P-glycoprotein (ABCB1) activity decreases raltegravir disposition in primary CD4+P-gp high cells and correlates with HIV-1 viral load

Altres ajuts: SAF2014-25560-RTo evaluate the role of P-glycoprotein (P-gp) and multidrug-resistant-protein 1 (MRP1) on raltegravir intracellular drug disposition in CD4+ T cells, investigate the effect of HIV-1 infection on P-gp expression and correlate HIV-1 viraemia with P-gp activity in primary CD4+ T cell subsets. The cellular accumulation ratio of [ 3 H]raltegravir was quantified in CD4+ T cell lines overexpressing either P-gp (CEM-P-gp) or MRP1 (CEM-MRP1) and in primary CD3+CD4+ T cells with high (P-gp high) and low P-gp activity (P-gp low); inhibition of efflux transporters was confirmed by the intracellular retention of calcein-AM. The correlation of P-gp activity with HIV-1 viraemia was assessed in naive and memory T cell subsets from 21 HIV-1-infected treatment-naive subjects. [ 3 H]Raltegravir cellular accumulation ratio decreased in CEM-P-gp cells (P < 0.0001). XR9051 (a P-gp inhibitor) and HIV-1 PIs reversed this phenomenon. Primary CD4+P-gp high cells accumulated less raltegravir (38.4% ± 9.6%) than P-gp low cells, whereas XR9051 also reversed this effect. In vitro HIV-1 infection of PBMCs and stimulation of CD4+ T cells increased P-gp mRNA and P-gp activity, respectively, while primary CD4+P-gp high T cells sustained a higher HIV-1 replication than P-gp low cells. A significant correlation between HIV-1 viraemia and P-gp activity was found in different CD4+ T cell subsets, particularly memory CD4+ T cells (r = 0.792, P < 0.0001). Raltegravir is a substrate of P-gp in CD4+ T cells. Primary CD4+P-gp high T cells eliminate intracellular raltegravir more readily than P-gp low cells and HIV-1 viraemia correlates with P-gp overall activity. Specific CD4+P-gp high T cell subsets could facilitate the persistence of viral replication in vivo and ultimately promote the appearance of drug resistance

Farmacocinética poblacional de lopinavir y ritonavir en pacientes adultos infectados por el VIH

