Leiden University Scholarly Publications

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Smit, C. (2021)

Shaping the pharmacokinetic landscape for renally cleared antibiotics in obesity: Studies in adults, adolescents and children

Doctoral Thesis
The prevalence of obesity (BMI >40 kg/m2) has increased rapidly over the recent years, not only in adults, but also in children and adolescents. Although it is well known that (patho)physiological changes in obese individuals can influence drug pharmacokinetics, implying adjusted doses, there is still a need for specific dose guidelines for many classes of drugs. In this thesis, the pharmacokinetics of the renally cleared antibiotics gentamicin, tobramycin and vancomycin, drugs for which it is well known that both the efficacy and toxicity of these drugs closely relate to blood concentrations, are studied in non-obese and (morbidly) obese adults, adolescents and children. We present practical dose recommendations for the obese adult, paediatric and adolescent populations. Furthermore, some important questions are addressed regarding the pharmacokinetics of drugs in obesity: can we use the lipophilicity of a drug to predict changes in volume of distribution? Which pitfalls have to...Show moreThe prevalence of obesity (BMI >40 kg/m2) has increased rapidly over the recent years, not only in adults, but also in children and adolescents. Although it is well known that (patho)physiological changes in obese individuals can influence drug pharmacokinetics, implying adjusted doses, there is still a need for specific dose guidelines for many classes of drugs. In this thesis, the pharmacokinetics of the renally cleared antibiotics gentamicin, tobramycin and vancomycin, drugs for which it is well known that both the efficacy and toxicity of these drugs closely relate to blood concentrations, are studied in non-obese and (morbidly) obese adults, adolescents and children. We present practical dose recommendations for the obese adult, paediatric and adolescent populations. Furthermore, some important questions are addressed regarding the pharmacokinetics of drugs in obesity: can we use the lipophilicity of a drug to predict changes in volume of distribution? Which pitfalls have to be considered when using lean body weight as basis for drug dosing? And which methods for estimating glomerular filtration can predict the clearance of renally cleared drugs in obese patients? The work in this thesis provide some important steps in filling the current knowledge gaps regarding the pharmacokinetics of drugs in obesity.
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Morbid obesity
Pharmacokinetics
Obese children
Obese adolescents
Gentamicin
Tobramycin
Aminoglycosides
Vancomycin
All authors
Smit, C.
Supervisor
Knibbe, C.A.J.
Co-supervisor
Dongen, H.P.A. van; Brüggemann, R.J.M.
Committee
Irth, H.; Bouwstra, J.A.; Anker, J.N. van den; Roon, E.N. van; Hasselt, J.G.C. van; Guchelaar, H.J.; Lange, D.W. de
Qualification
Doctor (dr.)
Awarding Institution
Leiden Academic Centre for Drug Research (LACDR), Faculty of Science, Leiden University
Date
2021-03-11
ISBN (print)
9789464163308

Funding

Sponsorship
The work presented in this thesis was financially supported by the Netherlands Organization for Health Research and Development (ZonMw) under grant number 836041004.