Intra-Species Extrapolation in Risk Assessment of Different Classes of Antimicrobials

Abstract

The risk assessment process for non-carcinogens incorporates all available scientific information, including toxicokinetic and toxicodynamic data. A 10-fold uncertainty factor (UF) is most commonly used to account for underlying variability within the human species. The purposes of this investigation are to evaluate whether the magnitude of the 10X-UF can be reduced when pharmacokinetic and pharma-codynamic data are incorporated to characterize interindividual variability and whether another UF is needed for the children group. An extensive literature search was conducted on seven antimicrobials in order to incorporate information on kinetics and dynamics to allow extrapolation among susceptible humans. The drugs are cefaclor, cefuroxime, erythromycin, clarithromycin, ampicillin, gentamicin and amikacin. The composite factor was calculated using the highest ratio for appropriate parameters and default subfactor. According to the data, we concluded that when relevant kinetic and dynamic data are available, replacing the default factors with actual data-derived values was possible for the antimicrobials evaluated and that there is no need to add another UF to the children group.

Keywords:

• risk assessment
• uncertainty factor
• interindividual variability
• pharmacokinetics
• pharmacodynamics.