Background

The BAS technology is designed to enhance bioavailability through the inhibition of cytochrome P450 3A, a common enzyme responsible for the degradation of approximately 60% of all drugs delivered orally to man. The rapid degradation of oral drugs is commonly referred to as the first-pass-effect. BAS believes that in association with selected therapies its proprietary technology can reduce cost to market and cost per dose, revive failed drug candidates, eliminate risk associated with CYP 3A in new drug development, and extend patent life.

Oral bioavailability is one of the more difficult obstacles that a drug candidate faces. It is estimated that poor oral bioavailability is responsible for 40% of all drug failures. Even for drugs that are commercialized, doses are often increased to overcome metabolism by CYP 3A and achieve therapeutic efficacy. Compounds that inhibit CYP 3A can enhance the bioavailability of oral drugs, and therefore their efficacy, by boosting the concentration of the active drug that reaches the bloodstream and its intended target.

The ingestion of grapefruit and grapefruit products has been recognized to enhance the oral bioavailability of many drugs. The inhibition of CYP 3A by components in grapefruit was first publicly reported in 1991. It was found that clinical patients taking grapefruit juice to mask the taste of ethanol achieved abnormally high blood concentrations of a heart drug under investigation. Since 1991 over 100 studies of this effect have appeared in the scientific literature. BAS was the first to isolate, identify and synthesize several structurally similar compounds from grapefruit that are responsible for the grapefruit effect. In-vitro testing confirmed a high level of inhibition of human CYP 3A by these materials. The compounds are complex molecules containing a unique spiro-ortho-ester substructure. The uniqueness of these SOEs has enabled BAS to develop a powerful portfolio of 15 U.S. patents and a developing portfolio of international protection.

The inhibition of CYP 3A has many consequences in drug therapy development. In proper well-researched settings, a CYP 3A inhibitor can provide a valuable adjunct to certain treatments as an oral bioavailability booster. There are three possible favorable consequences of the booster principle:

  • reducing the dose of oral drug required to achieve optimal therapy, the ‘drug sparing effect’ (e.g. cyclosporine, saquinavir)
  • increasing the efficacy of the agent in a way that cannot be achieved by simply increasing dosage (e.g. some oral anti-cancer agents)
  • reducing the intra- and inter-subject variability of high first-pass drugs leading to better prediction of effect (e.g. calcium-channel antagonists, cyclosporine, anti-cancer cytostatics)
  • changing the administration of a drug from IV to oral (eg. taxanes)

 

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Copyright BAS 2007