Evaluating the 10X Uncertainty Factor for Children and Elderly with Data-Derived Values for Neuromuscular Blocking Agents

Abstract

Conventional risk assessment process utilizes a 10-fold uncertainty factor (UF) to extrapolate from the general human population to sensitive subgroups, such as children and elderly. The purpose of this investigation was to evaluate whether the magnitude of the 10X-UF can be reduced when pharmacokinetic and pharmacodynamic data are incorporated to characterize human sensitivity. An extensive literature search was conducted on seven neuromuscular blocking agents (mivacurium, atracurium, rocuronium, vecuronium, doxacurium, pancuronium, pipecuronium). Composite factors (kinetics × dynamics) were calculated using the highest dataderived kinetic and dynamic values. For the drugs examined, all of the composite factors for the sensitivity of children were lower than 5. In the elderly, all of the composite factors were lower than 10, and five of seven composite factors were less than 5. From this study, it was concluded that relevant compound-specific kinetic and dynamic data can reduce the uncertainties associated with sensitive subgroups.

Characterization of the human kinetic adjustment factor for the health risk assessment of environmental contaminants

“…Often, such studies were used to develop the so‐called “categorical” IVF, i.e., factors attributed to the TK component of groups of substances sharing similar characteristics. These characteristics might be related to their pharmacological activity (e.g., Naumann et al ., ; Silvermann et al ., 1999; Skowronski and Abdel‐Rahman, ; Suh and Abdel‐Rahman, ) or their metabolic pathways (e.g., Dorne et al ., ; Ginsberg et al ., , , 2004; Lin and Lu, ). Of particular interest, Ginsberg et al .…”