Analysis of Toxicokinetic and Pharmacokinetic Data from Animal Studies
In the development process of human pharmaceutical therapeutics, toxicology studies play an important role in establishing the safety profiles of compounds. A battery of in vitro and in vivo studies is conducted for this purpose. Animals commonly used in toxicology studies include rats, mice, dogs, and monkeys. Interpretation of toxicological studies often hinges on the actual exposure of the animals to the compound. The amount of the compound administered to an animal is not necessarily the same as the amount reaching the intended site of action. Knowledge of the systemic exposure of an animal to a compound gives us an indication of the amount of the compound that is responsible for the actions. The exposure information allows an assessment of the linear correlation with pharmacodynamic measurements. For example, if heart rate was the biological/toxicological endpoint of interest, then increases in the area under the plasma concentration-time curve (AUC) could be compared to increases in the heart rate to determine a correlation between the pharmacodynamic and pharmacokinetic measurements. If there is a good correlation, then the area under the plasma concentration-time curve can be used to predict heart rate changes. If there is not a good correlation, this would suggest that the compound may be sequestered in tissues and, thus, have biological activity beyond the exposure measured in the blood. Alternatively, it could indicate that the dose range used was not wide enough to cause a range of responses in the heart rate.
KeywordsDose Group Systemic Exposure Dose Proportionality Linear Trapezoidal Rule Biexponential Model
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- Bailer, A.J. (1998). Testing for the equality of area under the curves when using destructive measurement techniques. Journal of Pharmacokinetics and Biopharmaceutics 16, 303–309.Google Scholar
- Bullingham, R., Monroe, S., Nicholls, A. and Hale, M. (1996). Pharmacokinetics and bioavailability of mycophenolate mofetil in healthy subjects after single-dose oral and intravenous administration. Journal of Clinical Pharmacology 36, 315–324.Google Scholar
- International Conference on Harmonization (1995). Guideline on the assessment of systemic exposure in toxicity studies. Federal Register 60, 112641 1268.Google Scholar
- Piegorsch, W.W. and Bailer, A.J. (1989). Optimal design allocations for estimating area under curves for studies employing destructive sampling. Journal of Pharmacokinetics and Biopharmaceutics 17, 493–507.Google Scholar
- Rae, S., Raboud, J.M., Conway, B., Reiss, P., Vella, S., Cooper, D., Lange, J., Harris, M., Wainberg, M.A., Robinson, P., Myers, M., Hall, D., and Montaner, J.S.G. (1998). Estimates of the virological benefit of antiretroviral therapy are both assay-and analysis-dependent. AIDS. 12, 2185–2192.CrossRefGoogle Scholar
- Vandenhende, F., Dewe, W., and Hoffman, W.P. (1998). A likelihood-based analysis of drug exposure in toxicokinetic studies. The XIXth International Biometric Conference. IBC98, p. 297.Google Scholar
- Yeh, C. (1990). Estimation and significance tests of area under the curve derived from incomplete blood sampling. American Statistical Association, 1990 Proceedings of the Biopharmaceutical Section, pp. 74–81.Google Scholar