998 until 2012, with the following descriptors: food and bioavailability of antiretroviral drugs, food and antiretroviral failure, and food and antiretroviral pharmacokinetic. The search was limited to English, Portuguese and Spanish. Data synthesis: Eleven articles were selected, with the design of cohort studies. Of these, six studies were performed in the United States, two in Spain, one in Australia, one in Germany, and one in Switzerland. The assessment of agreement among raters in classifying the quality of the articles showed good agreement (k=0.74), this factor being significant (p<0.05). None of the studies analyzed was considered as quality A, seven (59.0%) were quality B, and five (41.0%) were quality C. All studies consider the effects of the interaction between food and drug that may result in increase, decrease, delay, or that do not affect drug absorption. Certain components of food, especially fat, are known to significantly affect the absorption of antiretroviral drugs, and adverse effects provided by the drug may result in worsening of treatment adherence. Conclusions: Scarce are the prospective studies with quality that have described the association between the interference of food on the bioavailability of antiretroviral drugs, and those who have investigated this association are contradictory. No studies were found that meet more than 80% of the quality criteria set by the Cochrane.

Related factors to atazanavir plasma levels in a cohort of HIV positive individuals with undetectable viral load

OBJECTIVE: To evaluate the factors associated with plasma concentrations of atazanavir (ATV) in a cohort of well-controlled HIV infected subjects (undetectable viremia). Design: Cross-sectional study where 69 subjects were consecutively enrolled between April and November, 2011. METHODS: Patients had to be on atazanavir for at least six months, undetectable viral load for a period equal to or longer than 12 months, T CD4+ lymphocyte count higher than 200 cells/mm³, and aged between 18 years and 70 years old. Exclusion criteria were pregnancy, any neurologic disease, active opportunistic disease, hepatitis or cancer. Atazanavir plasma levels were measured by ultra-performance liquid chromatography. RESULTS AND DISCUSSION: Overall, 54 patients (mean age of 47 years and 50% women) were included in the analysis. Those without ritonavir (unboosted atazanavir) had statistically lower plasma concentrations than those with ritonavir boosted atazanavir (p = 0.001) and total and indirect bilirubin were statistically associated with plasma concentration of atazanavir (r = 0.32 and r = 0.33 respectively; p < 0.05 in both cases). no statistical association was found among gender, ethnicity, age, weight, body mass index (BMI), lipid profile, and the plasma concentration of atazanavir. CONCLUSION: in summary, as expected, concomitant ritonavir use was the only factor associated with atazanavir plasma levels. prospective studies with a larger sample size might help to observe an association of atazanavir concentrations to other characteristics such as body weight, since the p-value showed to be close to significance (p = 0.068).

Resistência do HIV-1 aos antirretrovirais e novas perspectivas de tratamento / Resistance of the HIV-1 to the antiretroviral and new treatment perspectives

O acesso à terapia antirretroviral (TARV) tem garantido uma melhoria significativa na qualidade de vida dos indivíduos HIV--positivos, sobretudo em países onde a distribuição destes medicamentos é gratuita, como no Brasil. Entretanto, um dos principais fatores associados à falha terapêutica é o surgimento de resistência às drogas e a transmissão de vírus resistentes. O presente artigo apresenta os mecanismos de atuação das drogas antirretrovirais (ARVs) em uso, a epidemiologia da resistência do HIV-I, suas consequências, bem como novas perspectivas de tratamento.

Access to antiretroviral therapy has granted a significant improvement in quality of life for HIV-I positive individuals, especially in countries where treatment is free-of-charge, such as Brazil. However, one of the leading factors associated with treatment failure is the development and transmission of resistant viruses. This present article presents the mechanisms of action of antiretroviral drugs (ARVs) in use, the epidemiology and consequences of HIV-I resistance, and new treatment perspectlves.

Pharmacokinetics of lamivudine & stavudine in generic fixed-dose combinations in HIV-1 infected adults in India.

