Predictive Performance of a Vancomycin Population Pharmacokinetic Model in Neonates

Introduction The pharmacokinetics of vancomycin are highly variable among neonates, which makes dosing challenging in this population. However, adequate drug exposure is critical, especially when treating methicillin-resistant Staphylococcus aureus (MRSA) infections. Utilization of population pharmacokinetic models and Bayesian methods offers the potential for developing individualized therapeutic approaches. To meet this need, a neonatal vancomycin population pharmacokinetic model was recently published. The current study sought to externally evaluate the predictive performance and generalizability of this model. Methods A retrospective chart review of neonates who received vancomycin and had ≥1 peak and ≥1 trough concentrations at five Intermountain Healthcare neonatal intensive care units from 2006 to 2013 was performed and served as the external validation cohort. The published population pharmacokinetic model was implemented in NONMEM 7.2 with the structural and variance parameter values set equal to the estimates reported previously. The model was then used to predict the first peak and trough concentration for each neonate in the validation cohort and the model prediction error and absolute prediction error were calculated. Normalized prediction distribution errors (NPDE) were also evaluated. Results A total of 243 neonates were studied with a median postmenstrual age of 33 (range: 23–54) weeks and a median weight of 1.6 (range: 0.4–6.8) kg. The model predicted the observed vancomycin concentrations with reasonable precision. For all vancomycin concentrations, the median prediction error was −0.8 (95% CI: −1.4 to −0.4) mg/L and the median absolute prediction error was 3.0 (95% CI: 2.7–3.5) mg/L. No trends in NPDE across weight, postmenstrual age, serum creatinine, or time after dose were observed. Conclusion An evaluation of a recently published neonatal vancomycin population pharmacokinetic model in a large external dataset supported the predictive performance and generalizability of the model. This model may be useful in evaluating neonatal vancomycin dosing regimens and estimating the extent of drug exposure. Electronic supplementary material The online version of this article (doi:10.1007/s40121-015-0067-9) contains supplementary material, which is available to authorized users.

Results: A total of 243 neonates were studied with a median postmenstrual age of 33 (range: Electronic supplementary material The online version of this article (doi:10.1007/s40121-015-0067-9) contains supplementary material, which is available to authorized users.

INTRODUCTION
Optimizing vancomycin dosing to rapidly achieve adequate drug exposure is imperative in treating neonatal sepsis, particularly when treating invasive methicillin-resistant Staphylococcus aureus (MRSA) infections [1]. However, this has been challenging in neonates as the pharmacokinetics of vancomycin are highly variable among neonates due to developmental and pathophysiological changes [2,3]

Validation Cohort
Approval to conduct this study was granted by  (used in the current external validation cohort), a previously described linear conversion factor was applied to all of the enzymatic serum creatinine concentrations included in this external validation (enzymatic concentration ¼ 1:050 Â Jaffe method concentration À 0:122) [12]. Exclusion criteria included a diagnosis of congenital kidney disease, major congenital heart disease (other than ventricular septal defect, atrial septal defect, or patent ductus arteriosus), or extracorporeal membrane oxygenation during the vancomycin course.

Model Evaluation
The published neonatal vancomycin population pharmacokinetic model was implemented in the non-linear mixed effects modeling software NONMEM 7.2 (ICON Development Solutions, Ellicott City, MD, USA) as previously described [7]. Briefly, a one

External Validation Cohort
Overall, 243 neonates had vancomycin dose and concentration data available and served as the external validation cohort (see Fig. S1

Model Evaluation
The vancomycin pharmacokinetic model adequately described the observed vancomycin concentrations in the external cohort of APGAR Newborn scale based on Appearance, Pulse, Grimace, Activity, and Respiration a Patient characteristics of the 249 neonates used to develop the neonatal vancomycin population pharmacokinetic model described by Frymoyer et al. [7] b Patient characteristics of the 243 neonates used in the current external validation c The serum creatinine concentration in the model derivation cohort was measured using the Jaffe method. The serum creatinine concentration in the external validation cohort was measured using the enzymatic method and was converted to a Jaffe-standardized equivalent using a linear equation described by Srivastava et al. [12]. Converted values are presented in the table above neonates (Fig. 1a) (Fig. 2).  and higher trough concentrations was observed in the external validation cohort (r 2 = 0.60; Fig. 3a). AUC 24 was highly variable at a given trough concentration (i.e., a two-to threefold range of AUC 24 was achieved at a given trough concentration), and therefore, AUC 24 could not However, a trough concentration of 11 mg/L predicted the achievement of an AUC 24 C400 in 93% of neonates (Fig. 3b). The median (range) AUC 24 at this trough concentration was 542 (308 to 649) mg 9 hr/L.

DISCUSSION
External validation of a population pharmacokinetic model is described by the United States Food and Drug Administration as ''the most stringent method for testing a developed model'' [16]. Yet, external validation   Until more robust clinical dosing support tools are developed, clinicians will continue to rely on trough concentration monitoring to help guide vancomycin dosing in neonates. Our findings reinforce the large variability observed in vancomycin trough concentrations among neonates and the inability of a trough concentration alone to reliably predict an individual neonate's AUC 24 . Targeting an AUC 24 /MIC C400 is recommended by the Infectious Disease Society of America when treating invasive MRSA infections and a trough concentration of 15-20 mg/L is suggested in adults to achieve this target [1,21]. The current study provides further support that in neonates a vancomycin trough concentration of 15-20 mg/L is unnecessary to achieve an AUC 24 /MIC C400 with an MIC B1 mg/L and that lower trough concentrations are likely adequate based on AUC 24 considerations [7]. Accordingly, a trough concentration of approximately 10 mg/L is likely a reasonable first-line target that will provide adequate exposure for invasive MRSA while also appropriately covering for coagulase negative staphylococcal infections. Further dose adjustment and individualization of the therapeutic approach should be guided by the specific pathogen identified, susceptibility testing, clinical status, etc. For example, for MRSA infections with MICs C2 mg/L, an alternative to vancomycin may be necessary since an AUC 24 /MIC C400 will not be achieved in neonates even at trough concentrations of 15-20 mg/L [7]. Lastly, the extent to which the target AUC 24 /MIC C400 is generalizable to neonates is unclear and requires further study.