Pharmaceutical Research

, Volume 31, Issue 10, pp 2643–2654 | Cite as

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

  • Roosmarijn F. W. De Cock
  • Karel Allegaert
  • Janneke M. Brussee
  • Catherine M. T. Sherwin
  • Hussain Mulla
  • Matthijs de Hoog
  • Johannes N. van den Anker
  • Meindert Danhof
  • Catherijne A. J. Knibbe
Research Paper

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.

KEY WORDS

antibiotics developmental changes glomerular filtration pediatric age range 

ABBREVIATIONS

BDE

Bodyweight-dependent exponent

BW

Bodyweight

GFR

Glomerular filtration rate

NPDE

Normalized prediction distribution error method

PD

Pharmacodynamics

PK

Pharmacokinetics

PNA

Postnatal age

Notes

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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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Roosmarijn F. W. De Cock
    • 1
  • Karel Allegaert
    • 2
  • Janneke M. Brussee
    • 1
  • Catherine M. T. Sherwin
    • 3
  • Hussain Mulla
    • 4
  • Matthijs de Hoog
    • 5
  • Johannes N. van den Anker
    • 5
    • 6
  • Meindert Danhof
    • 1
  • Catherijne A. J. Knibbe
    • 1
    • 7
  1. 1.Division of Pharmacology, LACDRLeiden UniversityLeidenThe Netherlands
  2. 2.Neonatal Intensive Care UnitUniversity Hospital LeuvenLeuvenBelgium
  3. 3.Division of Clinical Pharmacology & Clinical Trials Office Department of PediatricsUniversity of Utah School of MedicineSalt Lake CityUSA
  4. 4.Department of PharmacyUniversity Hospitals of LeicesterLeicesterUK
  5. 5.Department of Pediatric Intensive CareErasmus MC - Sophia Children’s HospitalRotterdamThe Netherlands
  6. 6.Division of Pediatric Clinical PharmacologyChildren’s National Medical CenterWashingtonUSA
  7. 7.Department of Clinical PharmacySt. Antonius HospitalNieuwegeinThe Netherlands

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