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is a specific problem, toxicokinetic information should be sufficient to allow comparative exposure to be calculated and little additional information in animals is necessary. If the drug were to be used in pregnant females, then considerably more investigations would be necessary, but not in rats. The need for detailed distribution studies has been partially addressed in the ICH2 guidelines [59]. In brief, tissue single-dose distribution in rats measured by whole body autoradiography (WBA) and image analysis and, increasingly, by photoluminescence [60], is mainly used to measure radioactive tissue exposure prior to the administration of a labeled drug to man. Repeat dose distribution, for a long time used in Japan, where radioactive studies in man are not undertaken, have now been restricted to those compounds where there are specific or likely problems of toxicity. However the new guidelines are unclear since they ask for distribution studies if unexpected accumulation in repeat-dose studies is found. Since the only repeat-dose studies necessary are those that will be done during toxicity studies, unexpected accumulation is likely to occur frequently when metabolic saturation occurs at the higher doses. Unless this is associated with some unexpected nonpharmacological toxicity, distribution studies would have little relevance since high levels can not simply be |
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| Table 3 Essential Preclinical Biodisposition Studiesa | | Studyb | | Information | | In vitro metabolism | Toxicology species, human
Expressed enzymes | Rates and routes
Metabolite identification
Candidate choice
Whole-body clearance
Cytochrome P450 | | IV kinetics | Rat, dogc | Basic kinetic parameters
Allometric scaling | | PO kinetics | Rat, (dog) | Absorption characteristics | | Protein binding | Toxicological species human | Free-drug levels | | Radioactive balance | Rat, (dog) | Elimination routes
In vivo metabolism |  |
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Radioactive tissue distribution (WBA) |
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| Rat | |
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Exposure calculation for use of RA in human |
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Unexplained toxicity | | aAssuming Toxicokinetics studies undertaken according to ICH Guidelines (1993). | | bSingle doses studies. | | cMay be mice and monkey depending on species used in toxicology and if allometric scaling is usedsee text for details. | | ( ) = May not be necessary if no unexplained problems. |
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