Integrated pharmacokinetics and pharmacodynamics of epoprostenol in healthy subjects

AIM

The aim of the study was to report the first thorough characterization of the pharmacokinetics (PK) and pharmacodynamics (PD) of epoprostenol in an integrated manner.

METHOD

Twenty healthy male subjects received two formulations of i.v. epoprostenol, in a crossover design, in sequential infusions of 2, 4, 6 and 8 ng kg⁻¹ min⁻¹ for 2 h each. A sensitive assay was developed which allowed accurate PK characterization of epoprostenol via analysis of the concentration–time profiles of its two primary metabolites, 6-keto-prostacyclin F_1α and 6,15-diketo-13,14-dihydro-prostacyclin F_1α. PD parameters included cardiac output (CO), cardiac index (CIn) and heart rate (HR).

RESULTS

The pharmacokinetics of epoprostenol deviated slightly from dose-proportionality, probably due to a food effect. After infusion of the two formulations of epoprostenol, the t_1/2 values expressed as geometric mean (95% confidence interval) were 0.25 h (0.14, 0.46) and 0.22 h (0.13, 0.38) for 6-keto-prostacyclin F_1α, and 0.32 h (0.22, 0.45) and 0.34 h (0.26, 0.46) for 6,15-diketo-13,14-dihydro-prostacyclin F_1α. A single compartment infusion model with first order elimination adequately described the PK of 6-keto-prostacyclin F_1α. This model also characterized the food effect. Stepwise infusions with epoprostenol resulted in a progressive increase in CO, CIn and HR.

CONCLUSION

Of the two metabolites analyzed, the appearance of 6-keto-prostacyclin F_1α in plasma was more closely associated with the haemodynamic effects of i.v. epoprostenol. PK and PD profiles showed that CIn relates proportionally and linearly to the plasma concentrations of 6-keto-prostacyclin F_1α. These results suggest that 6-keto-prostacyclin F_1α is a suitable surrogate marker of plasma concentrations of epoprostenol.