A Comprehensive Review of Treprostinil Pharmacokinetics via Four Routes of Administration.

Treprostinil is available in three different formulations and four different routes of administration: Remodulin® (treprostinil sodium, intravenous and subcutaneous administration), Tyvaso® (treprostinil sodium, inhaled administration), and Orenitram® (treprostinil diolamine, oral administration) for the treatment of pulmonary arterial hypertension (PAH). Pharmacokinetic studies have been performed in healthy volunteers and patients with PAH. The intent of this review is to outline pharmacokinetic considerations of the three treprostinil formulations and provide clinicians with a resource that may support clinical decisions in treating patients with PAH.

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.

Rapid switch from intravenous epoprostenol to intravenous treprostinil in patients with pulmonary arterial hypertension.

Intravenous epoprostenol improves exercise capacity and survival in patients with pulmonary arterial hypertension (PAH); however, chemical instability and a short half-life have caused limitations in its use. The chemically stable prostacyclin analogue treprostinil has a longer half-life, and improves hemodynamics and signs/symptoms of PAH. This study investigated the feasibility of transitioning patients with PAH from intravenous epoprostenol to intravenous treprostinil using a rapid switch protocol. Twelve PAH patients were enrolled in a 12 week prospective open label study. Patients were switched from intravenous epoprostenol to intravenous treprostinil (1:1 ng/kg/min) by a direct switch of the medication reservoir from epoprostenol to treprostinil. The dose of treprostinil was adjusted throughout the study to achieve a 2-fold increase of treprostinil compared with the baseline epoprostenol dose. Rapid transition to treprostinil was achieved without serious adverse events and, baseline clinical status was maintained over 12 weeks. The mean baseline epoprostenol dose was 28 +/- 14 ng/kg/min. At week 12, the mean treprostinil dose was 62 +/- 30 ng/kg/min. All patients reported less prostacyclin-related side effects with treprostinil and remained on treprostinil after study completion. Selected patients with PAH can be safely transitioned from intravenous epoprostenol to intravenous treprostinil using a rapid switch protocol.

Surfactant replacement for ventilator-associated pneumonia: a preliminary report.

BACKGROUND: Surfactant abnormalities have been described in bacterial pneumonia. OBJECTIVE: To determine the safety and effect of exogenous surfactant replacement in patients with ventilator-associated pneumonia (VAP). METHODS: Patients with VAP were randomized in a double-blind study to receive either an artificial surfactant (Exosurf) consisting mostly of disaturated phospholipids (DSPL) or saline via a continuous nebulizer system for 5 days. Patients underwent bronchoscopy and bronchoalveolar lavage (BAL) prior to and after 4 days of therapy. RESULTS: Twenty-two patients were randomized, with 8 receiving Exosurf. There was no detected difference in outcome between the saline- and Exosurf-treated patients in terms of days on ventilator, 30-day or hospital mortality. At the follow-up lavage, the patients treated with Exosurf had a significant rise in the level of DSPL (p < 0.05), while the saline group did not, suggesting delivery of drug. Also at the follow-up lavage, the percentage of neutrophils in the BAL fell in the Exosurf patients (p < 0.01), but not in the saline group. CONCLUSION: Exogenous surfactant replacement given to patients with VAP increased the amount of DSPL retrieved by BAL. This treatment was associated with a fall in the neutrophil response to pneumonia.