Pharmacokinetics of treprostinil sodium administered by 28-day chronic continuous subcutaneous infusion.

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 sub-cutaneous 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 r(2) 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.

Absolute bioavailability and pharmacokinetics of treprostinil sodium administered by acute subcutaneous infusion.

The objective of this study was to evaluate the absolute bioavailability and acute pharmacokinetics of treprostinil sodium administered by continuous, short-term subcutaneous infusion in normal subjects. Fifteen healthy volunteers received treprostinil via an intravenous infusion at 15 ng/kg/min over 150 minutes, followed by a 5- to 7-day washout and a subcutaneous infusion at the same rate administered over 150 minutes. Serial plasma samples were collected predosing, during dosing, and postdosing, and plasma treprostinil concentration levels were 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. Acute administration of treprostinil administered by subcutaneous infusion at a rate of 15 ng/kg/min for 150 minutes achieved a mean Cmax of 1.47 ng/mL. Mean AUC infinity values for intravenous and subcutaneous dosing were 3.52 and 3.97 ng.h/mL, respectively, resulting in a mean apparent absolute bioavailability of 113% for subcutaneous administration. It was possible that the area under of the curve for the intravenous administration was underestimated because most of the terminal elimination phase could not be documented due to the LLOQ of the assay. The mean apparent elimination half-life of treprostinil following subcutaneous administration was 1.38 hours, compared to 0.87 hours following intravenous administration. It was concluded that treprostinil administered by subcutaneous administration is completely absorbed, with a slightly longer half-life compared to intravenously administered treprostinil.

Effect of continuous subcutaneous treprostinil therapy on the pharmacodynamics and pharmacokinetics of warfarin.

Treprostinil sodium was recently approved in the United States for continuous subcutaneous infusion in the treatment of pulmonary arterial hypertension (PAH). Anticoagulation with warfarin is recommended in PAH therapy. Given the likelihood for treprostinil and warfarin coadministration, a single-blind, controlled, crossover study was conducted to evaluate the effect of treprostinil infusion on the pharmacodynamics and pharmacokinetics of a single dose of warfarin. Area under the effect-time curve (AUEC(0-1)) and maximum effect over the entire sampling phase (E(max)) for warfarin INR were 219.58 and 2.071 with treprostinil and 218.93 and 2.041 with vehicle, respectively. Mean time to attain the peak concentration of R-enantiomer of warfarin (T(max)), half-life, and elimination rate constant (k(el)) were 1.9 hours, 51.688 hours, and 0.0137 per hour, respectively, in the presence of treprostinil and 1.5 hours, 52.579 hours, and 0.0137 per hour, respectively, in the presence of vehicle (control). Results were similar for the S-enantiomer. The 90% confidence intervals for warfarin INR and warfarin R- and S-enantiomer pharmacokinetic parameter (C(max) and AUC( infinity )) ratios were within 0.80-1.25, which was established as the no-effect criterion for treprostinil coadministration. No serious or severe adverse events, anticoagulation-related events, or clinically significant physical or laboratory findings were reported. These findings suggest that a clinically important interaction between treprostinil and warfarin during therapy is unlikely.