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1.
J Clin Pharmacol ; 55(10): 1093-100, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25903940

RESUMEN

Suvorexant is an orexin receptor antagonist for treating insomnia. The maximum approved dose in the United States and Japan is 20 mg. We evaluated suvorexant effects on respiration during sleep in a randomized, double-blind, 3-period crossover study of healthy adult men (n = 8) and women (n = 4) ≤ 50 years old who received single-dose suvorexant 40 mg, 150 mg, and placebo. Respiration during sleep was measured by oxygen saturation (SpO2 , primary end point) and the Apnea Hypopnea Index (AHI). The study was powered to detect a reduction greater than 5% in SpO2 . There was no effect of suvorexant on mean SpO2 during sleep. The mean (90%CI) treatment differences versus placebo were -0.3 (-1.2-0.6) for 40 mg and 0.0 (-0.9-0.9) for 150 mg. There were no dose-related trends in individual SpO2 values. Mean SpO2 was >96% for all treatments during total sleep time and during both non-REM and REM sleep. There was no effect of either suvorexant dose on AHI. The mean (90%CI) treatment differences versus placebo were 0.8 (-0.7-2.3) for 40 mg and -0.2 (-1.7-1.3) for 150 mg. Suvorexant was generally well tolerated; there were no serious adverse experiences or discontinuations. These data from healthy subjects suggest that suvorexant lacks clinically important respiratory effects during sleep at doses greater than the maximum recommended dose for treating insomnia.


Asunto(s)
Azepinas/farmacología , Antagonistas de los Receptores de Orexina/farmacología , Respiración/efectos de los fármacos , Fármacos Inductores del Sueño/farmacología , Triazoles/farmacología , Adulto , Azepinas/efectos adversos , Azepinas/sangre , Azepinas/farmacocinética , Estudios Cruzados , Método Doble Ciego , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Antagonistas de los Receptores de Orexina/efectos adversos , Antagonistas de los Receptores de Orexina/sangre , Antagonistas de los Receptores de Orexina/farmacocinética , Oximetría , Oxígeno/metabolismo , Polisomnografía , Fármacos Inductores del Sueño/efectos adversos , Fármacos Inductores del Sueño/sangre , Fármacos Inductores del Sueño/farmacocinética , Triazoles/efectos adversos , Triazoles/sangre , Triazoles/farmacocinética
2.
Cancer Chemother Pharmacol ; 70(1): 177-82, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22669570

RESUMEN

PURPOSE: Ridaforolimus, a potent inhibitor of the mammalian target of rapamycin (mTOR), is under development for the treatment for solid tumors. This open-label, randomized, 3-period crossover study investigated the effect of food on the pharmacokinetics of ridaforolimus 40 mg as well as safety and tolerability of the study medication. METHODS: Ridaforolimus was administered to 18 healthy, male subjects (mean age 36.4 years) in the fasted state, following ingestion of a light breakfast, and following a high-fat breakfast. Whole blood samples were collected from each subject pre-dose and 1, 2, 3, 4, 6, 8, 24, 48, 72, 96, and 168 h post-dose. RESULTS: The geometric mean (95 % confidence interval, CI) fasted blood area under the curve (AUC(0-∞)) and maximum concentration (C(max)) were 1940 (1510, 2500) ng h/mL and 116 (87, 156) ng/mL, respectively, and median time to C(max) (T(max)) and average apparent terminal half-life (t(1/2)) were 6.0 and 64.5 h, respectively. Both T(max) and t(1/2) were similar in the fasted and fed states. With a light breakfast, the geometric mean intra-individual ratios (GMRs) for AUC(0-∞) and C(max) (fed/fasted) and 90 % CIs were 1.06 (0.85, 1.32) and 1.15 (0.83, 1.60); following a high-fat breakfast, the AUC(0-∞) and C(max) GMRs (90 % CI) were 1.46 (1.18, 1.81) and 1.12 (0.81, 1.53), respectively. CONCLUSIONS: Increases in ridaforolimus exposure following both the light and high-fat breakfasts were not considered to be clinically meaningful. Ridaforolimus was generally well tolerated, and there were no discontinuations due to drug-related AEs. Ridaforolimus should be given without regard to food.


Asunto(s)
Grasas de la Dieta/farmacología , Interacciones Alimento-Droga , Sirolimus/análogos & derivados , Adulto , Área Bajo la Curva , Disponibilidad Biológica , Estudios Cruzados , Grasas de la Dieta/administración & dosificación , Ayuno , Humanos , Masculino , Tasa de Depuración Metabólica , Sirolimus/efectos adversos , Sirolimus/farmacocinética , Estomatitis/inducido químicamente , Factores de Tiempo , Tonsilitis/inducido químicamente , Adulto Joven
3.
Cancer Chemother Pharmacol ; 69(5): 1247-53, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22290273

RESUMEN

PURPOSE: Ridaforolimus is an inhibitor of the mammalian target of rapamycin protein, with potent activity in vitro and in vivo. Ridaforolimus is primarily cleared by metabolism via cytochrome P450 3A (CYP3A) and is a P-glycoprotein (P-gp) substrate. Since potential exists for ridaforolimus to be co-administered with agents that affect CYP3A and P-gp activity, this healthy volunteer study was conducted to assess the effect of rifampin or ketoconazole on ridaforolimus pharmacokinetics. METHODS: Part 1: single-dose ridaforolimus 40 mg followed by rifampin 600 mg daily for 21 days and singledose ridaforolimus 40 mg on day 14. Part 2: single-dose ridaforolimus 5 mg followed by ketoconazole 400 mg daily for 14 days and single-dose ridaforolimus 2 mg on day 2. RESULTS: Part 1: the geometric mean ratios (GMRs) (90% confidence interval [CI]) for ridaforolimus area under the concentration-time curve to the last time point with a detectable blood concentration (AUC0-∞) and maximum blood concentration (Cmax) (rifampin + ridaforolimus/ ridaforolimus) were 0.57 (0.41, 0.78) and 0.66 (0.49, 0.90), respectively. Both time to Cmax (Tmax) and apparent halflife (t1/2) were similar. Part 2: the GMRs (90% CI) based on dose-normalized AUC0-∞ and Cmax (ketoconazole + ridaforolimus/ridaforolimus alone) were 8.51 (6.97, 10.39) and 5.35 (4.40, 6.52), respectively. Ridaforolimus apparent t1/2 was *1.5-fold increased for ketoconazole ? ridaforolimus; however, Tmax values were similar. CONCLUSIONS: Rifampin and ketoconazole both have a clinically meaningful effect on the pharmacokinetics of ridaforolimus.


Asunto(s)
Antineoplásicos/farmacocinética , Cetoconazol/farmacología , Rifampin/farmacología , Sirolimus/análogos & derivados , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/efectos de los fármacos , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Adulto , Antineoplásicos/administración & dosificación , Área Bajo la Curva , Citocromo P-450 CYP3A/efectos de los fármacos , Citocromo P-450 CYP3A/metabolismo , Interacciones Farmacológicas , Semivida , Humanos , Cetoconazol/administración & dosificación , Masculino , Persona de Mediana Edad , Rifampin/administración & dosificación , Sirolimus/administración & dosificación , Sirolimus/farmacocinética , Adulto Joven
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