Open label study of escalating doses of oral treprostinil diethanolamine in patients with systemic sclerosis and digital ischemia: pharmacokinetics and correlation with digital perfusion
Arthritis Research & Therapy 2013, 15:R54 doi:10.1186/ar4216Published: 18 April 2013
Treprostinil 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.
In this dual-center, open-label, phase I pharmacokinetic study, scleroderma patients with digital ulcers were enrolled. Drug concentrations and perfusion, quantified by laser Doppler imaging, were measured over 12 hours at the 2mg and 4mg (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.
Nineteen scleroderma patients (84% female, 53% limited scleroderma) received treprostinil diethanolamine SR with dose titration up to 4mg twice daily as tolerated. Peak concentrations (mean maximum plasma concentration [Cmax] = 1176 and 2107 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] = 7187 and 12992 hr*pg/mL) was linear between the 2mg and 4mg doses. Perfusion and digital skin temperature were positively associated with log-transformed plasma concentration at the 4mg dose (p=0.015 and p=0.013, respectively). The most frequent adverse events were similar to those seen with prostacyclin analogues.
Oral 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 Registration: ClinicalTrials.gov NCT00848939.