title: Integrated pharmacokinetics and pharmacodynamics of epoprostenol in healthy subjects.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil, Switzerland. laurent.nicolas@actelion.com
authors.forename: Laurent B
authors.initials: LB
authors.lastname: Nicolas
authors.forename: Andreas
authors.initials: A
authors.lastname: Krause
authors.forename: Marcelo M
authors.initials: MM
authors.lastname: Gutierrez
authors.forename: Jasper
authors.initials: J
authors.lastname: Dingemanse
mesh_terms: D000293:Adolescent; D000328:Adult; D000959:Antihypertensive Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D011464:Epoprostenol / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D000959:Antihypertensive Agents; D011464:Epoprostenol