Absolute Bioavailability: The Complete Picture

Obtaining information on the metabolic fate of a drug in humans is a key requirement in drug development. Of the various metabolic (pharmacokinetic) parameters such as half-life and clearance, absolute bioavailability is one parameter that is not routinely measured. Although some data on the bioavailability of new drugs has to be submitted as part of the drug approval process, pharmaceutical companies may not necessarily perform a full absolute bioavailability study in humans in every case.

Although there are scientific benefits to such studies, the pharmaceutical industry do not often perceive the cost-benefit to be sufficiently favourable in order to warrant the performance of an absolute bioavailability study unless there are very good reasons, such as when a regulatory agency demands it.

However, there are many reasons for low bioavailability of a drug, including incomplete dissolution when administered as a solid, inability to permeate the membranes separating the absorption site from the systemic circulation, and metabolic instability as drug moves from absorption site to within the systemic circulation (first pass metabolism). Understanding the contribution of each of these sources of loss is important in drug development. For example, if the major problem is poor dissolution, this can often be overcome by appropriate reformulation of the product, whereas poor permeability generally cannot be overcome.

THE POPULARITY STAKES

Absolute bioavailability studies in humans are unpopular in the pharmaceutical industry, primarily because such studies require the inclusion of an intravenous reference dose in the clinical study design. An intravenous dose guarantees that the entire administered drug reaches the systemic circulation. Such intravenous studies come at considerable cost, not least of which is the necessity to conduct intravenous preclinical toxicity tests in two animal species, one of which is a non-rodent to ensure adequate safety. In addition, there are potential problems due to solubility limitations. Indeed, for drugs where the intended clinical route of administration is purely extravascular, an absolute bioavailability study in humans may be the only occasion when the drug is administered intravenously.