Objetivos: 1.- Determinar la variabilidad interindividual de la concentración valle en plasma de los fármacos inhibidores de la transcriptasa inversa no análogos de los nucleósidos (ITINAN) y de los inhibidores de la proteasa (IP) del virus de la inmunodeficiencia humana (VIH), así como la proporción de pacientes infectados por el VIH en tratamiento antirretroviral con concentraciones valle de los fármacos por debajo de la concentración mínima eficaz en la practica clínica habitual. 2.- Evaluar la influencia de la co-infección por el virus de la hepatitis C (VHC) y el grado de fibrosis hepática asociado a la misma en la exposición a lopinavir y ritonavir en un grupo de pacientes infectados por el VIH sin evidencia de insuficiencia hepática. 3.- Desarrollar y validar un modelo farmacocinético poblacional simultáneo para lopinavir y ritonavir incluyendo las características individuales que explican parte de la variabilidad cinética de los fármacos observada en la práctica clínica así como la interacción entre lopinavir y ritonavir.Métodos: Para alcanzar el primer objetivo de realizó un estudio transversal en el que se determinó la concentración valle de los ITINAN e IP en todos los pacientes que acudieron a a unidad de VIH del Hospital Universitari Germans Trias i Pujol durante un periodo de dos semanas. Para alcanzar el segundo y tercer objetivos se realizó un estudio en el que se determinó la concentración de lopinavir y ritonavir en plasma en un grupo de pacientes en tratamiento estable con lopinavir/ritonavir, inmediatamente antes y durante las 12 siguientes a la administración de una dosis de lopinavir/ritonavir de 400/100 mg. Para lograr el segundo objetivo se realizó un análisis farmacocinético no compartimental mediante el programa informático WinNonlin (Versión 2.0; Pharsight, Mountain View, CA). El modelo farmacocinético poblacional simultáneo para ritonavir y lopinavir se desarrolló mediante el programa informático NONMEM.Resultados: La variabilidad interindividual de la concentración valle de los ITINAN e IP se estimó en aproximadamente el 50% (coeficiente de variación), y un 12% de los pacientes infectados por el VIH presentaban concentraciones valle de ITINAN o IP en plasma inferiores a la concentración mínima eficaz. Utilizando un análisis de datos no compartimental, los pacientes co-infectados por el VHC que tenían fibrosis hepática avanzada (F3-F4) mostraron un aumento significativo del volumen de distribución aparente de lopinavir así como una reducción del 50% en el aclaramiento y una mayor exposición a ritonavir que los pacientes no co-infectados o que los co-infectados sin fibrosis hepática avanzada. El mejor modelo farmacocinético poblacional que mejor describió la evolución temporal de las concentraciones de lopinavir y ritonavir fue un modelo monocompartimental con absorción y eliminación de primer orden. El análisis poblacional confirmó a reducción del aclaramiento de ritonavir en los pacientes co-infectados por el VHC en presencia de grados avanzados de fibrosis hepática. Además, el aclaramiento y el volumen de distribución aparentes de lopinavir se relacionaron de forma inversa con la concentración plasmática de alfa-1 glicoproteína ácida. Aunque la inhibición del aclaramiento de lopinavir por parte de ritonavir se describió en función del área bajo a curva de concentración-tiempo y de la concentración de ritonavir en cada punto de tiempo, la segunda estrategia proporcionó una mejor descripción de los datos observados. Utilizando un modelo de efecto máximo, se estimó que ritonavir podía ser capaz de inhibir por completo el aclaramiento de lopinavir (Imax 1), y la concentración de ritonavir necesaria para inhibir el aclaramiento de lopinavir fue de 0.36 mg/L. El modelo final fue posteriormente validado mediante simulaciones y en un grupo de pacientes no empleado para el desarrollo del modelo, sin objetivarse desviaciones sistemáticas y con una precisión adecuada.Objectives: 1.- To assess interindividual variability in trough concentrations in plasma of non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI) among HIV-infected adults as well as the proportion of patients with drug concentrations below the proposed minimum effective concentration in an outpatient routine clinical practice setting. 2.- To assess the influence of hepatitis C virus (HCV) co-infection and the extent of liver fibrosis on lopinavir and ritonavir pharmacokinetics in HIV-infected subjects without evident liver function impairment. 3.- To develop and validate a simultaneous population pharmacokinetic model for lopinavir and ritonavir in a population of HIV-infected adults. The model sought was to incorporate patient characteristics influencing variability in drug concentration and the interaction between the lopinavir and ritonavirMethods: To achieve the first objective, a cross-sectional study was performed. Trough concentration of NNRTI and PI in plasma was determined in patients who consecutively attended the HIV Unit of the Hospital Universitari Germans Trias i Pujol during a two weeks period for routine outpatient blood tests and who were receiving antiretroviral therapy which included NNRTI or PI. To achieve the second and third objectives, lopinavir and ritonavir concentrations in plasma were determined in a group of patients on stable therapy with lopinavir/ritonavir immediately before and during 12 hours following the administration of a lopinavir/ritonavir 400/100 mg dose. To reach the second objective, a pharmacokinetic analysis was performed using a non-compartmental approach by means of Winnonlin (Version 2.0; Pharsight, Mountain View, CA). Population analysis was performed using non-linear effects modeling (NONMEM, version V)Results: Interindividual variability in NNRTI and PI plasma concentrations was approximately 50% (coefficient of variation), and12% of the patients showed drug concentrations below the minimum effective concentration. Using a non-compartmental pharmacokinetic analysis, HCV co-infected patients who had advanced liver fibrosis (F3-F4) showed a significant increase in lopinavir apparent volume of distribution as well as a reduction of 50% in ritonavir clearance and an increase in ritonavir exposure compared with not co-infected patients or with co-infected patients without advanced liver fibrosis. The best population pharmacokinetic model which described the time course of lopinavir and ritonavir concentrations was a monocompartmental model with first order absorption and elimination. The population analysis confirmed the reduction in ritonavir clearance in HCV co-infected patients with advanced liver fibrosis. In addition, lopinavir clearance and volume of distribution were inversely correlated to concentration of &#945;1-acid glycoprotein in plasma. Although, the inhibition of lopinavir clearance by ritonavir was assumed to be dependent on ritonavir area under the time-concentration curve or on ritonavir concentration at each time point, the second strategy resulted in a better description of the observed data. Using a maximum effect equation, it was estimated that lopinavir metabolism could be completely inhibited at high ritonavir concentrations (Imax 1), and the estimated ritonavir concentration necessary for producing half-inhibition of lopinavir CL/F was 0.36 mg/L. The population pharmacokinetic model was validated by means of simulations in a set of patients not included during the model-building step, showing absence of evident bias and good precision

