title: Phase I study of Solulin, a novel recombinant soluble human thrombomodulin analogue.
abstract: Solulin is a novel recombinant soluble derivative of human thrombomodulin. In this first human study of Solulin, the safety, tolerability, pharmacokinetics and pharmacodynamics of Solulin in 30 healthy volunteers in response to single (0.6-30 mg) and 12 healthy volunteers in response to multiple (1 and 10 mg) ascending intravenous bolus doses compared to placebo are described. Solulin was shown to be well tolerated, and demonstrated linear pharmacokinetics over the clinically relevant dose range, with a plasma elimination half-life of 15-30 hours, indicating that a less than daily dose may be required for therapeutic use. Steady-state plasma levels after multiple dosing were reached after 48 hours. Solulin has shown to be able to inhibit thrombin generation without increasing levels of aPC/PCI complexes. Coagulation parameters INR and PT were not changed, aPTT was elevated to about 10% above the upper limit of normal after the highest single dose only. Thrombin clotting time was prolonged after administration of high dose Solulin (10, 30 mg). No effect on in vitro bleeding time has been found. There was no evidence of bleeding risk with Solulin administration. The pharmacodynamic effects correlated with Solulin plasma concentrations. This demonstrates that the antithrombotic effect of Solulin is predictable, suggesting that patient monitoring is not expected. The results of this study provide evidence that Solulin can be expected to be an effective and safe anticoagulant, and further clinical investigation is warranted.
authors.affiliation: QPS Netherlands B.V., Groningen, The Netherlands.
authors.forename: Thijs
authors.initials: T
authors.lastname: van Iersel
authors.forename: Heimo
authors.initials: H
authors.lastname: Stroissnig
authors.forename: Peter
authors.initials: P
authors.lastname: Giesen
authors.forename: Johan
authors.initials: J
authors.lastname: Wemer
authors.forename: Karin
authors.initials: K
authors.lastname: Wilhelm-Ogunbiyi
mesh_terms: D000293:Adolescent; D000328:Adult; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D001682:Biological Availability; D001777:Blood Coagulation / Q000187:drug effects*; D001780:Blood Coagulation Tests; D004305:Dose-Response Relationship, Drug; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D006207:Half-Life; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D007275:Injections, Intravenous; D019934:International Normalized Ratio; D008297:Male; D008657:Metabolic Clearance Rate; D009426:Netherlands; D010314:Partial Thromboplastin Time; D011517:Prothrombin Time; D018179:Receptors, Thrombin / Q000008:administration & dosage; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D018570:Risk Assessment; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D005343:Fibrinolytic Agents; D018179:Receptors, Thrombin; D011994:Recombinant Proteins; C558438:solulin protein