The use of kinetic and dynamic data in risk assessment of drugs

The risk assessment process for non-carcinogens must incorporate all availa ble scientific information, including toxicokinetic and toxicodynamic data. The framework for exposure limit setting proposed by Renwick and the Inter national Programme on Chemical Safety (IPCS) subdivides traditional 10X unc ertainty factors (UFs) into separate partial-log default values based on ki netic and dynamic considerations and allows for incorporation of compound-s pecific data when available. In this investigation, an extensive literature search was conducted on nine pharmaceuticals in order to incorporate infor mation on kinetics and dynamics to allow extrapolation across species and a mong susceptible humans. The drugs are diazepam, oxazepam, midazolam, buspi rone, fluoxetine, venlafaxine, amlodipine, felodipine, and nifedipine. The composite factors were calculated using the highest ratio or the average ra tio for appropriate parameters and default subfactor. For the drugs examine d, most of the subfactors for kinetics and dynamics were less than the prop osed values by Renwick and IPCS, and the composite factors were far less th an 100. From this study, it was concluded that relevant compound-specific k inetic and dynamic data can reduce uncertainties associated with interspeci es differences and interindividual variability.