Farmacocinética poblacional de Lopinavir y Ritonavir en pacientes adultos infectados por el VIH

Descripció del recurs: 25 gener 2011Objetivos: 1.- Determinar la variabilidad interindividual de la concentración valle en plasma de los fármacos inhibidores de la transcriptasa inversa no análogos de los nucleósidos (ITINAN) y de los inhibidores de la proteasa (IP) del virus de la inmunodeficiencia humana (VIH), así como la proporción de pacientes infectados por el VIH en tratamiento antirretroviral con concentraciones valle de los fármacos por debajo de la concentración mínima eficaz en la practica clínica habitual. 2.- Evaluar la influencia de la co-infección por el virus de la hepatitis C (VHC) y el grado de fibrosis hepática asociado a la misma en la exposición a lopinavir y ritonavir en un grupo de pacientes infectados por el VIH sin evidencia de insuficiencia hepática. 3.- Desarrollar y validar un modelo farmacocinético poblacional simultáneo para lopinavir y ritonavir incluyendo las características individuales que explican parte de la variabilidad cinética de los fármacos observada en la práctica clínica así como la interacción entre lopinavir y ritonavir. Métodos: Para alcanzar el primer objetivo de realizó un estudio transversal en el que se determinó la concentración valle de los ITINAN e IP en todos los pacientes que acudieron a a unidad de VIH del Hospital Universitari Germans Trias i Pujol durante un periodo de dos semanas. Para alcanzar el segundo y tercer objetivos se realizó un estudio en el que se determinó la concentración de lopinavir y ritonavir en plasma en un grupo de pacientes en tratamiento estable con lopinavir/ritonavir, inmediatamente antes y durante las 12 siguientes a la administración de una dosis de lopinavir/ritonavir de 400/100 mg. Para lograr el segundo objetivo se realizó un análisis farmacocinético no compartimental mediante el programa informático WinNonlin (Versión 2.0; Pharsight, Mountain View, CA). El modelo farmacocinético poblacional simultáneo para ritonavir y lopinavir se desarrolló mediante el programa informático NONMEM. Resultados: La variabilidad interindividual de la concentración valle de los ITINAN e IP se estimó en aproximadamente el 50% (coeficiente de variación), y un 12% de los pacientes infectados por el VIH presentaban concentraciones valle de ITINAN o IP en plasma inferiores a la concentración mínima eficaz. Utilizando un análisis de datos no compartimental, los pacientes co-infectados por el VHC que tenían fibrosis hepática avanzada (F3-F4) mostraron un aumento significativo del volumen de distribución aparente de lopinavir así como una reducción del 50% en el aclaramiento y una mayor exposición a ritonavir que los pacientes no co-infectados o que los co-infectados sin fibrosis hepática avanzada. El mejor modelo farmacocinético poblacional que mejor describió la evolución temporal de las concentraciones de lopinavir y ritonavir fue un modelo monocompartimental con absorción y eliminación de primer orden. El análisis poblacional confirmó a reducción del aclaramiento de ritonavir en los pacientes co-infectados por el VHC en presencia de grados avanzados de fibrosis hepática. Además, el aclaramiento y el volumen de distribución aparentes de lopinavir se relacionaron de forma inversa con la concentración plasmática de alfa-1 glicoproteína ácida. Aunque la inhibición del aclaramiento de lopinavir por parte de ritonavir se describió en función del área bajo a curva de concentración-tiempo y de la concentración de ritonavir en cada punto de tiempo, la segunda estrategia proporcionó una mejor descripción de los datos observados. Utilizando un modelo de efecto máximo, se estimó que ritonavir podía ser capaz de inhibir por completo el aclaramiento de lopinavir (Imax 1), y la concentración de ritonavir necesaria para inhibir el aclaramiento de lopinavir fue de 0.36 mg/L. El modelo final fue posteriormente validado mediante simulaciones y en un grupo de pacientes no empleado para el desarrollo del modelo, sin objetivarse desviaciones sistemáticas y con una precisión adecuada.Objectives: 1.