Toxicokinetics/toxicodynamic correlations: goals, methods, and limitations.

Toxicokinetic (TK) studies are the basis for demonstrating dose-related drug exposure in animals and for ensuring that drug exposure is substantially greater in animals than that expected in humans at therapeutic doses. The usefulness of TK studies can be further enhanced by correlating TK parameters with relevant toxicologic end points. The so-called TK/toxicodynamic (TD) correlations can be extremely useful in bridging data from studies both within and across species and in designing early Phase I clinical trials. These correlations assume that toxicologic responses are comparable among species at comparable plasma concentrations. This assumption may apply for certain drugs but not for others. Therefore, TK/TD correlations should be developed and utilized on a case-by-case basis. Such correlations have proven to be extremely useful with anticancer drugs in formulating dose escalation strategies in cancer patients to rapidly attain the maximum tolerated and/or effective dose. However, these correlations have not been utilized effectively in other therapeutic areas. The development of TK/TD correlations, their scope, and limitations are discussed in this paper.