Summary.  Background: Anticoagulants are often given for extended periods of time to patients at high risk for venous thromboembolism, such as after orthopedic surgery. Daily subcutaneous (sc) injections can be inconvenient to the patient. A long‐acting anticoagulant requiring less frequent dosing could make treatment more acceptable. Thrombomodulin is a natural anticoagulant that activates protein C, which leads to inactivation of factor (F)Va and FVIIIa and decreased thrombin formation. Recombinant human thrombomodulin is a novel anticoagulant with a long half‐life in animal models. Methods and results: This phase I study examined pharmacokinetics, pharmacodynamics, and safety of recombinant human soluble thrombomodulin (ART‐123) after administration of doses between 0.02 and 0.06 mg kg−1 body weight intravenously (iv), and between 0.02 and 0.45 mg kg−1 sc in 55 healthy volunteers. The plasma half‐life was 2–3 days after sc injection of various single doses. Plasma ART‐123 levels estimated to be needed for prevention of thrombus formation in humans were maintained for at least 6 days after single sc injection of 0.30 and 0.45 mg kg−1 ART‐123. Antithrombotic activity with these doses was demonstrated by achieving prothrombinase inhibition of more than 80% for more than 6 days after administration. No major bleeding occurred. Pharmacodynamic modeling revealed that adequate antithrombotic ART‐123 levels can be achieved for 6 days with one dose of 0.45 mg kg−1 ART‐123, and for 12 days with 2 doses of 0.30 mg kg−1, given 5 days apart. Conclusions: Recombinant human soluble thrombomodulin (ART‐123) has a long half‐life after sc injection and is well tolerated, making it a suitable agent to be tested in clinical thromboprophylaxis trials.

Protein C (PC) is a vitamin K-dependent plasma protein that is structurally similar to other coagulation factors such as prothrombin and Factor X. PC is converted to its active anticoagulant form by a thrombin-thrombomodulin complex on the surface of capillary endothelial cells. Activated PC (APC) prevents the formation of blood clots by specifically inactivating factors Va and VIIIa in the clotting cascade. Both acquired and hereditary forms of PC deficiency exist, with hereditary further categorised as heterozygous, homozygous as well as doubly heterozygous. Patients suffering from symptomatic heterozygous PC deficiency present with purpura fulminans, venous thrombosis and/or pulmonary embolism. Homozygous PC deficiency is usually associated with the development of severe and often fatal, purpura fulminans and disseminated intravascular coagulation (DIC) during the neonatal period. Various therapeutic options have been described for long-term management of severe heterozygous and homozygous PC deficiencies. For the treatment of heterozygous PC deficiency, oral anticoagulation with a coumarin derivative or heparin therapy remains standard therapy. Homozygous patients may be treated with fresh frozen plasma (FFP) and iv. PC concentrate or coumarin derivatives. Other therapeutic options for the treatment of hereditary PC deficiency include the use of low-molecular weight heparin (LMWH), steroids and liver transplantation. Maintenance of a symptom-free life depends on response to therapy. Patients responding well to treatment can expect normalisation of haemostasis as well as improvement of microcirculation and resolution of purpura fulminans.

6119 Background: IM (Glivec, Gleevec) is an oral targeted therapy with unprecedented efficacy in CML and GIST. Prescription compliance and persistency of pts receiving IM were measured by analysis of pt-level pharmacy claims data. Methods: Compliance and persistency were determined by analyzing the prescription-filling activity of pts (N=4043) compared with the prescribing activity of their physicians (N=3316) using pt pharmacy records accrued over 24 months (1/03–12/04). Observed average daily consumption (DACON) and average prescribed days of therapy were calculated and compared. Also, compliance and persistency were examined by pt demographics and initial IM dose prescribed. Results: Overall compliance (defined as medication possession ratio = apparent mg taken/mg prescribed) was 75%, with CML pts showing slightly greater compliance (78%) than GIST pts (73%). Fifty percent of pts were 100% compliant, the greatest compliance being found in pts initially treated with IM 300 or 400 mg/day (77%). Persistency (time on therapy without significant gaps in refills) averaged 255 days over 24 months. The most persistent pts were those initially given 300 or 400 mg/day (13.0 and 12.9 months, respectively). DACON was 400 mg/day for 65% of patients, but fluctuated above and below 400 mg/day in 18% and 17% of pts, respectively. Conclusions: This is the first assessment of pt compliance and persistency with prescribed IM therapy. Although less pronounced than with most other non-oncology products, suboptimal compliance and persistency with IM are a concern as doses <300–400 mg may result in plasma levels lower than needed to eliminate cancer cells. Patient support programs and improved communication on the importance of adhering to recommended dosing could potentially optimize outcome and further reduce risk of relapse and progression. [Table: see text]

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