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Gentamicin, an aminoglycoside antibiotic, is commonly administered via intermittent intravenous infusion to treat severe infections. An intermittent one-hour infusion of gentamicin, administered at eight-hour intervals, allows for precise control of plasma drug concentrations, minimizing toxicity while ensuring therapeutic efficacy. Pharmacokinetic principles govern the dynamics of plasma concentrations and can be mathematically described using specific equations.The plasma drug concentration...
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A loading dose is an essential pharmacological strategy to rapidly achieve the target plasma drug concentration necessary for an immediate therapeutic effect. This approach is especially critical for drugs characterized by slow absorption or extended half-lives, where delaying therapeutic plasma levels could compromise treatment outcomes. By administering a loading dose, clinicians ensure a prompt onset of drug action, even for agents with complex pharmacokinetic profiles.Achieving steady-state...
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Optimal control for colistin dosage selection.

Aline Vidal Lacerda Gontijo1,2, André V G Cavalieri3

  • 1Department of Clinical and Toxicological Analysis, Federal University of Alfenas, Rua Gabriel Monteiro da Silva 700, Centro, Alfenas, MG, 37130-001, Brazil. aline.gontijo@gmail.com.

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|June 22, 2021
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Summary

Optimizing antibiotic dosing with pharmacokinetic models reduces bacterial resistance. This study uses optimal control to refine colistin dosage, minimizing harmful concentration deviations for better patient outcomes.

Keywords:
ColistinOptimal controlOptimization of drug administrationPK model

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Area of Science:

  • Pharmacology
  • Mathematical Modeling
  • Infectious Disease

Background:

  • Antibiotic resistance necessitates optimized drug administration.
  • Current trial-and-error dosing methods using pharmacokinetic (PK) models have limitations, especially for loading doses.
  • Colistin, a last-resort antibiotic, has a narrow therapeutic window requiring precise dosing to avoid toxicity or sub-therapeutic levels.

Purpose of the Study:

  • To formulate an optimal control problem for colistin dosage selection using a PK model.
  • To minimize deviations between colistin plasma concentration and a target value (2 mg/L).
  • To enable personalized dosage optimization for individual patients.

Main Methods:

  • A three-compartment pharmacokinetic (PK) model was employed.
  • An optimal control problem was formulated to minimize concentration deviations.
  • An adjoint model was utilized to determine the sensitivity of concentration deviations to dose changes.

Main Results:

  • Shorter administration intervals (e.g., every 8 hours) resulted in significantly lower deviations from the target concentration compared to longer intervals (e.g., every 24 hours).
  • An optimal loading dose regimen involves dividing the dose into two or more administrations, with a high initial dose followed by lower ones.
  • This optimized regimen is more effective in reaching target concentrations quickly than traditional trial-and-error methods, particularly for patients with varying renal function.

Conclusions:

  • The optimal control method offers a refined approach to antibiotic dosage optimization, improving upon traditional methods.
  • Dividing colistin loading doses is crucial for rapidly achieving therapeutic concentrations and avoiding adverse effects.
  • This approach enhances antibiotic treatment efficacy by minimizing sub-therapeutic or toxic concentrations, crucial for last-resort drugs like colistin.