Discussion
Because of the increasing number of bariatric surgery procedures that are performed to date, healthcare professionals will be increasingly confronted with the care of these patients. Since during this procedure, alterations to the gastro-intestinal tract are being made which results in substantial weight loss over time, changes in the absorption, distribution, metabolism and elimination of drugs can be expected, and special considerations, particularly regarding the dosing of oral drugs, may apply. In this overview, we report on the influence of bariatric surgery on the different steps of the process of oral drug absorption and give practical dosing considerations for several commonly used potent drugs for patients with a history of bariatric surgery based on a review of the available literature.
In general, the pharmacokinetic profile of orally administered drugs seems to change after bariatric surgery; the Tmax can be earlier and Cmax higher, with less consistent results on the AUC, which can be similar 37,38,46,64,65, lower30,46,50,52,117,119 or higher27,45,47 after surgery. Many reports compare the pharmacokinetics in patients after bariatric surgery to the pharmacokinetics before surgery, while some studies also consider the pharmacokinetics in non-obese individuals for comparison. The latter may particularly be of relevance for drugs for which altered pharmacokinetics in obese patients compared to non-obese patients have been reported, or when the pharmacodynamics are different in obese individuals as is the case for VKAs or platelet inhibitors. We note that even for similar drugs, different results may be observed, as shown for phenoxymethylpenicilin 44,45. Also for controlled release formulations, conflicting results were obtained in different studies 35,36. While these differences may result from large inter and intra-individual variability known in oral drug dosing, they may also result from different surgical techniques and formulations.
Another important issue to consider is that the shape of the pharmacokinetic profile of orally administered drugs may change substantially over time (for instance with psychotropic drugs). Although conclusions like earlier and higher concentration peaks seem applicable, general predictions on oral absorption after bariatric surgery are difficult to ascertain.
As such, advice regarding oral drug use after bariatric surgery should be given on a case by case basis.
Figure 1 shows some guidance about this issue. Firstly, available literature on the drug before and after surgery should be considered. Predictions based on drug properties such as the Log P or the location of absorption in the gastrointestinal tract are to be discouraged. For drugs where a direct effect can be measured (e.g. blood pressure, INR, blood glucose, T3, T4 and TSH), this can be monitored and the dose be adjusted accordingly. Another possibility is to measure serum concentrations of the specific drug through TDM. When measuring a trough concentration, the shape of the concentration-time curve may have changed after surgery. In such a case, a lower trough concentration may not be reflective of a lower AUC and therefore conclusions based on a trough sample alone may not be predictive of the ultimate effect of the drug. This phenomenon may be relevant for drugs that exert their pharmacodynamic effects based on the AUC0-24h (e.g., some antibiotics, DOACs, pain killers). For drugs dependent on time above a certain concentration such as antibiotics, these considerations are less relevant, as long as the peak concentration does not result in potential safety issues, as may be the case for oral morphine22 or midazolam 23.
In addition, a risk assessment for the drug of interest can be made when prescribing oral drugs to post-bariatric surgery patients. During this assessment, the risk of reduced absorption and therapy failure and overdosing is weighed. If this risk is high (i.e. severe toxicity upon overdosing or increased morbidity and mortality upon underdosing), another therapy should be proposed. An example of such a drug are DOACs for which VKAs are a proposed alternative. For drugs which it is known that earlier and higher peaks may occur, for example, morphine and midazolam, adjusted doses or additional monitoring may be proposed. In this respect, also the type of surgery and period of time after bariatric surgery should be taken in to consideration.
Different surgical techniques may lead to differences in alterations in the GI-tract. The period of time after bariatric surgery is also relevant since there is evidence that pharmacokinetic changes might change over time (for example VKAs and psychotropic drugs). Here also the formulation needs to be considered, as studies on oral suspensions, open capsules and direct release and controlled release tablets have generally shown conflicting research (see table 3).