Dissertation

Concepts and applications for evidence-based dosing in morbidly obese patients before and after weight loss surgery

Promotor: C.A.J. Knibbe, Co-promotores: H.P.A. van Dongen, B. van Ramshorst

Author: M.J.E. Brill
Date: 03 December 2015
Links: Thesis in Leiden Repository

Drug concentrations and effects may be different in morbidly obese patients (body mass index > 40 kg/m2). In addition, also such changes may be expected in patients after a weight loss surgery. This thesis aims to develop evidence-based dosing recommendations for these patient groups and focuses on two drugs: cefazolin and midazolam. Cefazolin is an antibiotic that is often used as a prophylactic before surgery in order to prevent surgical wound infections. This research demonstrates that in morbidly obese patients, cefazolin subcutaneous tissue penetration in lower in comparison to non-obese patients and dosing adjustments are needed. Midazolam is a commonly used drug for short term or long term sedation. This thesis shows that in particular the distribution of midazolam is strongly influenced by obesity requiring dosing adjustments. Furthermore, it was found that midazolam metabolism (through cytochrome P450 3A enzymes, CYP3A) appears to be lower in comparison to non-obese healthy volunteers, while the total clearance was the same for both groups. After weight loss surgery, midazolam clearance increased, probably because the CYP3A enzyme activity is restored. In the future, these results may be used for other drugs which also undergo CYP3A metabolism (approximately 25% of all clinical used drugs).