RESUMEN
This study assessed the relationship between dose and plasma concentration following administration of treprostinil sodium infusion therapy in pulmonary arterial hypertension patients. This was a multicenter, open-label, multiple-cohort, steady-state, pharmacokinetic study in subjects with pulmonary arterial hypertension receiving treprostinil by continuous intravenous or subcutaneous infusion at doses between 10 and 125 ng/kg/min. A blood sample was obtained from each patient at steady state and analyzed via a liquid chromatography/tandem mass spectrometry method. Forty-nine subjects receiving treprostinil were enrolled. Treprostinil doses ranged from 12.1 to 125 ng/kg/min; treprostinil plasma concentrations ranged from 14.9 to 18 248 pg/mL. Linear regression analysis revealed a correlation between treprostinil dose and treprostinil plasma concentration with an R2 value of 0.561. Using a power model to assess dose proportionality, the estimated nonproportionality parameter was 0.641 (95% confidence interval: 0.083-1.199), reflecting consistency with dose proportionality. Subset linear regression analysis, which excluded 2 subjects with anomalous treprostinil plasma concentrations, increased the R2 value to 0.796. Using a power model to assess dose proportionality of this subset, the estimated nonproportionality parameter was 0.941 (95% confidence interval: 0.809-1.073). This study supports previous findings of linearity at lower doses up to 15 ng/kg/min and demonstrates linearity at treprostinil doses up to 125 ng/kg/min.
Asunto(s)
Antihipertensivos/farmacocinética , Epoprostenol/análogos & derivados , Hipertensión Pulmonar/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticoagulantes/administración & dosificación , Anticoagulantes/uso terapéutico , Antihipertensivos/administración & dosificación , Bloqueadores de los Canales de Calcio/administración & dosificación , Bloqueadores de los Canales de Calcio/uso terapéutico , Cromatografía Liquida , Digoxina/administración & dosificación , Digoxina/uso terapéutico , Diuréticos/administración & dosificación , Diuréticos/uso terapéutico , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Epoprostenol/administración & dosificación , Epoprostenol/sangre , Epoprostenol/farmacocinética , Femenino , Humanos , Hipertensión Pulmonar/metabolismo , Infusiones Intravenosas , Inyecciones Subcutáneas , Masculino , Espectrometría de Masas , Persona de Mediana Edad , Oxígeno/administración & dosificación , Oxígeno/uso terapéutico , Inhibidores de Fosfodiesterasa 5 , Análisis de RegresiónRESUMEN
A general and novel solution to the synthesis of biologically important stable analogues of prostacyclin PGI(2), namely benzindene prostacyclins, has been achieved via the stereoselective intramolecular Pauson-Khand cyclization (PKC). This work illustrates for the first time the synthetic utility and reliability of the asymmetric PKC route for synthesis and subsequent manufacture of a complex drug substance on a multikilogram scale. The synthetic route surmounts issues of individual step stereoselectivity and scalability. The key step in the synthesis involves efficient stereoselection effected in the PKC of a benzoenyne under the agency of the benzylic OTBDMS group, which serves as a temporary stereodirecting group that is conveniently removed via benzylic hydrogenolysis concomitantly with the catalytic hydrogenation of the enone PKC product. Thus the benzylic chiral center dictates the subsequent stereochemistry of the stereogenic centers at three carbon atoms (C(3a), C(9a), and C(1)).