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Evaluation of vancomycin dosing regimens in preterm and term neonates using Monte Carlo simulations

Nitin Mehrotra, Lisa Tang, Stephanie J Phelps, Bernd Meibohm
Pharmacotherapy 2012, 32 (5): 408-19

STUDY OBJECTIVE: To compare four common dosing regimens for vancomycin in preterm and term neonates by assessing the probability that each regimen would achieve the widely used therapeutic target serum trough concentrations of 5-15 mg/L and the newly suggested target of 15-20 mg/L.

DESIGN: Retrospective population pharmacokinetic analysis using therapeutic drug monitoring data obtained from 1990-2007, with a subsequent simulation study performed on the pharmacokinetic model.

SETTING: Tertiary-care children's hospital.

PATIENTS: One hundred thirty-four preterm (66%) and term (34%) neonates, with a postnatal age of 1-121 days and postmenstrual age of 24.6-44 weeks.

MEASUREMENTS AND MAIN RESULTS: Therapeutic drug monitoring data for vancomycin were used to develop a population pharmacokinetic model in the target population. Parameter estimates for the derived pharmacostatistical model were used to perform Monte Carlo simulations for four recommended dosing regimens: a standard dose for all neonates, postmenstrual age-based dosing, postmenstrual and postnatal age-based dosing, and serum creatinine-based dosing. Multivariate age-weight distributions were established for term and preterm neonates using Centers for Disease Control and Prevention growth charts and intrauterine and postnatal growth charts from the literature, respectively. Each dosing regimen was treated as a separate scenario in which 200 replicates with 100 patients/replicate were simulated. The 5-15-mg/L target trough serum concentration was achieved in 34% (90% confidence interval [CI] 20-53%), 42% (90% CI 31-55%), 52% (90% CI 43-60%), and 63% (90% CI 54-72%) of patients receiving the standard dose, postmenstrual age-based dose, postmenstrual and postnatal age-based dose, and serum creatinine-based dose, respectively. Serum creatinine-based dosing produced trough concentrations predominantly in the 5-15-mg/L target range, with the smallest variability in both term and preterm neonates. As expected, when the target range was narrow and higher (15-20 mg/L), only 13-21% of patients were within the range across the four dosing regimens.

CONCLUSION: Monte Carlo simulations based on our population pharmacokinetic model suggest that vancomycin dosing guidelines based on serum creatinine concentration have a greater likelihood of achieving trough concentrations in the 5-15-mg/L range compared with other evaluated dosing regimens. None of the four dosing regimens is suitable to produce target trough concentration of 15-20 mg/L in an acceptable number of patients.


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