For a new drug to receive market approval, data have to be provided on its bioavailability or bioequivalence. Absolute bioavailability is traditionally determined using a cross-over study design where the drug is administered extravascularly (eg orally) and intravenously (iv) on separate dosing occasions. The absolute bioavailability is calculated by comparison of the areas under the plasma concentration time curves (AUC) for the oral and iv doses. Such a design however, can suffer from artefacts arising from dose-dependant kinetics, if the systemic drug concentrations are significantly different between the two dose routes. In an alternative method, the oral and iv doses are given simultaneously, with the iv dose containing an isotopic tracer. The principle of isotopic dilution is employed to separate the AUCs for the two dose routes, thereby determining the absolute bioavailability. The advantage of this technique is that the pharmacokinetics for both the iv and oral doses are determined from the same plasma sample and therefore any dose-dependant effects are removed. This method has been used for some years with stable isotopes but it suffers from a lack of sensitivity. The use of 14C as a tracer, which offers much greater sensitivity, has been tried but this has not been favoured traditionally because of issues of radioactivity, particularly when human volunteers are involved. With the advent of AMS however, very low levels of 14C, along with very low levels of drug (a microdose) can be administered by the iv route. The oral AUC is determined with a “cold” analytical method such as LC-MS, whilst AMS is used to measure the iv (14C-labelled) AUC. The low levels of radioactivity (ca 100 nCi or less) ameliorates the difficulties of administering 14C to humans and, from a regulatory perspective, can be considered negligible. The low levels of drug (100 mg or less) can remove the need for specific toxicology testing via the iv route of administration. Examples of absolute bioavailability determination using 14C-labelled drug and AMS analysis will be presented, along with the underlying pharmacokinetic principles.
See more of AMS in Low Dose Bioscience Workshop
See more of The 10th International Conference on Accelerator Mass Spectrometry (September 5-10, 2005)