Vancomycin Pharmacokinetics Throughout Life: Results from a Pooled Population Analysis and Evaluation of Current Dosing Recommendations

Abstract
Background and Objectives
Uncertainty exists regarding the optimal dosing regimen for vancomycin in diferent patient populations, leading to a plethora of subgroup-specifc pharmacokinetic models and derived dosing regimens. We aimed to investigate whether a single model for vancomycin could be developed based on a broad dataset covering the extremes of patient characteristics. Furthermore, as a benchmark for current dosing recommendations, we evaluated and optimised the expected vancomycin exposure throughout life and for specifc patient subgroups.

Methods
A pooled population-pharmacokinetic model was built in NONMEM based on data from 14 diferent studies in diferent patient populations. Steady-state exposure was simulated and compared across patient subgroups for two US Food and Drug Administration/European Medicines Agency-approved drug labels and optimised doses were derived.

Results
The fnal model uses postmenstrual age, weight and serum creatinine as covariates. A 35-year-old, 70-kg patient with a serum creatinine level of 0.83 mg dL−1 (73.4 µmol L−1) has a V1, V2, CL and Q2 of 42.9 L, 41.7 L, 4.10 L h−1 and 3.22 L h−1. Clearance matures with age, reaching 50% of the maximal value (5.31 L h−1 70 kg−1) at 46.4 weeks postmenstrual age then declines with age to 50% at 61.6 years. Current dosing guidelines failed to achieve satisfactory steady-state exposure across patient subgroups. After optimisation, increased doses for the Food and Drug Administration label achieve consistent target attainment with minimal (±20%) risk of under- and over-dosing across patient subgroups.

Conclusions
A population model was developed that is useful for further development of age and kidney function-stratifed dosing regimens of vancomycin and for individualisation of treatment through therapeutic drug monitoring and Bayesian forecasting.