Pharmacokinetics of bosentan in routinely treated Japanese pediatric patients with pulmonary arterial hypertension

Abstract

  We evaluated the pharmacokinetics of routinely administered bosentan in 46 Japanese pediatric patients with pulmonary arterial hypertension. Plasma samples were taken twice corresponding to the peak and trough concentrations following repetitive oral administration. The population pharmacokinetic parameters of bosentan were estimated by use of the NONMEM program, where a one-compartment model with repetitive bolus dosing was parameterized in terms of the oral clearance (CL/F) and elimination rate constant (k). Polymorphisms of CYP3A5, SLCO1B1, SLCO1B3, and SLCO2B1 had no significant effect on the drug disposition. In addition, the pharmacokinetics of bosentan was not altered by coadministration of sildenafil and heart failure. On the other hand, weight (WT)-normalized values of CL/F were correlated negatively with age (AGE). The final population mean values of CL/F and k were estimated to be 0.409·(1–0.0377·(AGE–3.81))·WT L/hr and 0.175 hr^-1, respectively.