Study Design

The optimal design of an ADME study is a crossover, or a parallel group, study where an intravenous (IV) dose serves as a reference to the enteral (e.g., oral, rectal, or sublingual) or other parenteral (e.g., topical or pulmonary) routes of administration. Even if the development of the new chemical entity is only focused on, e.g., an oral route of administration, the pharmacokinetic information from an IV dose will significantly enhance the understanding of the pharmacokinetics of the drug, especially information regarding absorption processes, presystemic metabolism, and first-pass effects. However, a study design, where only one route of administration is chosen, would be satisfactory, although more limited information regarding the ADME processes will be collected.

Blood and plasma samples, aliquots of urine and feces, and in certain cases expiration air, are collected over an extended period of time. The time period for collection of biological specimens is obviously governed by the terminal half-life of the drug and/or metabolite(s), and can be determined by "on the spot" quick-counts of radioactivity in, e.g., urine or feces. The blood-sampling period is usually terminated well ahead of urine and feces collection, where the latter usually continues for 7-10 terminal half-lives of the drug or metabolite(s). It is essential that the recovery of the total radioactivity in the different biological fluids is 85-90% or above, therefore strict provisions regarding sampling collection need to be made. The volunteers need to be fully informed and understand the importance of complete collection of urine and feces specimens, and comply with the instructions.

The metabolite identification is performed in the biological samples after extraction and separation (e.g., by fractional collection). Metabolite identification should be attempted in all the collected biological specimens (e.g., blood or plasma, urine, feces). The metabolite structures are generally identified by use of liquid chromatography-(tandem) mass spectrometry methods [14]. Accelerator mass spectrometry (ACL), which has been used for areas such as age determination of archeological objects, has recently been applied in biomedical research, e.g., ADME studies [15, 16]. The main advantage with this technique is a very high sensitivity and precision, which permits the use of extremely low doses of radiolabeled materials and quantitation of low levels of radioactivity. However, this promising technique is not yet used routinely, and may require further validation. All analytical methods need to be adequately assessed, as described in Chapter 8.

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