Evaluating Bayesian Vancomycin Dosage Adjustment in Neonates: A Simulation-Based Virtual TDM Study

Therapeutic drug monitoring (TDM) of vancomycin, ideally based on the ratio of the daily area under the curve to the minimal inhibitory concentration at steady state (AUC_24,SS/MIC), is hindered by sampling limitations in neonates, so trough concentration (C_trough) is often used as a surrogate. This virtual TDM study aimed to evaluate the performance of Bayesian model-informed precision dosing (MIPD) for vancomycin in neonates.

Reference pharmacokinetic (PK) parameters and drug concentrations were simulated in NONMEM for 1000 virtual neonates using a published population PK model. Four TDM strategies were compared based on the percentage of patients achieving an AUC_24,SS/MIC between 360 and 540 h. Strategy 1 maintained the initial regimen unchanged; strategy 2 adjusted doses using a standard rule of three to target a C_trough of 10-15 mg/L; strategies 3 and 4 used the MIPD software Tucuxi with a steady-state C_trough and two concentrations after the first dose, respectively, for Bayesian dosage optimization. Individual dosages were adjusted following each strategy, recalculating AUC_24,SS to determine the percentage of target attainment. Iterative adjustments were performed by resampling C_trough. A sub-study evaluated optimal sampling time by comparing Tucuxi-estimated AUC_24,SS with the reference value.

Less than 49% of patients reached the target with strategy 1, leading to frequent vancomycin overexposure. Strategy 2 enabled over 75% of patients to achieve AUC_24,SS/MIC between 360 and 540 h with every-8-h regimens, but only 31% with longer dosing intervals. Strategies 3 and 4 allowed over 74% of patients to reach the target after one TDM cycle and 100% after four cycles, regardless of the initial dosing regimen. A single sample sufficed for accurate AUC_24,SS prediction.

This virtual TDM study indicates that Bayesian MIPD optimizes vancomycin exposure in neonates, while simplifying the sampling strategy. This approach deserves to be integrated and validated in routine neonatal care.