Choice of Dose

The dose of the radiolabeled drug should be kept as low as possible. Information regarding tissue distribution in animals, e.g., from whole body autoradiography studies, provides valuable information about high drug accumulation in specific tissues, as well as the time course of elimination from specific tissues. The information can also be utilized in the risk assessment of the use of radioactive isotopes for human studies. The regulations regarding the use of isotopes in human research vary between different countries. Dosimetry calculations to estimate exposure in different tissues need to be performed, and in general the protocol has to be approved by a Radioactive Drug Research Committee as well as an Investigational Research Committee. In the United States, the rules for the use of radiolabeled drugs in research can be found in 21 CFR 361.1, and the reader is also referred to a related overview by Dain et al. [12].

The choice of radiolabel for the drug is usually dependent on the isotope that was chosen for the mass balance studies in the animal species. The same isotope should be used in the human in vivo study to enable crossspecies comparisons of metabolic patterns. This is important, since the metabolic pattern should be similar between the animal species chosen for the preclinical carcinogenicity and long-term toxicity studies and humans. If the metabolic profiles differ substantially between humans and animals, additional (preclinical) studies may be needed. For example, if a major metabolite is formed in humans, which has not been observed in animal studies, then this metabolite may have to be synthesized and administered to animals to assess the pharmacological and toxicological properties of the particular metabolite. In such cases, the appropriate regulatory agency should be contacted to get their guidance on which additional studies may be needed, or to discuss the adequacy of additional study protocol proposals. The radiolabel should be properly positioned in the molecule to yield relevant information regarding the drug metabolism. The radiochemical purity is also important, especially for protein-binding assessments of highly (>99%) protein-bound drugs [13].

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