Exponential intravenous infusions in toxicological studies: achieving identical serum drug concentration profiles in individuals with altered pharmacokinetic states.

ABSTRACT

It is common practice in the clinical setting to adjust the dosage of a drug administered to a patient with altered pharmacokinetic characteristics, e.g., renal impairment, in such a way that the steady-state level of the drug is the same as that which would be observed in normal patients. This may also be done in experimental studies of the interaction of drug toxicity and a disease state. Dosage adjustment does alter average steady-state serum concentrations but the resulting concentration-time profiles of the normal and the diseased groups will be of entirely different shapes due to differences in elimination. In a toxicological study, this would lead to a confounding of the disease state and the difference in exposure. In this paper, model-independent deconvolution analysis is applied to derive the infusion schedule needed to achieve a constant serum concentration followed by a predetermined monoexponential decline in concentration. The resulting exponential infusion is applied to attain identical serum gentamicin concentration-time profiles in five pairs of subtotally nephrectomized and normal dogs during a 12-h infusion.