Tan Zhang (1), Elke H.J. Krekels (1), Cornelis Smit (1, 2), Catherijne A.J. Knibbe (1,2)
(1) Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands; (2) Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands
Objectives:
Overweight and obesity is rising worldwide and pharmacotherapy of these patients is challenging. As the number of studies on the influence of obesity on the pharmacokinetics (PK) of drugs is increasing rapidly, the time has come to re-evaluate the common assumptions about how the PK of drugs change in obese people. The aim of this literature review was to report the latest evidence on common assumptions regarding the PK of drugs in obese population and thus providing some guidance on drug dosing in obese patients.
Methods:
Literature was searched to explore what is known about the following assumptions for obese individuals:
1) Lean body weight (LBW) is the best descriptor of body size and of dosing requirements [1];
2) Volume of distribution (Vd) increases for lipophilic drugs, but not for hydrophilic drugs [2,3];
3) Glomerular filtration rate is enhanced, which may necessitate higher doses of renally cleared drugs [4-7];
4) Obese patients are considered to be in a state of low-grade inflammation, which is known to suppress the activity of CYP3A enzymes. Therefore, clearance of CYP3A substrates is believed to be suppressed [8-11], while other found that glucuronidation clearance of some drugs may be increased [12,13], meaning dose adaptations may be required for drugs metabolized by these pathways;
5) While only a limited number of studies and guidelines is available for obese children and adolescents [14,15], it is often anticipated that dose adjustments for obese adults can be used for obese adolescents as well [16,17].
Results:
1) Of recently studied drugs, only for paracetamol, tobramycin and gentamicin, LBW has been reported as the better predictor for variability in PK parameters in obese population compared to total body weight (TBW) [13,18]. Evaluation of LBW as descriptor of body size reveals that LBW can only be of predictive value when gender is an important predictor, because LBW for males is about 35 % higher compared to females of the same TBW [19].
2) In recent studies, Vd showed an increase in obese people for some hydrophilic drugs such as gentamicin and vancomycin, whereas no increase was found for lipophilic drugs such as lorazepam [20-23]. As a result, lipophilicity parameters should not be regarded a priori as predictors of Vd differences in obese patients .
3) While an increase in clearance is observed for gentamicin and vancomycin, no increase in clearance is found for cefazolin and ciprofloxacin [20,24-28]. This means that it cannot be known whether clearance of a specific renally excreted drug is increased in obese population or not, unless this has been studied.
4) Metabolic plasma clearance of midazolam, a marker for CYP3A activity, was found to be unchanged in obese patients [29,30]. With respect to glucuronidation, increased paracetamol glucuronidation was reported, while on the other hand unchanged morphine glucuronidation was found [31,32]. These contradictory results reveal that more studies in obese patients are needed for predicting the clearance of drugs that are hepatically metabolized and/or substrates for transporters.
5) For metformin, dose adjustments for obese adults extrapolated well to obese adolescents[33], however for midazolam and fentanyl, higher clearance is found in obese adolescents compared to obese adults even though the two populations had similar body weights [34,35]. This indicates that information from obese adults may or may not always be informative for obese adolescents.
Conclusions:
This literature review reports recent evidence that often contradicts common assumptions regarding the PK of drugs in obese population. More research on comparison of results from clinical studies with concepts from physiologically-based PK modeling approaches is needed to obtain further insight into the changes in mechanisms underlying drug PK and making generalizable predictions for PK variability obese population.
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Reference: PAGE () Abstr 9467 [www.page-meeting.org/?abstract=9467]
Poster: Methodology - Covariate/Variability Models