Background & objectives: Antiretroviral drug concentrations are important determinants of clinical response to a drug accounting for both toxicity and efficacy. Several factors such as age, ethnicity, body weight and patients’ immune status may influence antiretroviral drug concentrations. The aim of the study was to determine the influence of immunological status, sex and body mass index on the steady state pharmacokinetics of lamivudine (3TC) and stavudine (d4T) in HIV-infected adults, who were undergoing treatment with generic fixed dose combinations (FDC) of these drugs in India. Methods: Twenty seven HIV-1 infected patients receiving antiretroviral treatment (ART) for at least two weeks at the Government ART clinic at Tambaram, Chennai, took part in the study. Serial blood samples were collected predosing and at different time points after drug administration. Plasma 3TC and d4T levels were estimated by HPLC. Results: The patients’ immune status, sex or body mass index had no impact on the pharmacokinetics of 3TC. In the case of d4T, peak concentration was significantly lower in patients with CD4 cell counts < 200 cells/μl than those with ≥ 200 cells/ μl (P < 0.05), but were within the therapeutic range. The mean CD4 cell counts increased from 101 cells/μl at initiation of ART to 366 cells/μl at 12 months of treatment. Interpretation & conclusions: Blood levels of 3TC and d4T drugs that are part of generic FDCs commonly used by HIV-infected individuals in India were within the therapeutic range and not influenced by nutritional or immune status. There was a significant improvement in CD4 cell counts over 12 months of treatment. Indian generic FDCs manufactured and used widely in the developing world provide effective concentrations of antiretroviral drugs.

A new model for the population pharmacokinetics of didanosine in healthy subjects

Didanosine (ddI) is a component of highly active antiretroviral therapy drug combinations, used especially in resource-limited settings and in zidovudine-resistant patients. The population pharmacokinetics of ddI was evaluated in 48 healthy volunteers enrolled in two bioequivalence studies. These data, along with a set of co-variates, were the subject of a nonlinear mixed-effect modeling analysis using the NONMEM program. A two-compartment model with first order absorption (ADVAN3 TRANS3) was fitted to the serum ddI concentration data. Final pharmacokinetic parameters, expressed as functions of the co-variates gender and creatinine clearance (CL CR), were: oral clearance (CL = 55.1 + 240 x CL CR + 16.6 L/h for males and CL = 55.1 + 240 x CL CR for females), central volume (V2 = 9.8 L), intercompartmental clearance (Q = 40.9 L/h), peripheral volume (V3 = 62.7 + 22.9 L for males and V3 = 62.7 L for females), absorption rate constant (Ka = 1.51/h), and dissolution time of the tablet (D = 0.43 h). The intraindividual (residual) variability expressed as coefficient of variation was 13.0 percent, whereas the interindividual variability of CL, Q, V3, Ka, and D was 20.1, 75.8, 20.6, 18.9, and 38.2 percent, respectively. The relatively high (>30 percent) interindividual variability for some of these parameters, observed under the controlled experimental settings of bioequivalence trials in healthy volunteers, may result from genetic variability of the processes involved in ddI absorption and disposition.

Intracellular studies of the nucleoside reverse transcriptase inhibitor active metabolites: a review

Nucleoside reverse transcriptase inhibitors (NRTIs) plasma concentrations do not correlate with clinical efficacy or toxicity. These agents need to be phosphorylated to become active against HIV-infection. Thus, the characterization of the NRTIs intracellular metabolite pharmacological parameters will provide a better understanding that could lead to the development of more rational dose regimens in the HIV-infected population. Furthermore, intracellular measurements of NRTIs may provide a better marker with respect to clinical efficacy and toxicity than plasma concentrations. Thus, in this article we review the latest information regarding the intracellular pharmacological parameters of zidovudine (ZDV) and lamivudine (3TC) active metabolites in HIV infected patients including the results from our recent clinical studies. We will start the discussion with ZDV and 3TC clinical efficacy, followed by systemic pharmacokinetics studies. We will then discuss the in vitro and in vivo intracellular studies with particular emphasis in the method development to measure these metabolites and we will conclude with the most current data from our clinical trials.