Integrated pharmacokinetics and pharmacodynamics of epoprostenol in healthy subjects

Authors

  • Laurent B. Nicolas,

    Corresponding author
    1. Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil, Switzerland
      Dr Laurent B. Nicolas PhD, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland. Tel.: +41 61 565 6945, Fax: +41 61 565 6200, E-mail: laurent.nicolas@actelion.com
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  • Andreas Krause,

    1. Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil, Switzerland
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  • Marcelo M. Gutierrez,

    1. Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil, Switzerland
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  • Jasper Dingemanse

    1. Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil, Switzerland
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Dr Laurent B. Nicolas PhD, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland. Tel.: +41 61 565 6945, Fax: +41 61 565 6200, E-mail: laurent.nicolas@actelion.com

Abstract

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 F and another primary metabolite, 6,15-diketo-13,14-dihydro-prostacyclin F. Overall, PK/pharmacodynamic (PD) modelling showed that CIn relates proportionally and linearly to the plasma concentrations of 6-keto-prostacyclin F 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 F and 6,15-diketo-13,14-dihydro-prostacyclin F. 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 F, 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. A single compartment infusion model with first order elimination adequately described the PK of 6-keto-prostacyclin F. 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 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. These results suggest that 6-keto-prostacyclin F is a suitable surrogate marker of plasma concentrations of epoprostenol.

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