PURPOSE: This study assessed the relationship between dose and plasma concentration following administration of treprostinil sodium (Remodulin®) infusion therapy in pulmonary arterial hypertension (PAH) patients.
METHODS: This was a multi-center, open-label, multiple cohort, steady-state, pharmacokinetic study in subjects with PAH receiving treprostinil by continuous intravenous or subcutaneous infusion at doses between 10-125 ng/kg/min. A blood sample was obtained from each patient at steady-state and analyzed via a validated liquid chromatography tandem mass spectrometry (LC/MS/MS) method.
RESULTS: Forty-nine PAH subjects receiving treprostinil, 37 (76%) intravenously and 12 (24%) subcutaneously, were enrolled. Treprostinil doses ranged from 12.1-125 ng/kg/min; treprostinil plasma concentrations ranged from 14.9-18,248 pg/mL. Linear regression analysis revealed a correlation between treprostinil dose and treprostinil plasma concentration with an R2 value of 0.561 (n=49). Using a power model to assess dose proportionality, the estimated non-proportionality parameter was 0.641 (95% CI: 0.083-1.199), reflecting consistency with dose proportionality. Subset linear regression analysis, which excluded two subjects with anomalous treprostinil plasma concentrations, increased the R2 value to 0.796 (n=47). Using a power model to assess dose proportionality of this subset, the estimated non-proportionality parameter was 0.941 (95% CI: 0.809-1.073). A post-hoc review of the data, using a general linear model for analysis, revealed the relationship between dose and concentration was not related to route of drug administration [p=0.25 for n=49 (with outliers); p=0.83 for n=47 (with outliers excluded)].
CONCLUSION: 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.
CLINICAL IMPLICATIONS: These results provide added assurance that, for the vast majority of patients, an increase in the infusion rate of treprostinil, whether via the subcutaneous or intravenous routes, yields a proportional increase in treprostinil plasma concentrations.
DISCLOSURE: Vallerie McLaughlin, No Product/Research Disclosure Information; Shareholder I, Christopher Shane McSwain, possess stock options to purchase shares of United Therapeutics’ stock; Employee I, Christopher Shane McSwain, am employed by United Therapeutics Corporation as an Associate Manager, Clinical Affairs.