Efecto de las concentraciones de ritonavir en la farmacocinética de atazanavir: aplicación de técnicas de modelado y simulación farmacocinético poblacional /

"Introduccion: La infeccion por VIH se ha convertido en una enfermedad cronica debido principalmente a la introduccion de la terapia antirretroviral. Atazanavir(ATV) se administra potenciado con ritonavir (RTV), siendo la dosis habitual 300mg de ATV y 100mg de RTV una vez al dia, aunque tambien se puede administrar sin potenciar. Actualmente la simplificacion de los tratamientos antirretrovirales es uno de los objetivos mas importantes para facilitar el cumplimiento de la terapia y evitar el fallo terapeutico. Hipotesis general: Se pueden optimizar los regimenes de atazanavir recomendados actualmente. Objetivos: Evaluar diferentes regimenes de dosificacion de atazanavir comparando sus concentraciones con las de los regimenes aprobados por las agencias regulatorias. Estudio ""in vivo"": Evaluar la farmacocinetica, tolerabilidad y seguridad de 300mg de ATV potenciado con 100mg o 50mg de RTV, administrado una vez al dia, en el estado de equilibrio estacionario. Estudio ""In numero"": Desarrollar un modelo farmacocinetico poblacional simultaneo que incorpore el efecto de RTV en el aclaramiento de ATV y predecir las concentraciones de ATV en diferentes regimenes de dosificacion en pacientes infectados por el VIH-1. Metodos: Estudio ""in vivo"": Estudio prospectivo, simple-ciego, de dosis multiples, cruzado y aleatorizado. Trece hombres sanos VIH-1-negativos recibieron ATV (300mg) y RTV 100mg o 50mg durante 10 dias (15 dias de lavado). A dia 10 se determinaron las concentraciones plasmaticas de ATV y RTV durante 24h. Se compararon los parametros farmacocineticos individuales log-transformados entre tratamientos y se calculo la diferencia entre los mismos en escala logaritmica y los intervalos de confianza del 95%. Se midieron y compararon los niveles de colesterol total y LDL, trigliceridos, glucosa y bilirrubina al inicio y al final de cada periodo(Wilcoxon-rank test). Se registraron los acontecimientos adversos. Estudio ""in numero"": Estudio transversal que incluyo 83 adultos VIH-1+ tratados con ATV 400mg o ATV 300mg/RTV 100mg una vez al dia. Se determinaron las concentraciones en plasma de ambos farmacos. Se construyo un modelo farmacocinetico y se simularon seis escenarios de dosificacion utilizando la aproximacion poblacional no lineal de efectos mixtos. Resultados: Estudio ""in vivo"": La Cmax y AUC0-24 de RTV fueron menores tras 50mg que 100mg (ratio de media geometrica [GMR 95% intervalo de confianza], 0.40 [0.31-0.51] y 0.35 [0.29-0.42], respectivamente). No se observaron diferencias en la exposicion a ATV con RTV 50mg o 100mg (GMR, Cmax, 1.00[0.79-1.28]; AUC0-24, 0.98 [0.79-1.21]). La concentracion valle de ATV fue >0.15mg/L en todos los voluntarios. El colesterol total y LDL aumentaron 0.40 mmol /L (p = 0.01) y 0.37 mmol/L (p = 0.003) respectivamente en el periodo RTV 100mg; no hubo cambios significativos en el periodo RTV 50mg. Al decimo dia la bilirrubina aumento levemente pero sin diferencias entre los tratamientos. Estudio ""in numero"": Un modelo monocompartimental simultaneo describio la farmacocinetica de RTV y ATV, mostrando una inhibicion exponencial directa de RTV en el aclaramiento de ATV, lo que explico el 17.5% de la variabilidad. Una concentracion media de RTV=0.63 mg/L predice un 18% de disminucion en el aclaramiento de ATV. El porcentaje de pacientes simulados con concentraciones de ATV al final de intervalo posologico fuera del rango 0.15-0.85mg/L favorece los regimenes de una vez al dia (ATV 400mg, ATV 300mg/RTV 100mg, ATV 300mg/RTV 50mg, ATV 200/RTV 100mg) con respecto a los regimenes de dos veces al dia no potenciados (ATV 300mg, ATV 200mg). Conclusiones: Ambos estudios sugieren que una reduccion en la dosis de potenciacion de ritonavir de 100 a 50mg beneficiaria a los pacientes disminuyendo la incidencia de eventos adversos sin disminuir la exposicion a ATV. Ademas, el estudio ""in numero"" favorece la bajada de la dosis de ATV a 200mg