- To assess interindividual variability in trough concentrations in plasma of non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI) among HIV-infected adults as well as the proportion of patients with drug concentrations below the proposed minimum effective concentration in an outpatient routine clinical practice setting. 2.- To assess the influence of hepatitis C virus (HCV) co-infection and the extent of liver fibrosis on lopinavir and ritonavir pharmacokinetics in HIV-infected subjects without evident liver function impairment. 3.- To develop and validate a simultaneous population pharmacokinetic model for lopinavir and ritonavir in a population of HIV-infected adults. The model sought was to incorporate patient characteristics influencing variability in drug concentration and the interaction between the lopinavir and ritonavir Methods: To achieve the first objective, a cross-sectional study was performed. Trough concentration of NNRTI and PI in plasma was determined in patients who consecutively attended the HIV Unit of the Hospital Universitari Germans Trias i Pujol during a two weeks period for routine outpatient blood tests and who were receiving antiretroviral therapy which included NNRTI or PI. To achieve the second and third objectives, lopinavir and ritonavir concentrations in plasma were determined in a group of patients on stable therapy with lopinavir/ritonavir immediately before and during 12 hours following the administration of a lopinavir/ritonavir 400/100 mg dose. To reach the second objective, a pharmacokinetic analysis was performed using a non-compartmental approach by means of Winnonlin (Version 2.0; Pharsight, Mountain View, CA). Population analysis was performed using non-linear effects modeling (NONMEM, version V) Results: Interindividual variability in NNRTI and PI plasma concentrations was approximately 50% (coefficient of variation), and12% of the patients showed drug concentrations below the minimum effective concentration. Using a non-compartmental pharmacokinetic analysis, HCV co-infected patients who had advanced liver fibrosis (F3-F4) showed a significant increase in lopinavir apparent volume of distribution as well as a reduction of 50% in ritonavir clearance and an increase in ritonavir exposure compared with not co-infected patients or with co-infected patients without advanced liver fibrosis. The best population pharmacokinetic model which described the time course of lopinavir and ritonavir concentrations was a monocompartmental model with first order absorption and elimination. The population analysis confirmed the reduction in ritonavir clearance in HCV co-infected patients with advanced liver fibrosis. In addition, lopinavir clearance and volume of distribution were inversely correlated to concentration of α1-acid glycoprotein in plasma. Although, the inhibition of lopinavir clearance by ritonavir was assumed to be dependent on ritonavir area under the time-concentration curve or on ritonavir concentration at each time point, the second strategy resulted in a better description of the observed data. Using a maximum effect equation, it was estimated that lopinavir metabolism could be completely inhibited at high ritonavir concentrations (Imax 1), and the estimated ritonavir concentration necessary for producing half-inhibition of lopinavir CL/F was 0.36 mg/L. The population pharmacokinetic model was validated by means of simulations in a set of patients not included during the model-building step, showing absence of evident bias and good precision

