title: Single ascending oral dose pharmacokinetics and pharmacodynamics study of EV-077: the specific inhibitor of prostanoid- and isoprostane-induced cellular activation.
abstract: OBJECTIVE
  This study was performed to determine the oral pharmacokinetics (PK) of EV-077 and its effects on pharmacodynamic (PD) markers. EV-077 blocks prostanoid-induced and isoprostane-induced cellular activation, and is in development for the treatment of vascular inflammation and associated complications of type-2 diabetes..
  
  
  METHODS
  This single-ascending-dose mono-centre study was randomised, placebo-controlled, and double-blinded within each dose group. Seven EV-077 doses were administered sequentially as an oral solution: 0.0125, 0.125, 0.375, 0.75, 1.25, 1.875 and 2.5 mg/kg body weight. PK, platelet aggregation, bleeding time and safety parameters were measured. Seven to eight healthy male subjects were dosed per group: five to six subjects received EV-077 and two subjects received placebo.
  
  
  RESULTS
  Tmax was reached rapidly between 0.5 h and 1.0 h. Both Cmax and AUC increased linearly with the dose. The apparent terminal half-life (t½z) increased with the dose, most likely reflecting the increasing last quantifiable concentration with increasing dose; at 2.5 mg/kg, it was 2.7-6.9 h. Measurement of platelet aggregation showed no effect at 0.0125 mg/kg, and a full and reversible inhibition at doses of 0.125-2.5 mg/kg. The average bleeding time was dose-dependently prolonged, but was always below 9 min. The PK/PD profile showed that at plasma concentrations above 20 ng/ml, EV-077 platelet aggregation was completely inhibited (>90 %). All tested doses were well tolerated.
  
  
  CONCLUSIONS
  Orally administered EV-077 was well tolerated, readily absorbed, reached Cmax within 1 h, with a linear PK based on Cmax and AUC. The inhibition of platelet aggregation was complete and reversible at doses of 0.125 mg/kg and higher, and average bleeding time was below 9 min.
authors: AR Pharma Projects, Marlow, SL7 3PG, UK.
authors: A
authors: A
authors: Richardson
authors: K S
authors: KS
authors: Sakariassen
authors: J-P
authors: JP
authors: Meyer
authors: P
authors: P
authors: Alberts
authors: A S
authors: AS
authors: Sorensen
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001760:Bleeding Time; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D016014:Linear Models; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D055815:Young Adult
chemical_list: D004791:Enzyme Inhibitors; D010975:Platelet Aggregation Inhibitors; D017482:Receptors, Thromboxane; D013930:Thromboxane-A Synthase