Population Pharmacokinetics of Sildenafil in Dogs With Naturally Occurring Pulmonary Hypertension.

Abstract

The pharmacokinetics of sildenafil are ill-defined in dogs with naturally occurring pulmonary hypertension (PH). Because the plasma concentrations of sildenafil have not been reported for dogs with this disease, this study aimed to describe the population pharmacokinetics of sildenafil in a sample of dogs with PH. Twenty client-owned dogs with spontaneous PH associated with diverse comorbidities and receiving orally administered sildenafil were enrolled in a prospective, open-label, steady-state population pharmacokinetic study. Dogs underwent a sparse-sampling blood collection protocol after the morning dose of sildenafil. Plasma sildenafil concentrations were determined using high-pressure liquid chromatography and mass spectrometry. Population pharmacokinetic analysis with nonlinear mixed effects modeling was performed, and selected covariates were evaluated in the model. Sildenafil was rapidly absorbed (absorption half-life 1.1 h) but variable (CV 94%) and reached maximal plasma concentrations at 2.51 h. The estimated elimination half-life was 2.9 h. However, substantial individual variability in pharmacokinetics of sildenafil was evident, unexplained by the covariates examined, and attributed primarily to the high variability in absorption. This finding supports the need for a large-scale study to identify the source of this variability to better guide therapy in poor responders to initial therapy with this drug.