A005: Implications of Being Born Small for Gestational Age on the Exposure of Vancomycin & Gentamicin In Neonates

Statement of Purpose, Innovation or Hypothesis: The pharmacokinetics (PK) of drugs in neonates vary widely due to variation with gestational age (GA), birth bodyweight (bBW), postnatal age (PNA) and current bodyweight (cBW). In neonatal PK studies and for neonatal dosing, the influence of being born small for gestational age (SGA) (i.e., bBW < 10th percentile of the bBW for GA) has largely been ignored. Here, we determine the influence of being born SGA on the PK of vancomycin and gentamicin in neonates and quantify its influence on exposure when dosing vancomycin and gentamicin according to a national dosing guideline.

Description of Methods & Materials: Fenton growth charts [1] were used to identify the SGA or AGA status of the neonates included in two previously published population PK models for vancomycin and gentamicin (Table 1) [2]. Within these models, a covariate analysis was performed quantifying the influence of SGA in the context of other covariates like bBW, GA and PNA. The impact of SGA on different exposure measures of vancomycin and gentamicin was evaluated using deterministic simulations based on individual patient characteristics for the patients in the datasets. Vancomycin and gentamicin were dosed according to the Dutch Pediatric Formulary using four different subgroups based on bBW (< or > 2.5 kg) and PNA (< or > 7 days) or GA ( < 32, 32-37 and > 37) and PNA ( > or > 7 days), respectively [3]. Target for vancomycin and gentamicin efficacy was an AUC 400 – 600 mg*h/L and AUC > 90 mg* h/L, respectively, and peak levels 8 - 12 mg/L for gentamicin. For gentamicin toxicity, target trough levels were < 0.5 - 1 mg/L.

Data & Results: For both vancomycin and gentamicin, SGA proved a significant covariate for clearance (CL). CL was 30% or 19% higher in SGA neonates compared to AGA neonates with the same bBW and PNA for vancomycin and gentamicin, respectively (p < 0.001), in a model with bBW and PNA as covariates. Implications of being born SGA are a lower AUC in SGA versus AGA neonates with 70% versus 39.5%  of the individuals having an AUC < 400 mg*h/L when vancomycin is dosed according to the Dutch Pediatric Formulary [3] (Figure 1). For gentamicin, there were no major differences in target attainment for AUC and peak levels in SGA versus AGA neonates. For the majority of the SGA and AGA neonates trough levels were > 1 mg/L (78.6% versus 83%).

Interpretation, Conclusion or Significance: Being born SGA has a significant impact on CL of both vancomycin and gentamicin in neonates. The results show that SGA neonates have higher CL of these renally excreted drugs, likely as a result of a higher GA in comparison to AGA neonates of the same bBW and PNA. Model-based evaluations show that below-target AUC occurs more often in SGA neonates when dosed according to a national dosing guideline, particularly for vancomycin, which requires further attention in neonatal dosing guidelines.

Disclosures: This research was sponsored by STIMAG (Stichting Management Apothekers en de Gezondheidszorg).

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