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Simultaneous Pharmacokinetic Modeling of Gentamicin, Tobramycin and Vancomycin Clearance from Neonates to Adults: Towards a Semi-physiological Function for Maturation in Glomerular Filtration

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ABSTRACT

Purpose

Since glomerular filtration rate (GFR) is responsible for the elimination of a large number of water-soluble drugs, the aim of this study was to develop a semi-physiological function for GFR maturation from neonates to adults.

Methods

In the pharmacokinetic analysis (NONMEM VI) based on data of gentamicin, tobramycin and vancomycin collected in 1,760 patients (age 1 day–18 years, bodyweight 415 g–85 kg), a distinction was made between drug-specific and system-specific information. Since the maturational model for clearance is considered to contain system-specific information on the developmental changes in GFR, one GFR maturational function was derived for all three drugs.

Results

Simultaneous analysis of these three drugs showed that maturation of GFR mediated clearance from preterm neonates to adults was best described by a bodyweight-dependent exponent (BDE) function with an exponent varying from 1.4 in neonates to 1.0 in adults (ClGFR = Cldrug*(BW/4 kg)BDE with BDE = 2.23*BW−0.065). Population clearance values (Cldrug) for gentamicin, tobramycin and vancomycin were 0.21, 0.28 and 0.39 L/h for a full term neonate of 4 kg, respectively.

Discussion

Based on an integrated analysis of gentamicin, tobramycin and vancomycin, a semi-physiological function for GFR mediated clearance was derived that can potentially be used to establish evidence based dosing regimens of renally excreted drugs in children.

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Abbreviations

BDE:

Bodyweight-dependent exponent

BW:

Bodyweight

GFR:

Glomerular filtration rate

NPDE:

Normalized prediction distribution error method

PD:

Pharmacodynamics

PK:

Pharmacokinetics

PNA:

Postnatal age

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ACKNOWLEDGMENTS AND DISCLOSURES

This study was performed within the framework of Top Institute Pharma project number D2-104. The clinical research of K. Allegaert is supported by the Fund for Scientific Research, Flanders (Belgium) (clinical fellowship 1800214N) and has been supported by an IWT-SBO project (130033). The clinical research of J. van den Anker is supported by NIH grants (R01HD060543, K24DA027992, R01HD048689, U54HD071601) and FP7 grants TINN (223614), TINN2 (260908), NEUROSIS (223060), and GRIP (261060). The authors also would like to thank LAP&P Consultants for their technical support with NONMEM.

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Authors and Affiliations

  1. Division of Pharmacology, LACDR, Leiden University, Leiden, The Netherlands

    Roosmarijn F. W. De Cock, Janneke M. Brussee, Meindert Danhof & Catherijne A. J. Knibbe

  2. Neonatal Intensive Care Unit, University Hospital Leuven, Leuven, Belgium

    Karel Allegaert

  3. Division of Clinical Pharmacology & Clinical Trials Office Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah, USA

    Catherine M. T. Sherwin

  4. Department of Pharmacy, University Hospitals of Leicester, Leicester, England, UK

    Hussain Mulla

  5. Department of Pediatric Intensive Care, Erasmus MC - Sophia Children’s Hospital, Rotterdam, The Netherlands

    Matthijs de Hoog & Johannes N. van den Anker

  6. Division of Pediatric Clinical Pharmacology, Children’s National Medical Center, Washington, District of Columbia, USA

    Johannes N. van den Anker

  7. Department of Clinical Pharmacy, St. Antonius Hospital, P.O. Box 2500, 3430 EM, Nieuwegein, The Netherlands

    Catherijne A. J. Knibbe

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  1. Roosmarijn F. W. De Cock
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Correspondence to Catherijne A. J. Knibbe.

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De Cock, R.F.W., Allegaert, K., Brussee, J.M. et al. Simultaneous Pharmacokinetic Modeling of Gentamicin, Tobramycin and Vancomycin Clearance from Neonates to Adults: Towards a Semi-physiological Function for Maturation in Glomerular Filtration. Pharm Res 31, 2643–2654 (2014). https://doi.org/10.1007/s11095-014-1361-z

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