Precision Daptomycin Dosing: Comparison of 3-, 2-, 1-, and 0-Concentration Sample Strategies

Area of Science:

• Pharmacokinetics and Pharmacodynamics
• Infectious Diseases
• Clinical Pharmacy

Background:

• Daptomycin, a lipopeptide antibiotic, has a narrow therapeutic window, necessitating precise dosing.
• Increasing use of higher daptomycin doses (8-12 mg/kg) for resistant gram-positive infections heightens the need for effective therapeutic drug monitoring (TDM).
• Optimizing daptomycin TDM strategies is crucial for balancing therapeutic efficacy and minimizing toxicity.

Purpose of the Study:

• To evaluate the precision and bias of estimating daptomycin's 24-hour area under the curve (AUC24) using a mid-point sample.
• To compare the mid-point sampling strategy against traditional peak and trough samples for AUC24 determination.
• To assess both simple calculation and Bayesian modeling methods for AUC24 estimation versus no TDM.

Main Methods:

• Analysis included adult patients with at least three steady-state daptomycin concentrations (peak, mid-point, trough).
• A one-compartment population pharmacokinetic model was employed using Bayesian estimation (Monolix Suite 2024R1).
• AUC24 was estimated using all concentrations (AUCref), and re-estimated with individual or paired samples (peak + trough); performance was assessed via regression analysis (R² and mean bias).

Main Results:

• Of 210 patients, only 45.7% achieved the target AUC24 range (666-939 mg·h/L) with a mean AUC24 of 869 mg·h/L.
• A single mid-point sample showed similar correlation to AUC24 (R²=0.57) as trough-only (R²=0.55), outperforming peak-only (R²=0.44).
• Bayesian estimation using peak and trough samples yielded the highest accuracy (R²=0.87) and lowest bias.

Conclusions:

• A mid-interval sampling strategy for daptomycin offers a practical alternative for AUC estimation when full sampling is unfeasible.
• The two-sample Bayesian approach demonstrates superior accuracy, supporting its broader implementation for individualized daptomycin dosing.
• Optimized TDM strategies are vital for maximizing daptomycin's effectiveness in treating challenging gram-positive infections.