Brequinar sodium.

Abstract

The future use of BQR as a component of a treatment regimen for preventing graft rejection is uncertain. The drug exhibits a number of characteristics that are considered desirable for inclusion in a multidrug antirejection protocol. BQR is an effective immunosuppressive agent and can act as a single agent to prevent the rejection of allografts and xenografts. Its immunosuppressive activity is especially useful in those situations for which inhibition of antibody production is an important objective of the treatment protocol. The activity of BQR is substantially improved by including the drug with other immunosuppressive agents, such as CsA, that differ in the mechanisms by which they prevent immune responses. This type of combination therapy provides for effective and safe immunosuppression in rodent models. Additional desirable characteristics include the high level of bioavailability, patient acceptance, and ease of monitoring plasma drug levels. The primary difficulties associated with the application of BQR therapy to humans is the narrow ratio of the level of drug therapy necessary to provide for effective prevention of graft rejection and the appearance of side effects that limit the use of the drug. The principal feature of BQR's pharmacologic activity that appears to be responsible for this narrow therapeutic window may be the extended plasma half-life of the drug. The most effective treatment schedule for preventing graft rejection in rodents is administration of the drug on alternate days. Treating with smaller doses more frequently does not improve graft survival, suggesting that reducing the plasma half-life may allow for more frequent peaks of drug activity without increasing the severity of the side effects. The phase I trials of BQR have been completed and the extension of these studies for a more careful examination of the efficacy of the drug may depend upon biochemical modification of the parent drug.