Emmanuel Roilides

BackgroundAlthough glycopeptides are among the most commonly used antimicrobials in neonates with suspected late-onset sepsis, little is known about the pharmacokinetics (PK) of teicoplanin in term and preterm neonates. We aimed to develop a population pharmacokinetic model in order to evaluate currently recommended dosing regimen.MethodsBy using D-Optimal design approach, a sparse PK study was designed and implemented in 60 neonates with post-menstrual age (PMA) of 26-43wks. Dosing regimen: loading dose 16mg/kg, maintenance dose 8mg/kg once daily (i.v. 30min infusion). Four blood samples per neonate were collected. Concentrations were quantified by high-pressure liquid chromatographyu2013mass spectrometry. Population PK analysis was performed using NONMEM software. Final PK model was validated by nonparametric bootstrapping and visual predictive check and Monte-Carlo (MC) simulation were performed.ResultsThe covariate model used was CL=0.0234(WT/1765)0.75 L/h ,V1=0.287(/1765) L, Q=0.159(WT/1765)0.75 L/h, V2=0.515(WT/1765) L, while CRCL was also found to be a significant covariate on CL, it was removed for the MC simulations. Inter-individual variability on clearance (CL), central volume (V1), peripheral volume (V2) was 40%, 47%, 51.2%. MC simulation demonstrated that with dose of 8 mg/kg: 81.6% of neonates with weight (WT)1kg versus 89.6%, 95.1% and 97% of neonates with WT: 1-2kg, 2-3kg, u22654kg, respectively reach the Ctrough(120h)15mg/L. Increase in dose at 12mg/kg results in 93.5% of neonates with WT1kg achieving Ctrough(120h)15mg/L. Respective results were found with the use of AUC/MIC>400 as a target.ConclusionsTeicoplanin population PK is variable in neonates with weight having the most significant impact on pharmacokinetics. Based on MC simulation ELBW and VLBW neonates need higher doses especially for Staphylococcus spp. with MICu22651.

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