Quantitative interpretation of corticosteroid pharmacokinetics in inner fluids using computer simulations

Abstract

The delivery of drugs to the inner ear by applying them directly onto the round window membrane is a promising way to treat human inner ear disorders. To further develop this strategy, and to design controlled clinical trials, additional preclinical studies are necessary. It is especially important to derive the time course and total dose for the various target regions within the inner ear. Since direct pharmacokinetic measurements in the human cochlea are not possible, simulations provide a valuable tool for the interpretation and planning of animal studies, for evaluating changes of application protocols and drug delivery systems, and for extrapolating the results from animal studies to the human. The present study has analyzed two previously published data sets in which concentration time courses of corticosteroids in the cochlear fluids were reported. Drug movements were simulated with a finite element computer model of the inner ear fluids. The time course of corticosteroid pharmacokinetics could be approximated for each study by consideration of the specific experimental paradigm. Although the experimental studies reported considerably different drug levels in the fluid samples taken from the cochlea, these differences were largely explained by considering the experimental design of the respective studies. After correction for experimental differences, the calculated perilymph levels of drug were within a factor of two of each other. The simulations demonstrated that an important factor controlling the drug level achieved is the time the drug solution remains in the middle ear. It can be concluded that small differences in delivery protocols may cause large variations in the drug levels achieved in the inner ear fluids.