Prognostic factors associated with increased survival in patients with pulmonary arterial hypertension treated with subcutaneous treprostinil in randomized, placebo-controlled trials.

BACKGROUND: Because of the challenges associated with conducting large survival studies of patients with pulmonary arterial hypertension (PAH), we analyzed the surrogate markers predictive of long-term survival in a large cohort of patients treated with subcutaneous treprostinil. METHODS: A retrospective review was conducted using data from a total of 811 patients with New York Heart Association Functional Class (NYHA FC) II to IV PAH, who were treated with subcutaneous treprostinil. Patient baseline disease and on-treatment parameters were analyzed by uni- and multivariate analyses for predictive value of 3-year survival with PAH. RESULTS: Among the baseline disease-related factors analyzed, there was a significantly higher risk of death (p < 0.001) associated with connective tissue disease-associated PAH relative to idiopathic PAH (hazard ratio for death [HR] 1.93), NYHA FC IV vs III (HR 2.31), pulmonary vascular resistance index (PVRI) >30 vs ≤16 mm Hg/liter/min/m(2) (HR 2.44) and mixed venous oxygen saturation (SVO(2)) ≤55% vs >55%. The 6-minute walk distance (6MWD) of ≤295 m after 12 weeks of treprostinil treatment was associated with reduced survival at 3 years (58%). A ≥20-m increase from baseline in 6MWD was associated with greater survival (80%) vs smaller walk increments (69%; p = 0.039). Treprostinil dose of ≥40 ng/kg/min (p < 0.001) and every 10-ng/kg/min dose increase (p = 0.009) resulted in improved long-term survival. In a multivariate analysis, only SVO(2), 6MWD and treprostinil dose were significant on-treatment predictors (p < 0.02) of survival. CONCLUSIONS: Disease etiology, baseline factors (NYHA FC, PVRI and SVO(2)) and on-treatment factors (6MWD, SVO(2) and treprostinil dose) were predictors of survival in this study and may be used to aid in treatment optimization.

Dose proportionality of treprostinil sodium administered by continuous subcutaneous and intravenous infusion.

This study assessed the relationship between dose and plasma concentration following administration of treprostinil sodium infusion therapy in pulmonary arterial hypertension patients. This was a multicenter, open-label, multiple-cohort, steady-state, pharmacokinetic study in subjects with pulmonary arterial hypertension receiving treprostinil by continuous intravenous or subcutaneous infusion at doses between 10 and 125 ng/kg/min. A blood sample was obtained from each patient at steady state and analyzed via a liquid chromatography/tandem mass spectrometry method. Forty-nine subjects receiving treprostinil were enrolled. Treprostinil doses ranged from 12.1 to 125 ng/kg/min; treprostinil plasma concentrations ranged from 14.9 to 18 248 pg/mL. Linear regression analysis revealed a correlation between treprostinil dose and treprostinil plasma concentration with an R2 value of 0.561. Using a power model to assess dose proportionality, the estimated nonproportionality parameter was 0.641 (95% confidence interval: 0.083-1.199), reflecting consistency with dose proportionality. Subset linear regression analysis, which excluded 2 subjects with anomalous treprostinil plasma concentrations, increased the R2 value to 0.796. Using a power model to assess dose proportionality of this subset, the estimated nonproportionality parameter was 0.941 (95% confidence interval: 0.809-1.073). This study supports previous findings of linearity at lower doses up to 15 ng/kg/min and demonstrates linearity at treprostinil doses up to 125 ng/kg/min.

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.