potenciada con 100mg de RTV. Introduction: HIV infection has become a chronic and manageable condition mainly due to the successful introduction of triple antiretroviral therapy. Atazanavir(ATV) is a protease inhibitor, with a good lipid profile and high genetic barrier, but undergoes first pass metabolism, which causes low bioavailability. Because of that, atazanavir is usually boosted with ritonavir (RTV), a CYP3A4 inhibitor, being the standard dose: ATV 300mg/RTV 100mg once a day, although ATV can also be administered unboosted. Simplification of antiretroviral treatment is currently one of the most important objectives to facilitate therapy compliance and avoid treatment failure. General hypothesis: ATV actual dose regimens can be optimized. Objectives: To evaluate different dose regimens of atazanavir and compare their concentrations with those from the approved by the regulatory agencies. ""in vivo"" study: To evaluate the pharmacokinetics, tolerability, and safety of ATV 300mg boosted with RTV 100mg or 50mg, both once-daily, at steady-state. ""in numero"" study: To develop a simultaneous population pharmacokinetic model for ATV incorporating the effect of RTV on clearance to predict ATV concentrations under different dosing regimens in HIV-1-infected patients. Methods: ""in vivo"" study: This was a single-blind, multiple-dose, crossover, sequence-randomized trial. Thirteen healthy HIV-1-negative men received witnessed once-daily doses of ATV (300mg) and RTV 100mg or 50mg for 10 days (15-day washout). ATV and RTV plasma concentrations were determined for 24h on day 10. Log-transformed individual pharmacokinetic parameters were compared between treatments (analysis of variance); the difference between treatments on the log-scale and 95% confidence intervals were calculated. Fasting cholesterol, triglycerides, glucose and bilirubin plasma levels were measured at the beginning and end of each period and compared (Wilcoxon signed-rank test). Adverse events were recorded. ""in numero"" study: A cross-sectional study was carried out in 83 HIV-1-infected adults taking ATV 400mg or ATV 300mg/RTV 100mg both once daily. Demographic and clinical characteristics were registered and blood samples collected to measure drug concentrations. A population pharmacokinetic model was constructed using nonlinear mixed-effects modeling and used to simulate six dosing scenarios. Results: ""in vivo"" study: RTV Cmax and AUC0-24 were lower after the 50-mg booster dose than after 100mg (geometric mean ratio [GMR 95% confidence interval], 0.40 [0.31–0.51] and 0.35 [0.29–0.42], respectively). No differences were observed in ATV exposure with RTV 50 or 100mg (GMR, Cmax, 1.00 [0.79–1.28]; AUC0-24, 0.98 [0.79–1.21]). ATV trough concentration was >0.15 mg/L in all volunteers. Total and LDL cholesterol increased 0.40 mmol/L (p=0.01) and 0.37 mmol/L (p=0.003) in the 100mg period; there were no significant changes on 50mg. Mild increases in bilirubin were detected on day 10 after both treatments without differences between treatments. ""in numero"" study: A one-compartmental model described the pharmacokinetics of RTV and ATV simultaneously, showing exponential, direct inhibition of ATV clearance according to the RTV plasma concentration, which explained 17.5% of the variability. A mean RTV plasma concentration of 0.63 mg/L predicted an 18% decrease in ATV clearance. The percentages of patients with an end-of-dose-interval concentration of ATV below or above the minimum and maximum target concentrations of 0.15 mg/L and 0.85mg/L favored the selection of the simulated once-daily regimens (ATV 400mg, ATV 300mg/RTV 100mg, ATV 300mg/RTV 50mg, ATV 200mg/RTV 100mg) over the unboosted twice-daily regimens (ATV 300mg, ATV 200mg). Conclusions: The ""in vivo"" and ""in numero"" studies suggest that a reduction in RTV boosting dose from 100mg to 50mg would benefit the patients as the adverse events would decrease without decreasing atazanavir exposure. However, the ""in numero"" study favours the reduction in atazanavir to 200mg once daily boosted with 100mg of RTV. "