Rate and extent of drug accumulation after multiple dosing revisited

Abstract

For drugs that have a narrow therapeutic margin in their concentration-effect profile, blood concentration measurements can be an invaluable guide to the individualization of dosage regimens. For clinicians involved in therapeutic drug monitoring, background knowledge of basic pharmacokinetics related to drug behaviour with repeated dose regimens is crucial, especially recognition of the factors affecting the rate and extent of drug accumulation, which ultimately determine the steady-state drug concentrations in the blood. Much of the available literature describing accumulation focuses on average steady-state concentrations or its related parameter, the area under the blood/plasma concentration-time curve. However, in practice, for most drugs, it is the individual concentrations at different times within each dosing interval at steady state that can be more predictive of the effectiveness and/or toxicity of the drug. Furthermore, most reference textbooks describe accumulation in terms of drugs that follow a one-compartment model with bolus administration, whereas the mode of dose administration can have an impact on measures of accumulation in a manner that differs from intravascular bolus dosing. Additionally, the accumulation kinetics in the plasma are profoundly influenced by multicompartment or nonlinear pharmacokinetics. Another consideration in accumulation kinetics is how tissue concentrations might be influenced by repeated doses - which, as shown in this review, can have clinical ramifications. In this article, drug accumulation is reviewed in a comprehensive manner, and the influences of the route of administration, nonlinear elimination and tissue concentrations are discussed.