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Dose Proportionality of Treprostinil Sodium Administered by Continuous Subcutaneous and Intravenous Infusion

From the University of Alabama, Birmingham (Dr Benza); West Los Angeles VA Healthcare Center, Los Angeles, California (Dr Shapiro); Tufts–New England Medical Center, Boston, Massachusetts (Dr Hill); University Hospitals of Cleveland, Cleveland, Ohio (Dr Schilz); LDS Hospital and University of Utah, Salt Lake City (Dr Elliott); St. Luke's Medical Center, Milwaukee, Wisconsin (Dr Zwicke); LA Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California (Dr Oudiz); United Therapeutics Corporation, Research Triangle Park, North Carolina (Mr McSwain, Dr Staszewski, Mr Arneson, Dr Wade, Dr Zaccardelli); University of Michigan Medical Center, Ann Arbor, Michigan (Dr McLaughlin).

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.

Key Words: Treprostinil • prostacyclin • pharmacokinetic • pulmonary arterial hypertension (PAH)

Address for reprints: C. Shane McSwain, MHSc, Associate Manager, Clinical Affairs, United Therapeutics Corporation, One Park Drive, 4th Floor, Research Triangle Park, NC 27709; e-mail: csmcswain{at}unither.com.

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