Population pharmacokinetic meta-analysis of individual data to design the first randomized efficacy trial of vancomycin in neonates and young infants

Evelyne Jacqz-Aigrain, Stephanie Leroux, Alison H. Thomson, Karel Allegaert, Edmund V. Capparelli, Valerie Biran, Nicolas Simon, Bernd Meibohm, Yoke-Lin Lo, Remedios Marques, José-Esteban Peris, Irja Lutsar, Jumpei Saito , Hidefumi Nakamura , Johannes N. van den Anker, Mike Sharland, Wei Zhao

Research output: Contribution to journalArticle

Abstract

OBJECTIVES: In the absence of consensus, the present meta-analysis was performed to determine an optimal dosing regimen of vancomycin for neonates. METHODS: A 'meta-model' with 4894 concentrations from 1631 neonates was built using NONMEM, and Monte Carlo simulations were performed to design an optimal intermittent infusion, aiming to reach a target AUC0-24 of 400 mg·h/L at steady-state in at least 80% of neonates. RESULTS: A two-compartment model best fitted the data. Current weight, postmenstrual age (PMA) and serum creatinine were the significant covariates for CL. After model validation, simulations showed that a loading dose (25 mg/kg) and a maintenance dose (15 mg/kg q12h if <35 weeks PMA and 15 mg/kg q8h if ≥35 weeks PMA) achieved the AUC0-24 target earlier than a standard 'Blue Book' dosage regimen in >89% of the treated patients. CONCLUSIONS: The results of a population meta-analysis of vancomycin data have been used to develop a new dosing regimen for neonatal use and to assist in the design of the model-based, multinational European trial, NeoVanc.

LanguageEnglish
Pages2128-2138
Number of pages11
JournalJournal of Antimicrobial Chemotherapy
Volume74
Issue number8
Early online date2 May 2019
DOIs
Publication statusPublished - 31 Aug 2019

Fingerprint

Vancomycin
Meta-Analysis
Pharmacokinetics
Newborn Infant
Population
Creatinine
Weights and Measures
Serum

Keywords

  • vancomycin
  • steady state
  • drug loading dose
  • drug maintenance dose
  • creatinine tests
  • infusion procedures

Cite this

Jacqz-Aigrain, Evelyne ; Leroux, Stephanie ; Thomson, Alison H. ; Allegaert, Karel ; Capparelli, Edmund V. ; Biran, Valerie ; Simon, Nicolas ; Meibohm, Bernd ; Lo, Yoke-Lin ; Marques, Remedios ; Peris, José-Esteban ; Lutsar, Irja ; Saito , Jumpei ; Nakamura , Hidefumi ; van den Anker, Johannes N. ; Sharland, Mike ; Zhao, Wei . / Population pharmacokinetic meta-analysis of individual data to design the first randomized efficacy trial of vancomycin in neonates and young infants. In: Journal of Antimicrobial Chemotherapy. 2019 ; Vol. 74, No. 8. pp. 2128-2138.
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abstract = "OBJECTIVES: In the absence of consensus, the present meta-analysis was performed to determine an optimal dosing regimen of vancomycin for neonates. METHODS: A 'meta-model' with 4894 concentrations from 1631 neonates was built using NONMEM, and Monte Carlo simulations were performed to design an optimal intermittent infusion, aiming to reach a target AUC0-24 of 400 mg·h/L at steady-state in at least 80{\%} of neonates. RESULTS: A two-compartment model best fitted the data. Current weight, postmenstrual age (PMA) and serum creatinine were the significant covariates for CL. After model validation, simulations showed that a loading dose (25 mg/kg) and a maintenance dose (15 mg/kg q12h if <35 weeks PMA and 15 mg/kg q8h if ≥35 weeks PMA) achieved the AUC0-24 target earlier than a standard 'Blue Book' dosage regimen in >89{\%} of the treated patients. CONCLUSIONS: The results of a population meta-analysis of vancomycin data have been used to develop a new dosing regimen for neonatal use and to assist in the design of the model-based, multinational European trial, NeoVanc.",
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Jacqz-Aigrain, E, Leroux, S, Thomson, AH, Allegaert, K, Capparelli, EV, Biran, V, Simon, N, Meibohm, B, Lo, Y-L, Marques, R, Peris, J-E, Lutsar, I, Saito , J, Nakamura , H, van den Anker, JN, Sharland, M & Zhao, W 2019, 'Population pharmacokinetic meta-analysis of individual data to design the first randomized efficacy trial of vancomycin in neonates and young infants' Journal of Antimicrobial Chemotherapy, vol. 74, no. 8, pp. 2128-2138. https://doi.org/10.1093/jac/dkz158

