Quantitative justification for target concentration intervention--parameter variability and predictive performance...

Area of Science:

• Pharmacokinetics and Pharmacodynamics
• Drug Metabolism and Disposition
• Clinical Pharmacology

Background:

• Aminoglycoside dosing requires individualization due to significant pharmacokinetic variability.
• Predicting aminoglycoside clearance, especially in patients with low creatinine, is challenging.
• Current dosing strategies may not consistently achieve target concentrations.

Purpose of the Study:

• To quantify variability in aminoglycoside clearance and volume of distribution.
• To develop predictive models for aminoglycoside clearance in specific patient populations.
• To evaluate the effectiveness of initial dosing strategies for achieving therapeutic aminoglycoside concentrations.

Main Methods:

• Collected demographic, dosing, and concentration data from 697 adult patients.
• Utilized a target concentration intervention approach for dose individualization.
• Developed a two-compartment pharmacokinetic model incorporating covariates like weight, age, sex, and creatinine.

Main Results:

• Covariate inclusion reduced between-subject variability in clearance from 94% to 36%.
• Key pharmacokinetic parameters were estimated: CL (4.7 L/h/70kg), CLic (1 L/h/70kg), V1 (19.5 L/70kg), V2 (11.2 L/70kg).
• Fixed dosing achieves target concentrations in 35% of patients; covariate-guided predictions improve this to 61%.

Conclusions:

• Target concentration intervention demonstrates potential to achieve safe and effective aminoglycoside doses in 90% of patients.
• Within-subject variability in clearance is less than the safe and effective variability range.
• Individualized dosing strategies are superior to fixed dosing for aminoglycoside therapy.