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Development and external evaluation of a population pharmacokinetic model for continuous and intermittent administration of vancomycin in neonates and infants using prospectively collected data
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. UCL, UCL Great Ormond St Inst Child Hlth, Inflammat Infect & Rheumatol Sect, 30 Guilford St, London WC1N 1EH, England.ORCID iD: 0000-0003-2935-0090
Barts Hlth NHS Trust, Royal London Hosp, Neonatal Unit, Whitechapel Rd, London E1 1BB, England.
Queen Mary Univ London, Barts & London Sch Med & Dent, Blizard Inst, Ctr Genom & Child Hlth, 4 Newark St, London E1 2AT, England.
Queen Mary Univ London, Barts & London Sch Med & Dent, Blizard Inst, Ctr Genom & Child Hlth, 4 Newark St, London E1 2AT, England.
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2019 (English)In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 74, no 4, p. 1003-1011Article in journal (Refereed) Published
Abstract [en]

Background: Vancomycin is commonly used for nosocomial bacterial pathogens causing late-onset septicaemia in preterm infants. We prospectively collected pharmacokinetic data aiming to describe pharmacokinetics and determine covariates contributing to the variability in neonatal vancomycin pharmacokinetics. Further, we aimed to use the model to compare the ratio of AUC(24) at steady-state to the MIC (AUC(24,ss)/MIC) of several intermittent and continuous dosing regimens.

Methods: Newborns receiving vancomycin for suspected or confirmed late-onset sepsis were included. Peak and trough concentrations for intermittent vancomycin dosing and steady-state concentrations for continuous vancomycin dosing were measured. NONMEM 7.3 was used for population pharmacokinetic analysis. Monte Carlo simulations were performed to compare dosing schemes.

Results: Data from 54 infants were used for model development and from 34 infants for the model evaluation {corrected gestational age [median (range)]=29 (23.7-41.9) weeks and 28 (23.4-41.7) weeks, respectively}. The final model was a one-compartment model. Weight and postmenstrual age were included a priori, and then no additional covariate significantly improved the model fit. Final model parameter estimates [mean (SEM)]: CL=5.7 (0.3) L/h/70kg and V=39.3 (3.7) L/70kg. Visual predictive check of the evaluation dataset confirmed the model can predict external data. Simulations using MIC of 1mg/L showed that for neonates with gestational age 25weeks and postnatal age 2weeks AUC(24,ss)/MIC was lower with the intermittent regimen (median 482 versus 663).

Conclusions: A population pharmacokinetic model for continuous and intermittent vancomycin administration in infants was developed. Continuous administration might be favourable for treating infections caused by resistant microorganisms in very young and immature infants.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS , 2019. Vol. 74, no 4, p. 1003-1011
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Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-382504DOI: 10.1093/jac/dky525ISI: 000463812100022PubMedID: 30668696OAI: oai:DiVA.org:uu-382504DiVA, id: diva2:1308086
Available from: 2019-04-30 Created: 2019-04-30 Last updated: 2019-04-30Bibliographically approved

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Germovsek, Eva

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