RESUMEN
Multipurpose technologies that simultaneously protect from sexually transmitted infections and unintended pregnancy are urgently needed. Pod-intravaginal rings (IVRs) formulated with the antiretroviral agents (ARVs) tenofovir, nevirapine, and saquinavir and the contraceptives etonogestrel and estradiol were evaluated in sheep. Steady-state concentrations were maintained for 28 days with controlled, sustained delivery. This proof-of-principle study demonstrates that pod IVRs can deliver three ARVs from different mechanistic classes and a progestin-estrogen combination over the wide range needed for putative preventative efficacy.
Asunto(s)
Antirretrovirales/farmacocinética , Anticonceptivos/farmacocinética , Dispositivos Intrauterinos Medicados , Adenina/administración & dosificación , Adenina/análogos & derivados , Adenina/farmacocinética , Administración Intravaginal , Animales , Antirretrovirales/administración & dosificación , Biopsia , Anticonceptivos/administración & dosificación , Desogestrel/administración & dosificación , Desogestrel/farmacocinética , Evaluación Preclínica de Medicamentos , Estradiol/administración & dosificación , Estradiol/farmacocinética , Femenino , Modelos Animales , Nevirapina/administración & dosificación , Nevirapina/farmacocinética , Organofosfonatos/administración & dosificación , Organofosfonatos/farmacocinética , Saquinavir/administración & dosificación , Saquinavir/farmacocinética , Enfermedades Virales de Transmisión Sexual/prevención & control , Ovinos , Tenofovir , Factores de TiempoRESUMEN
The effect of saquinavir-boosted ritonavir at therapeutic (1000/100 mg twice daily [bid]) and supratherapeutic (1500/100 mg bid) doses was evaluated in a double-blind, placebo- and positive-controlled (moxifloxacin 400 mg) 4-way crossover thorough QT/QTc study. Least squares mean estimated study-specific QTc (QTcS) change from dense predose baseline (ddQTcS(dense)) was the primary endpoint. Greatest mean increase in ddQTcS(dense) occurred 12 hours postdose for the 1000/100-mg group (18.9 ms) and 20 hours for the 1500/10-mg group (30.2 ms). The upper 1-sided 95% confidence interval was >20 ms from 2 to 20 hours postdose in both groups. ddQTcB(dense) and ddQTcF(dense) were similar to ddQTcS(dense). No QTcS, QTcF, or QTcB measurements were >500 ms. One participant receiving 1000/100 mg and 3 receiving 1500/100 mg had a maximum ddQTcS(dense) >60 ms. More participants with ≥1 adverse event received saquinavir/ritonavir. PubMed search and Roche postmarketing data did not reveal publications or reports directly presenting the effect of saquinavir on QT/QTc or causing torsade de pointes.
Asunto(s)
Inhibidores de la Proteasa del VIH/efectos adversos , Ritonavir/efectos adversos , Saquinavir/efectos adversos , Adolescente , Adulto , Compuestos Aza/efectos adversos , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Quimioterapia Combinada , Electrocardiografía , Femenino , Fluoroquinolonas , Inhibidores de la Proteasa del VIH/administración & dosificación , Humanos , Análisis de los Mínimos Cuadrados , Síndrome de QT Prolongado/inducido químicamente , Masculino , Persona de Mediana Edad , Moxifloxacino , Quinolinas/efectos adversos , Ritonavir/administración & dosificación , Saquinavir/administración & dosificación , Torsades de Pointes/inducido químicamente , Adulto JovenAsunto(s)
Uña de Gato , Inhibidores de la Proteasa del VIH , Interacciones de Hierba-Droga , Preparaciones de Plantas , Sulfato de Atazanavir , Uña de Gato/efectos adversos , Femenino , Inhibidores de la Proteasa del VIH/administración & dosificación , Inhibidores de la Proteasa del VIH/sangre , Inhibidores de la Proteasa del VIH/farmacocinética , Inhibidores de la Proteasa del VIH/uso terapéutico , Humanos , Tasa de Depuración Metabólica , Persona de Mediana Edad , Oligopéptidos/administración & dosificación , Oligopéptidos/sangre , Oligopéptidos/farmacocinética , Oligopéptidos/uso terapéutico , Preparaciones de Plantas/administración & dosificación , Preparaciones de Plantas/efectos adversos , Piridinas/administración & dosificación , Piridinas/sangre , Piridinas/farmacocinética , Piridinas/uso terapéutico , Ritonavir/administración & dosificación , Ritonavir/sangre , Ritonavir/farmacocinética , Ritonavir/uso terapéutico , Saquinavir/administración & dosificación , Saquinavir/sangre , Saquinavir/farmacocinética , Saquinavir/uso terapéuticoRESUMEN
The aim of this investigation was to develop novel oil-in-water (o/w) nanoemulsions containing Saquinavir (SQV), an anti-HIV protease inhibitor, for enhanced oral bioavailability and brain disposition. SQV was dissolved in different types of edible oils rich in essential polyunsaturated fatty acids (PUFA) to constitute the internal oil phase of the nanoemulsions. The external phase consisted of surfactants Lipoid-80 and deoxycholic acid dissolved in water. The nanoemulsions with an average oil droplet size of 100-200 nm, containing tritiated [(3)H]-SQV, were administered orally and intravenously to male Balb/c mice. The SQV bioavailability as well as distribution in different organ systems was examined. SQV concentrations in the systemic circulation administered in flax-seed oil nanoemulsions were threefold higher as compared to the control aqueous suspension. The oral bioavailability and distribution to the brain, a potential sanctuary site for HIV, were significantly enhanced with SQV delivered in nanoemulsion formulations. In comparing SQV in flax-seed oil nanoemulsion with aqueous suspension, the maximum concentration (C(max)) and the area-under-the-curve (AUC) values were found to be five- and threefold higher in the brain, respectively, suggesting enhanced rate and extent of SQV absorption following oral administration of nanoemulsions. The results of this study show that oil-in-water nanoemulsions made with PUFA-rich oils may be very promising for HIV/AIDS therapy, in particular, for reducing the viral load in important anatomical reservoir sites.