The Effects of Epoprostenol on Drug Disposition I: A Pilot Study of the Pharmacokinetics of Digoxin with and without Epoprostenol in Patients with Congestive Heart Failure

The influence of epoprostenol on the pharmacokinetics of drugs administered concurrently to patients with congestive heart failure (CHF) receiving epoprostenol was evaluated as a secondary objective of a Phase II pilot study. A total of 278 blood samples were collected from 30 patients with end-stage CHF receiving conventional therapy alone or conventional therapy plus epoprostenol. Estimates of oral clearance (Cl), volume of distribution, and absorption rate constant of digoxin were generated from plasma digoxin concentrations using nonlinear mixed effects modeling, and the effect of epoprostenol on Cl of digoxin was evaluated by univariate analysis. Additional factors that were evaluated by univariate analysis included age, obesity, time since study entry, cardiac output, concomitant use of angiotensin-converting enzyme (ACE) inhibitor, concomitant dobutamine, and estimated creatinine clearance. Backward elimination was used to arrive at a final model that included concomitant epoprostenol as a covariate. The final model revealed an approximate 15% decrease in Cl of digoxin in response to short-term administration of epoprostenol that was no longer apparent by the end of the 12-week treatment phase. Simulations revealed that this effect, although statistically significant, would not be clinically significant in most patients; however, the potential exists for short-term elevation of digoxin concentrations in response to concurrent administration of epoprostenol.