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Effect of Variability in Pharmacokinetic Parameters on the Derivation of Exposure Limits for Pharmaceutical Compounds

ABSTRACT The purpose of this study was to investigate how variability in pharmacokinetic parameters influences the determination of occupational exposure limits (OEL) for pharmaceutical compounds in potentially susceptible subpopulations. A compartmental pharmacokinetic model for quinidine was applied to derive OELs based on target blood concentrations in humans but relied on pharmacokinetic parameters in subjects with cirrhosis rather than normal subjects. Quinidine was used as the sample compound as this was used in the development of the methodology. The intent was not to set an OEL for quinidine for a particular population but rather to use the methodology to investigate how factors, which may influence susceptibility, could be incorporated into the analysis. The model was used to simulate exposure concentrations that would result in levels below those that cause undesirable pharmacological effects taking into account variability in parameters through incorporation of Monte Carlo sampling. Results indicate that cirrhotic patients did not require additional protection from occupational exposure to quinidine. These results cannot be extrapolated to other compounds, as the effects of variability in pharmacokinetics on systemic exposure are compound specific. However, this methodology does provide a framework for addressing issues related to the contribution of pharmacokinetics to susceptibility from occupational exposure to pharmaceutical compounds.