Oral DTIs in Clinical Development

Ximelagatran is a prodrug of melagatran, a dipeptide mimetic of the portion of fibrinopeptide A that interacts with the active site of thrombin and blocks the enzyme's interaction with its substrate (Linkins and Weitz, 2005). After oral ingestion, ximelagatran undergoes rapid biotransformation to melagatran. Melagatran is eliminated via the kidneys and has a half-life in the plasma of 4-5 h. It has no known interactions with food, drugs or alcohol and is administered twice-daily.

Ximelagatran has been extensively evaluated in large phase III RCTs for the prevention and treatment of VTE, for the prevention of stroke or systemic embolism in AF, and for the management of MI. Despite favorable efficacy and bleeding results, ximelagatran was not approved for use in North America because 5-10% of patients developed abnormal liver function tests, typically between 6 wk and 6 mo of treatment, and several deaths possibly related to hepatotoxicity occurred. The drug has been withdrawn from European markets (Bauer, 2006).

Dabigatran etexilate is a prodrug of dabigatran, a specific, competitive, and reversible inhibitor of thrombin. Dabigatran etexilate is rapidly absorbed after oral administration and is converted to dabigatran. The plasma half life is approximately 8 h after a single dose and 14-17 h after multiple doses. Dabigatran is renally cleared. Promising results of phase II trials of dabigatran etexilate for the prevention of VTE in major orthopedic surgery, for the initial and long-term management of VTE, and for the prevention of stroke and systemic embolism in AF have prompted several phase III trials currently in progress (Bauer, 2006). There are no reports to date of liver toxicity with dabigatran etexilate.

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