Pharmacokinetic dynamic relationships
Integrated pharmacokinetics and pharmacodynamics of epoprostenol in healthy subjects
Article first published online: 13 NOV 2012
© 2012 Actelion Pharmaceuticals Ltd.. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society
British Journal of Clinical Pharmacology
Volume 74, Issue 6, pages 978–989, December 2012
How to Cite
Nicolas, L. B., Krause, A., Gutierrez, M. M. and Dingemanse, J. (2012), Integrated pharmacokinetics and pharmacodynamics of epoprostenol in healthy subjects. British Journal of Clinical Pharmacology, 74: 978–989. doi: 10.1111/j.1365-2125.2012.04301.x
- Issue published online: 13 NOV 2012
- Article first published online: 13 NOV 2012
- Accepted manuscript online: 20 APR 2012 05:02AM EST
- Received; 28 October 2011; Accepted; 13 April 2012; Accepted Article Published Online; 20 April 2012
WHAT IS ALREADY KNOWN
• Continuous infusion with synthetic prostacyclin (epoprostenol) is generally regarded as the most effective treatment against severe cases of primary pulmonary arterial hypertension, associated with decreased pulmonary vascular resistance, increased cardiac index (CIn), and survival benefits. To date, the pharmacokinetics (PK) of epoprostenol have not been fully characterized due in part to the instability of epoprostenol.
WHAT THIS STUDY ADDS
• The present study provides the first characterization of the PK of epoprostenol in man via assessment of 6-keto-prostacyclin F1α and another primary metabolite, 6,15-diketo-13,14-dihydro-prostacyclin F1α. Overall, PK/pharmacodynamic (PD) modelling showed that CIn relates proportionally and linearly to the plasma concentrations of 6-keto-prostacyclin F1α suggesting that this major metabolite represents a suitable surrogate marker of plasma concentrations of epoprostenol.
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 F1α and 6,15-diketo-13,14-dihydro-prostacyclin F1α. 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 t1/2 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 F1α, and 0.32 h (0.22, 0.45) and 0.34 h (0.26, 0.46) for 6,15-diketo-13,14-dihydro-prostacyclin F1α. A single compartment infusion model with first order elimination adequately described the PK of 6-keto-prostacyclin F1α. 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 F1α 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 F1α. These results suggest that 6-keto-prostacyclin F1α is a suitable surrogate marker of plasma concentrations of epoprostenol.