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 different patient populations, leading to a plethora of subgroup-specific 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 specific patient subgroups. Methods A pooled population-pharmacokinetic model was built in NONMEM based on data from 14 different studies in different 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 final 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 V 1 , V 2 , CL and Q 2 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-stratified dosing regimens of vancomycin and for individualisation of treatment through therapeutic drug monitoring and Bayesian forecasting.

Genetic Algorithms as a Tool for Dosing Guideline Optimization: Application to Intermittent Infusion Dosing for Vancomycin in Adults

“…Guidelines for dose individualization in routine clinical practice are often based on local experience or expert opinion and it is unclear to what extent such guidelines actually achieve target concentrations or exposure. A recent study 8 found that consensus guidelines produced by the US Food and Drug Administration (FDA) and also the Summary of Product Characteristics for vancomycin performed poorly when tested using a large population of patients. Furthermore, even when guidelines are available, they may not be in a form that can be implemented effectively.…”

“…Furthermore, even when guidelines are available, they may not be in a form that can be implemented effectively. For example, although Colin et al 8 . found that modified versions of the FDA and Summary of Product Characteristics guidelines were more likely to achieve target exposure, the resulting dose amounts were impractical for routine clinical application.…”

“…The present study uses a novel approach to define a dosing guideline and, due to the extensive patient database used for the original population PK study, 8 covers a wide range of patient characteristics with no specific exclusions except renal replacement therapy. This study aimed to optimize dosing during the first 3 days of therapy, with the assumption that early target attainment potential avoids therapy failure, 31 and that therapeutic drug monitoring samples will be measured within this timescale that can be used to further individualize therapy.…”

“…For all other candidate solutions, the fitness criterion was derived from the simulated concentration time profiles. To simulate concentration time profiles, we used a virtual adult patient population based on the adult data from the vancomycin PK model developed by our group 8 ( n = 1,635 patients from 10 studies). From this dataset, 10,000 sets of patient characteristics were randomly sampled.…”

“…PK parameters were then simulated according to the model by Colin et al ., 8 taking into account interindividual variability. Vancomycin administration was simulated as a short infusion.…”