P-glycoprotein (ABCB1) activity decreases raltegravir disposition in primary CD4+P-gp high cells and correlates with HIV-1 viral load

To evaluate the role of P-glycoprotein (P-gp) and multidrug-resistant-protein 1 (MRP1) on raltegravir intracellular drug disposition in CD4+ T cells, investigate the effect of HIV-1 infection on P-gp expression and correlate HIV-1 viraemia with P-gp activity in primary CD4+ T cell subsets. The cellular accumulation ratio of [ 3 H]raltegravir was quantified in CD4+ T cell lines overexpressing either P-gp (CEM-P-gp) or MRP1 (CEM-MRP1) and in primary CD3+CD4+ T cells with high (P-gp high) and low P-gp activity (P-gp low); inhibition of efflux transporters was confirmed by the intracellular retention of calcein-AM. The correlation of P-gp activity with HIV-1 viraemia was assessed in naive and memory T cell subsets from 21 HIV-1-infected treatment-naive subjects. [ 3 H]Raltegravir cellular accumulation ratio decreased in CEM-P-gp cells (P < 0.0001). XR9051 (a P-gp inhibitor) and HIV-1 PIs reversed this phenomenon. Primary CD4+P-gp high cells accumulated less raltegravir (38.4% ± 9.6%) than P-gp low cells, whereas XR9051 also reversed this effect. In vitro HIV-1 infection of PBMCs and stimulation of CD4+ T cells increased P-gp mRNA and P-gp activity, respectively, while primary CD4+P-gp high T cells sustained a higher HIV-1 replication than P-gp low cells. A significant correlation between HIV-1 viraemia and P-gp activity was found in different CD4+ T cell subsets, particularly memory CD4+ T cells (r = 0.792, P < 0.0001). Raltegravir is a substrate of P-gp in CD4+ T cells. Primary CD4+P-gp high T cells eliminate intracellular raltegravir more readily than P-gp low cells and HIV-1 viraemia correlates with P-gp overall activity. Specific CD4+P-gp high T cell subsets could facilitate the persistence of viral replication in vivo and ultimately promote the appearance of drug resistance

Introduction: New Perspectives on the Irish Literary Revival

Included in tex

Etravirine pharmacokinetics in HIV-infected pregnant women

CLINICAL TRIAL REGISTRATION: The IMPAACT protocol P1026s and PANNA study are registered at ClinicalTrials.gov under NCT00042289 and NCT00825929.Altres ajuts: National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) UM1AI068632 (IMPAACT LOC), UM1AI068616 (IMPAACT SDMC) i UM1AI106716 (IMPAACT LC)BACKGROUND: The study goal was to describe etravirine pharmacokinetics during pregnancy and postpartum in HIV-infected women. METHODS: IMPAACT P1026s and PANNA are on-going, non-randomized, open-label, parallel-group, multi-center phase-IV prospective studies in HIV-infected pregnant women. Intensive steady-state 12-h pharmacokinetic profiles were performed from 2nd trimester through postpartum. Etravirine was measured at two labs using validated ultra performance liquid chromatography (detection limits: 0.020 and 0.026 mcg/mL). RESULTS: Fifteen women took etravirine 200 mg twice-daily. Etravirine AUC0-12 was higher in the 3rd trimester compared to paired postpartum data by 34% (median 8.3 vs. 5.3 mcg*h/mL, p = 0.068). Etravirine apparent oral clearance was significantly lower in the 3rd trimester of pregnancy compared to paired postpartum data by 52% (median 24 vs. 38 L/h, p = 0.025). The median ratio of cord blood to maternal plasma concentration at delivery was 0.52 (range: 0.19-4.25) and no perinatal transmission occurred. CONCLUSION: Etravirine apparent oral clearance is reduced and exposure increased during the third trimester of pregnancy. Based on prior dose-ranging and safety data, no dose adjustment is necessary for maternal health but the effects of etravirine in utero are unknown. Maternal health and infant outcomes should be closely monitored until further infant safety data are available