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).