Development and validation of equilibrium dialysis UHPLC-MS/MS measurement procedures for total and unbound concentrations of bictegravir, dolutegravir, darunavir and doravirine in human plasma. Application to patients with HIV.

BACKGROUND: Fixed-dose combinations of antiretroviral drugs are commonly used to treat HIV infection and therapeutic monitoring is not part of routine clinical practice. However, drug concentrations monitoring might have role in different clinical scenarios as well as for research purposes. This study aimed to develop and validate UHPLC-MS/MS procedures for measuring total and unbound concentrations of bictegravir, dolutegravir, darunavir and doravirine in human plasma. MATERIAL AND METHODS: Equilibrium dialysis preceded sample preparation (based on protein precipitation) for measuring unbound antiretroviral concentrations. Chromatographic separations were achieved on an Acquity®-UPLC® HSS™-T3 column (50 mm × 2.1 mm; 1.8 µm) using a non-linear water/acetonitrile gradient containing 0.1 % formic acid at a 0.5 mL/min flow rate. Antiretrovirals were detected by tandem mass spectrometry in positive electrospray ionisation and multiple reaction monitoring modes. RESULTS: No significant interferences or carry-over were observed. Imprecisions, absolute relative biases, normalised matrix effects and recoveries were ≤15.0 %, ≤11.1 %, (94.7-104.1)% and (96.7-105.5)%, respectively. Non-linear measuring intervals were observed between (25-10,000) µg/L for total/plasma dialysate concentrations and linearity schemes (1.00-100) µg/L for buffer dialysate concentrations. CONCLUSIONS: The UHPLC-MS/MS procedures developed could be used for research purposes and therapeutic drug monitoring of antiretrovirals in routine clinical practice.

Etravirina en pacientes ampliamente pretratados / Etravirine in highly treatment-experienced patients

Etravirina (ETR) se ha mostrado eficaz en pacientes multitratados con fallos virológicos previos y mutaciones de resistencia a varias familias de fármacos antirretrovirales. La mayor evidencia surge de los estudios DUET. Éstos son 2 ensayos clínicos multicéntricos idénticos, aleatorizados y doble ciego, que incluyeron alrededor de 1.200 pacientes, donde se observó una respuesta virológica e inmunológica superior a placebo y que se tradujo en una reducción en la incidencia de ingresos hospitalarios y de progresión a sida/muerte. Además, ETR fue muy bien tolerado en estos pacientes. El efecto adverso más frecuente fue el exantema que, generalmente, fue leve o moderado y únicamente obligó a suspender el tratamiento en el 2% de los pacientes. No hubo diferencias en cuanto a toxicidades gastrointestinales, hepáticas o lipídicas, comparado con la rama placebo. El desarrollo reciente de nuevos fármacos permite disponer hoy de pautas activas eficaces para pacientes multitratados. El estudio TRIO ha evaluado la eficacia y tolerabilidad de una de las pautas más utilizadas actualmente en la práctica habitual: ETR/raltegravir/darunavir/r, con excelentes resultados de respuesta virológica e inmunológica (el 86% de carga viral < 50 copias y CD4 +108 a las 48 semanas) y, al mismo tiempo, una muy buena tolerabilidad. ETR es eficaz y bien tolerada y es el primer inhibidor de la transcriptasa inversa no análogo de nucleósidos (ITINAN) que permite el uso secuencial de fármacos de esta familia, gracias a su elevada barrera genética comparando con los ITINAN de primera generación. Además, su larga vida media permite su administración una vez al día en caso de que los pacientes necesitaran una pauta qd

Etravirine (ETR) has demonstrated efficacy in patients with multiple prior treatments with prior virological failure and resistance mutations to various families of antiretroviral drugs. Most of the evidence concerning this drug has been drawn from the DUET studies, consisting of two multicenter, randomized, double-blind clinical trials with identical designs that included 1,200 patients. These trials showed that ETR obtained a superior virological and immunological response to placebo, reducing the incidence of hospital admissions and progression to AIDS/death. The most frequent adverse effect was rash, which was generally mild to moderate and required treatment discontinuation in only 2%. There were no differences in gastrointestinal, liver or lipid toxicities compared with the placebo arm. Because of the recent development of new drugs, effective regimens are now available for multi-treated patients. The TRIO study evaluated the efficacy and tolerability of one of the regimens most widely used today (ETR/raltegravir/darunavir/r) with excellent virological and immunological response (86% of viral load < 50 copies and CD4 +108 at 48 weeks) and excellent tolerance. ETR is effective and well tolerated and is the first non-nucleoside reverse transcriptase inhibitor (NNRTI) that allows the sequential use of drugs in this family, due to its high genetic barrier compared with firstgeneration NNRTI. Moreover, its long half-life allows once daily administration in patients requiring a QD régimen