Population pharmacokinetic meta-analysis of individual data to design the first randomized efficacy trial of vancomycin in neonates and young infants. / Jacqz-Aigrain, Evelyne; Leroux, Stephanie; Thomson, Alison H.; Allegaert, Karel ; Capparelli, Edmund V.; Biran, Valerie; Simon, Nicolas; Meibohm, Bernd; Lo, Yoke-Lin; Marques, Remedios; Peris, José-Esteban ; Lutsar, Irja; Saito , Jumpei; Nakamura , Hidefumi; van den Anker, Johannes N.; Sharland, Mike; Zhao, Wei .

In: Journal of Antimicrobial Chemotherapy, Vol. 74, No. 8, 31.08.2019, p. 2128-2138.

Research output: Contribution to journalArticle

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T1 - Population pharmacokinetic meta-analysis of individual data to design the first randomized efficacy trial of vancomycin in neonates and young infants

AU - Jacqz-Aigrain, Evelyne

AU - Leroux, Stephanie

AU - Thomson, Alison H.

AU - Allegaert, Karel

AU - Capparelli, Edmund V.

AU - Biran, Valerie

AU - Simon, Nicolas

AU - Meibohm, Bernd

AU - Lo, Yoke-Lin

AU - Marques, Remedios

AU - Peris, José-Esteban

AU - Lutsar, Irja

AU - Saito , Jumpei

AU - Nakamura , Hidefumi

AU - van den Anker, Johannes N.

AU - Sharland, Mike

AU - Zhao, Wei

PY - 2019/8/31

Y1 - 2019/8/31

N2 - OBJECTIVES: In the absence of consensus, the present meta-analysis was performed to determine an optimal dosing regimen of vancomycin for neonates. METHODS: A 'meta-model' with 4894 concentrations from 1631 neonates was built using NONMEM, and Monte Carlo simulations were performed to design an optimal intermittent infusion, aiming to reach a target AUC0-24 of 400 mg·h/L at steady-state in at least 80% of neonates. RESULTS: A two-compartment model best fitted the data. Current weight, postmenstrual age (PMA) and serum creatinine were the significant covariates for CL. After model validation, simulations showed that a loading dose (25 mg/kg) and a maintenance dose (15 mg/kg q12h if <35 weeks PMA and 15 mg/kg q8h if ≥35 weeks PMA) achieved the AUC0-24 target earlier than a standard 'Blue Book' dosage regimen in >89% of the treated patients. CONCLUSIONS: The results of a population meta-analysis of vancomycin data have been used to develop a new dosing regimen for neonatal use and to assist in the design of the model-based, multinational European trial, NeoVanc.

AB - OBJECTIVES: In the absence of consensus, the present meta-analysis was performed to determine an optimal dosing regimen of vancomycin for neonates. METHODS: A 'meta-model' with 4894 concentrations from 1631 neonates was built using NONMEM, and Monte Carlo simulations were performed to design an optimal intermittent infusion, aiming to reach a target AUC0-24 of 400 mg·h/L at steady-state in at least 80% of neonates. RESULTS: A two-compartment model best fitted the data. Current weight, postmenstrual age (PMA) and serum creatinine were the significant covariates for CL. After model validation, simulations showed that a loading dose (25 mg/kg) and a maintenance dose (15 mg/kg q12h if <35 weeks PMA and 15 mg/kg q8h if ≥35 weeks PMA) achieved the AUC0-24 target earlier than a standard 'Blue Book' dosage regimen in >89% of the treated patients. CONCLUSIONS: The results of a population meta-analysis of vancomycin data have been used to develop a new dosing regimen for neonatal use and to assist in the design of the model-based, multinational European trial, NeoVanc.

KW - vancomycin

KW - steady state

KW - drug loading dose

KW - drug maintenance dose

KW - creatinine tests

KW - infusion procedures

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DO - 10.1093/jac/dkz158

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JO - Journal of Antimicrobial Chemotherapy

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JF - Journal of Antimicrobial Chemotherapy

SN - 0305-7453

IS - 8

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