title: Open label study of escalating doses of oral treprostinil diethanolamine in patients with systemic sclerosis and digital ischemia: pharmacokinetics and correlation with digital perfusion.
abstract: BACKGROUND
  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.
  
  
  METHODS
  Scleroderma 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.
  
  
  RESULTS
  Nineteen 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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00848939.
authors.forename: Ami A
authors.initials: AA
authors.lastname: Shah
authors.forename: Elena
authors.initials: E
authors.lastname: Schiopu
authors.forename: Laura K
authors.initials: LK
authors.lastname: Hummers
authors.forename: Michael
authors.initials: M
authors.lastname: Wade
authors.forename: Kristine
authors.initials: K
authors.lastname: Phillips
authors.forename: Cynthia
authors.initials: C
authors.lastname: Anderson
authors.forename: Robert
authors.initials: R
authors.lastname: Wise
authors.forename: Francesco
authors.initials: F
authors.lastname: Boin
authors.forename: James R
authors.initials: JR
authors.lastname: Seibold
authors.forename: Fredrick
authors.initials: F
authors.lastname: Wigley
authors.forename: Kristan D
authors.initials: KD
authors.lastname: Rollins
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D011464:Epoprostenol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005260:Female; D005385:Fingers / Q000098:blood supply; D006207:Half-Life; D006801:Humans; D007511:Ischemia / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D008875:Middle Aged; D012595:Scleroderma, Systemic / Q000150:complications*
chemical_list: D000959:Antihypertensive Agents; D011464:Epoprostenol; C427248:treprostinil