Pharmacodynamics species specificity

The ABPI/BIA taskforce recommendation of basing the first human dose on the MABEL, rather than solely on the NOAEL in a toxicology species, would have led to a lower and less hazardous human starting dose. These recommendations should guide design of future preclinical safety programs and future FIH clinical protocols, particularly for products with novel targets and mechanisms and pharmacodynamics and with restricted species specificity. 

For brevity, only the pivotal toxicology studies are given. Examples of studies not included are proof-of-concept, comparability, toxicokinetic, pharmacokinetic, pharmacodynamic, local tolerance, and miscellaneous in vitro and in vivo studies. Pharmacokinetic and pharmacodynamic experiments generally used the pivotal toxicology animal model(s) because of the species specificity of the biopharmaceutical. 

The use of pharmacodynamic end points for high-dose selection is considered to be highly compound specific and is considered for individual study designs on the basis of scientific merit. The high dose should produce a pharmacodynamic response in the test species that precludes further dose escalation but does not produce disturbances of physiology or homeostasis that would compromise the validity of the carcinogenicity study. Examples of such pharmacodynamic endpoints include hypotension and inhibition of blood clotting. 

The UEL for reproductive and developmental toxicity is derived by applying uncertainty factors to the NOAEL, LOAEL, or BMDL. To calculate the UEL, the selected UF is divided into the NOAEL, LOAEL, or BMDL for the critical effect in the most appropriate or sensitive mammalian species. This approach is similar to the one used to derive the acute and chronic reference doses (RfD) or Acceptable Daily Intake (ADI) except that it is specific for reproductive and developmental effects and is derived specifically for the exposure duration of concern in the human. The evaluative process uses the UEL both to avoid the connotation that it is the RfD or reference concentration (RfC) value derived by EPA or the ADI derived for food additives by the Food and Drug Administration, both of which consider all types of noncancer toxicity data. Other approaches for more quantitative dose-response evaluations can be used when sufficient data are available. When more extensive data are available (for example, on pharmacokinetics, mechanisms, or biological markers of exposure and effect), one might use more sophisticated quantitative modeling approaches (e.g., a physiologically based pharmacokinetic or pharmacodynamic model) to estimate low levels of risk. Unfortunately, the data sets required for such modeling are rare. 

---