Efficacy, nephrotoxicity and ototoxicity of aminoglycosides, mathematically modelled for modelling-supported therapeutic drug monitoring

Abstract

Therapeutic drug monitoring (TDM) of aminoglycosides has been a topic during the last thirty years. There is a tendency that - because of the once-daily regimen - TDM is considered not necessary anymore. Although once daily dosing has the potential for decreased toxicity, long-term usage can cause severe nephro- and ototoxicity. Furthermore, inadequate plasma concentrations can lead to treatment failure. This work is devoted to the development and application of the first mathematical model of aminoglycosides, which simulates in relation to the pharmacokinetics both their effects on bacteria as well as their nephrotoxicity and cochleotoxicity. Our software system is suitable for TDM. Based on theoretical considerations, a multi-compartment mathematical model in a numerical program in Matlab is derived that incorporates the antimicrobial effects of aminoglycosides, the saturable and active uptake into kidney cells, the reversible nephrotoxicity and the irreversible cochleotoxicity. Using fictitious person data, and an assumed pharmacokinetic and dynamic parameter set obtained from the literature, we simulated the drug concentrations, antibacterial effects, and toxicity over time in virtual patients to illustrate the benefits of optimized, efficacious dosage regimens that minimize (acceptable) nephro- and auditory ototoxicity. Our model confirms that extended-interval dosing seems the most appropriate to achieve this goal. By this manner, the present mathematical model contributes to an increase in our knowledge of how to obtain an optimized dosing strategy for individual patients. With the developed program, we are able to demonstrate that optimal aminoglycoside dosing still needs a sophisticated system of TDM.