Interim pharmacokinetic analysis of a multi-centre randomised open label phase IIb study in neonates to validate the meta-analysis population pharmacokinetic model used to simulate an optimised dosing regimen in neonates and infants aged < 90 days: the NeoVanc trial
Authors: L. Hill, E. Jacqz-Aigrain, V. Elie, W. Zhao, M. Clements, M. Turner, I. Lutsar, P. Heath, E. Roilides, S. Walker, M. Sharland
Published in: 30th European Congress on Clinical Microbiology and Infectious Diseases (ECCMID), April 2020
Background: Vancomycin remains one of the most widely prescribed antibiotics for Gram-positive neonatal late onset sepsis (LOS), however, a consensus on optimal vancomycin dosing and duration is lacking. Robust neonatal clinical pharmacokinetic (PK) data comparing different vancomycin dosing regimens remain sparse. NeoVanc (NCT02790996) is a European, randomised controlled, non-inferiority trial comparing an optimised and standard vancomycin regimen in infants aged ≤90 days with suspected/proven Gram-positive LOS. The optimised regimen was determined through pre-clinical studies including a population PK meta-analysis of individual data from >1600 babies.
Materials/methods: Babies with clinical sepsis (≥3 clinical/laboratory criteria) or confirmed sepsis (Gram-positive blood culture and ≥1 clinical/laboratory criterion) were recruited. Participants were randomised 1:1 to the optimised regimen (vancomycin loading dose (25 mg/kg) followed by 5±1 day course) or a standard regimen (no loading dose;10±2 day vancomycin course). An interim PK analysis was performed; the validation dataset was collected from 8 centres in 5 European countries. Data collected included demographic variables (gestational and postnatal age, birth and current weight), vancomycin admin- istration (dose, time of start and end of infusion, exact sampling time), creatinine concentrations (Jaffe, enzymatic), vancomycin concentrations (ultraperformance liquid chromatography-tandem mass spectrometry).
Results: 68 babies recruited between March 2017 and April 2018 were included in the interim analysis. Gestational age was <29 (n=16), 29–36 (n=22), >35 (n=30) weeks. Median (IQR) birthweight was 1258 (455–4040)g with median weight at randomisation being 1525 (590–4156)g. Median post-menstrual age at randomisation was 33.8(25.1–47) weeks. Median se- rum creatinine was 41.5(8.84–96.36) μmol/L. 240/255 PK and scavenged PK samples were evaluable. Vancomycin concen- trations were used to confirm the reliability of the meta-analysis model where clearance (CL) was dependant on current weight, method used to quantify creatininaemia, renal maturation (RM) and renal function (RF) according to CL= θ6×(CW/1350) θ7×RM×RF×FJaffé-Enzymatic × Frace
Conclusions: External validation with NeoVanc trial PK data confirmed the predictive performance of the model developed fromthe PK meta-analysis.