Leiden University Scholarly Publications

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Diepstraten, J. (2013)

The influence of morbid obesity on the pharmacokinetics and pharmacodynamics of drugs in adolescents and adults : focus on propofol and nadroparin.

Doctoral Thesis
For most commonly used drugs in morbidly obese patients evidence based dosing guidelines are not available. Therefore, current dosing is based on experience of the prescriber rather than on clinical evidence. Pharmacokinetic and pharmacodynamics data in non-obese patients are extrapolated without proper exploration of influence of overweight on the dose-exposure-effect relationship. The research described in this thesis focused on two commonly used drugs, propofol and the low-molecular-weight heparin (LMWH) nadroparin with the aim to develop weight appropriate dosing algorithms for these drugs in morbidly obese patients based on population pharmacokinetic and pharmacodynamics analysis. A non-linear relationship was found between propofol clearance and total body weight in both morbidly obese and non-obese adults, adolescents and children. Furthermore, the influence of age on propofol clearance was described using a bilinear function. A model based dosing algorithm using an adjusted...Show moreFor most commonly used drugs in morbidly obese patients evidence based dosing guidelines are not available. Therefore, current dosing is based on experience of the prescriber rather than on clinical evidence. Pharmacokinetic and pharmacodynamics data in non-obese patients are extrapolated without proper exploration of influence of overweight on the dose-exposure-effect relationship. The research described in this thesis focused on two commonly used drugs, propofol and the low-molecular-weight heparin (LMWH) nadroparin with the aim to develop weight appropriate dosing algorithms for these drugs in morbidly obese patients based on population pharmacokinetic and pharmacodynamics analysis. A non-linear relationship was found between propofol clearance and total body weight in both morbidly obese and non-obese adults, adolescents and children. Furthermore, the influence of age on propofol clearance was described using a bilinear function. A model based dosing algorithm using an adjusted dosing weight for propofol maintenance infusion was successfully evaluated in a prospective study in morbidly obese adults and can therefore be implemented in daily practice. For nadroparin in both morbidly obese and non-obese patients, total body clearance increased linearly with total body weight whereas the central of volume distribution increased linearly with lean body weight, suggesting that lean body weight is clinically useful for nadroparin dosing. The developed pharmacodynamic model for nadroparin in non-obese and morbidly obese patients can be used as a starting point to further identify the appropriate anti-Xa targets in morbidly obese patients.Show less
Pharmacodynamics
Obesity
Nadroparin
Low-molecular-weight heparines
Drug dosing
Propofol
Pharmacokinetics
All authors
Diepstraten, J.
Supervisor
Knibbe, C.A.J.; Vinks, A.A.
Co-supervisor
Dongen, H.P.A. van,; Ramshorst, B. van
Qualification
Doctor (dr.)
Awarding Institution
Faculty of Science, Leiden University
Date
2013-06-13
ISBN (print)
9789491356018