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Aminoglycoside nephrotoxicity: modeling, simulation, and control.

Florent Rougier¹, Daniel Claude, Michel Maurin

¹UMR CNRS 5558-ADCAPT, Service Pharmaceutique, Hôpital Antoine Charial, Hospices Civils de Lyon, Francheville, France.

Antimicrobial Agents and Chemotherapy

|February 27, 2003

Summary

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Aminoglycoside nephrotoxicity can be predicted using a new deterministic model. Once-daily dosing and afternoon administration minimize kidney damage risk.

Area of Science:

Pharmacology
Nephrology
Mathematical Modeling

Background:

Aminoglycosides pose risks of nephrotoxicity and ototoxicity.
No reliable predictor of aminoglycoside-induced nephrotoxicity currently exists.

Purpose of the Study:

To develop and validate a deterministic model for predicting aminoglycoside nephrotoxicity.
To assess the impact of dosing regimens and circadian rhythms on renal function.

Main Methods:

A two-compartment pharmacokinetic model was developed.
Renal cortex accumulation, cellular effects, tubuloglomerular feedback, and serum creatinine were modeled.
Model parameters were estimated using NPEM and least-squares minimization.
A simulation program assessed dosing regimen influences and circadian rhythm effects.

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Main Results:

The model accurately predicted serum creatinine concentrations in patients (r² = 0.988).
Thrice-daily aminoglycoside administration led to more rapid, severe, and prolonged nephrotoxicity compared to less frequent schedules.
Once-daily administration showed that the time of day impacts nephrotoxicity, with 1:30 p.m. being optimal.

Conclusions:

The developed model reliably predicts aminoglycoside nephrotoxicity.
Optimizing aminoglycoside dosing schedules, including timing, can mitigate renal toxicity.
Clinical application of this model can personalize aminoglycoside therapy for improved efficacy and safety.