RESUMEN
Phosphodiesterase-5 (PDE-5) inhibitors and endothelin receptor antagonists (ERAs) are standard therapies for pulmonary arterial hypertension (PAH). The inter-individual variability of these pharmacokinetics is reported remarkably large, and therapeutic drug monitoring (TDM) can be useful to improve the likelihood of the desired therapeutic and safety outcomes. This study aimed to develop a LC-MS method to determine the concentrations of five PAH drugs (PDE-5 inhibitors: sildenafil and tadalafil, ERAs: bosentan, macitentan, and ambrisentan) from plasma samples using a simple process followed by a single mass spectrometric run, and to validate this approach through pharmacokinetic analyses in patients. A solid extraction method was used for sample preparation of the drugs from human plasma. The total run time for a single injection was within 10 min. The calibration curves for all drugs were linear, and the lower limits of quantitation were 1 (sildenafil), 2 (tadalafil), 5 (ambrisentan), and 10 ng/mL (bosentan, macitentan). The accuracy and precision values suggested that the assay had high accuracy and reliability. To prove the utility of this method, the plasma concentrations of the five PAH drugs were determined after their oral administration to nine PAH patients.
Asunto(s)
Antihipertensivos/análisis , Cromatografía Liquida/métodos , Antagonistas de los Receptores de Endotelina/análisis , Inhibidores de Fosfodiesterasa 5/análisis , Espectrometría de Masas en Tándem/métodos , Administración Oral , Adulto , Anciano , Antihipertensivos/administración & dosificación , Antihipertensivos/sangre , Antagonistas de los Receptores de Endotelina/administración & dosificación , Antagonistas de los Receptores de Endotelina/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de Fosfodiesterasa 5/administración & dosificación , Inhibidores de Fosfodiesterasa 5/sangre , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Reproducibilidad de los ResultadosRESUMEN
To elucidate whether the pharmacokinetics (PK) and pharmacodynamics (PD) of sildenafil are influenced differently when it is coadministered with bosentan (S+B) or with ambrisentan (S+A), we evaluated the PK and PD profiles of sildenafil before and after 4-5 weeks of S+A or S+B treatment in patients with pulmonary arterial hypertension. The area under the plasma concentration-time curve of sildenafil was significantly higher in S+A treatment than in S+B treatment (165.8 ngâ¢h/mL vs. 396.8 ngâ¢h/mL, P = 0.018) and the oral clearance of sildenafil was significantly lower after S+A treatment than after S+B treatment (120.6 L/h/kg vs. 50.4 L/h/kg, P = 0.018). In the PD study, incremental shuttle walking distance was superior during treatment with S+A than during treatment with S+B (S+B; 280 m vs. S+A; 340 m, P = 0.042). There were no concerns about safety with either combination therapy regime.