Abstract
IntroductionTreprostinil diethanolamine is an innovative salt form of the prostacyclin analogue, treprostinil sodium, developed as an oral sustained release (SR) osmotic tablet. The availability of a formulation permitting convenient systemic delivery might have applicability to scleroderma vascular complications. We evaluated pharmacokinetics and perfusion in scleroderma patients with digital ischemia following escalating twice-daily doses of treprostinil diethanolamine SR.MethodsScleroderma patients with digital ulcers were enrolled in this dual-center, open-label, phase I pharmacokinetic study. Drug concentrations and perfusion, quantified by laser Doppler imaging, were measured over 12 hours at the 2 mg and 4 mg (or maximally tolerated) doses. Pharmacokinetic parameters were determined from individual plasma concentration versus time profiles using non-compartmental analysis methods. Digital perfusion and skin temperature were modeled as a function of log-transformed drug concentration and other covariates by performing repeated measures analyses using random effects models.ResultsNineteen scleroderma patients (84% female, 53% limited scleroderma) received treprostinil diethanolamine SR with dose titration up to 4 mg twice daily as tolerated. Peak concentrations (mean maximum plasma concentration (Cmax) = 1,176 and 2,107 pg/mL) occurred approximately 3.6 hours after dose administration, and overall exposure (under the plasma concentration-time curve from time 0 to 12 hours post dose (AUC0-12) = 7,187 and 12,992 hr*pg/mL) was linear between the 2 mg and 4 mg doses. Perfusion and digital skin temperature were positively associated with log-transformed plasma concentration at the 4 mg dose (P = 0.015 and P = 0.013, respectively). The most frequent adverse events were similar to those seen with prostacyclin analogues.ConclusionsOral treprostinil diethanolamine was effectively absorbed in patients with scleroderma. Drug administration was temporally associated with improved cutaneous perfusion and temperature. Treprostinil diethanolamine may provide a new therapeutic option for Raynaud's phenomenon and the peripheral vascular disease of scleroderma.Trial RegistrationClinicalTrials.gov NCT00848939.Electronic supplementary materialThe online version of this article (doi:10.1186/ar4216) contains supplementary material, which is available to authorized users.
Highlights
Treprostinil diethanolamine is an innovative salt form of the prostacyclin analogue, treprostinil sodium, developed as an oral sustained release (SR) osmotic tablet
As an orally available formulation, treprostinil diethanolamine SR avoids the need for infusion devices and the associated demands and risks associated with the intravenous or subcutaneous route of delivery and may provide a treatment option for the peripheral vascular disease seen in systemic sclerosis (SSc)
Inclusion criteria Male and female subjects were eligible for participation in the study based on the following criteria: subjects were older than 18 years of age, met American College of Rheumatology criteria [20] for SSc, and had either an active digital ulcer or history of digital ulceration occurring within the past six months and at least six to ten Raynaud’s phenomenon episodes per week
Summary
Treprostinil diethanolamine is an innovative salt form of the prostacyclin analogue, treprostinil sodium, developed as an oral sustained release (SR) osmotic tablet. Treprostinil diethanolamine is an innovative salt form developed for oral delivery as a sustained release (SR) osmotic tablet. Both treprostinil sodium and treprostinil diethanolamine disassociate in blood and exist as the ionized, bioactive form of treprostinil. Patients with diseases, such as systemic sclerosis (scleroderma, SSc), which involve perturbation of the peripheral vasculature, experience abnormalities in the blood vessels and mal-distribution of blood flow away from the nutritive capillaries that supply the skin.
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