Pharmacokinetics of Treprostinil Sodium Administered by 28-Day Chronic Continuous Subcutaneous Infusion
Article first published online: 8 MAR 2013
2004 American College of Clinical Pharmacology
The Journal of Clinical Pharmacology
Volume 44, Issue 5, pages 503–509, May 2004
How to Cite
Wade, M., Baker, F. J., Roscigno, R., DellaMaestra, W., Arneson, C. P., Hunt, T. L. and Lai, A. A. (2004), Pharmacokinetics of Treprostinil Sodium Administered by 28-Day Chronic Continuous Subcutaneous Infusion. Journal of Clinical Pharma, 44: 503–509. doi: 10.1177/0091270004264638
- Issue published online: 8 MAR 2013
- Article first published online: 8 MAR 2013
- Submitted for publication July 18, 2003; revised version accepted February 15, 2004.
- Treprostinil sodium;
- subcutaneous infusion;
- chronic pharmacokinetics;
- pulmonary arterial hypertension;
The objective of this study was to assess the pharmacokinetics and safety of treprostinil sodium administered as a 28-day continuous subcutaneous infusion at escalating infusion rates of 2.5 to 15 ng/kg/min in normal subjects. Fourteen healthy adult volunteers received a 28-day continuous subcutaneous infusion of treprostinil at escalating infusion rates of 2.5, 5, 10, and 15 ng/kg/min. Doses were escalated every 7 days with no washouts between escalations. Serial plasma samples were collected predosing, during dosing, and postdosing. Samples were also collected every 3 hours on Day 7 of each dosing period to evaluate diurnal variation over a 24-hour steady-state interval. Plasma treprostinil concentration was measured by a validated liquid chromatography atmospheric pressure ionization tandem mass spectrometry (LC/MS/MS) method with a lower limit of quantitation (LLOQ) of 25 pg/mL. Distinct steady states were achieved for each of the four treprostinil doses. Linear regression analysis of mean steady-state treprostinil concentration versus targeted dose yielded a fitted line with an r2 of 0.92. Variation in apparent plasma clearance for the four doses was small (i.e., 9.77–10.4 mL/kg/min). Consistent diurnal cycles of two peak and two trough treprostinil concentrations were observed over a 24-hour steady-state interval for each dose with peak levels 20% to 30% higher than trough levels. The terminal half-life of treprostinil was 2.93 hours. Intersubject variability for mean pharmacokinetic parameters was small (coefficients of variation ranging from 13.6%–25.5%). At clinically relevant doses, the pharmacokinetics of treprostinil were linear and dose independent with modest, consistent diurnal cycles consisting of two daily peaks and two daily troughs observed for all four doses. In addition, the elimination half-life was about 3 hours.