\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[T2A]{fontenc}
\usepackage[ngerman,greek,polish,english]{babel}



\usepackage{float}








\begin{document}

\title{Oral drug dosing following bariatric surgery - General concepts and
specific dosing advices}



\author[1]{Jurjen Kingma}%
\author[1]{Desirée Burgers}%
\author[2]{Valerie Monpellier}%
\author[1]{Marinus Wiezer}%
\author[1]{Heleen Blussé van Oud-Alblas}%
\author[3]{Janelle Vaughns}%
\author[4]{Catherine Sherwin}%
\author[1]{Catherijne Knibbe}%
\affil[1]{Sint Antonius Hospital}%
\affil[2]{Nederlandse Obesitas Kliniek (Dutch Obesity Clinic)}%
\affil[3]{Children's National Health System}%
\affil[4]{Wright State University Boonshoft School of Medicine}%


\vspace{-1em}



  
  \date{May 19, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Bariatric or weight-loss surgery is a popular option for weight
reduction. Depending on the surgical procedure, gastric changes like
decreased transit time and volume and increased pH, decreased absorption
surface in the small intestine, decreased exposure to bile acids and
enterohepatic circulation, and decreased gastrointestinal transit time
may be expected. In the years after bariatric surgery, patients will
also substantially lose weight. As a result of these changes, the
absorption, distribution, metabolism, and/or elimination of drugs may be
altered. The purpose of this article is to report the general influence
of bariatric surgery on oral drug absorption, and to provide guidance
for dosing of commonly used or high-risk drugs in this special
population. Upon oral drug administration, the time to maximum
concentration is often earlier and this concentration may be higher with
less consistent effects on trough concentrations and exposure.
Additionally, prescription of liquid formulations to bariatric patients
is supported by some reports, even though the high sugar load of these
suspensions may be of concern. Studies on extended release medications
result in an unaltered exposure for a substantial number of drugs. Also,
studies evaluating the influence of timing after surgery show dynamic
absorption profiles. Although for this group a specific advice can be
proposed for many drugs, we conclude that there is insufficient evidence
for general advices for oral drug therapy after bariatric surgery
implying that a risk assessment on a case-by-case basis is required for
each drug.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Obesity (body mass index (BMI) above 30 kg/m\textsuperscript{2}) is
currently one of the major health issues, with a worldwide prevalence of
13\% \textsuperscript{1}. Individuals with (morbid) obesity are exposed
to an increased risk of cardiovascular disease, cancer, diabetes
mellitus, hypertension, arthritis, sleep apnea, and other
co-morbidities, at higher mortality rates \textsuperscript{2,3}.

For patients with morbid obesity (BMI above 40 kg/m\textsuperscript{2})
or obesity with a BMI above 35 kg/m\textsuperscript{2} with one or more
comorbidities like type 2 diabetes or hypertension, modification of the
gastro intestinal (GI) tract by bariatric surgery is currently the most
effective long term treatment \textsuperscript{4--7}. Surgery results in
weight loss up to 32 \selectlanguage{ngerman}± 8\% after two years and has shown to lead to
decreased incidence of diabetes, myocardial infarction, stroke, and
cancer, and in a reduction in overall long-term
mortality\textsuperscript{4,8,9}. In addition, obesity has a negative
impact on quality of life, which improves significantly after bariatric
surgery\textsuperscript{10}.

Common techniques used in bariatric surgery includes, the sleeve
gastrectomy (SG) and Roux-en-Y gastric bypass
(RYGB)\textsuperscript{11}. The RYGB is associated with several
anatomical and physiological changes. RYGB introduces a small gastric
pouch, which results in an increased gastric pH \textsuperscript{12,13}.
The gastric pouch is connected to the lower part of the intestine,
bypassing the small intestine and biliary limb. During the SG procedure,
a small longitudinal stomach in created. For both types of surgery,
these alterations in the GI tract are known to lead to nutritional
deficiencies for which standardized nutritional supplementation is
commonly advised \textsuperscript{7}. Similarly, it can be anticipated
that these changes may alter the absorption of drugs given orally.

Many patients who undergo bariatric surgery use one or more drugs to
manage their co-morbid disease(s). Relevant drugs to these patients
include cardiovascular (26\%) and antidiabetic drugs (26\%), analgesics
(21\%), anti-inflammatory and antirheumatic products (non-steroids)
(10\%), antidepressants (21\%), thyroid therapeutics (12\%) and drugs
for obstructive airway disease (25\%) \textsuperscript{14}.

In addition to the alterations in oral absorption due to modifications
in the digestive tract there are also changes in distribution,
metabolism and/or elimination of drugs as the result of substantial
weight-loss associated with bariatric surgery \textsuperscript{15,16}.
The purpose of this article is to provide an overview of how bariatric
surgery may influence the process of oral drug absorption and to give
specific dosage advice for commonly used potent drugs in this special
patient population.

\textbf{Bariatric surgery and oral drug absorption}

Theoretically, as a result of bariatric surgery, a number of alterations
in the process of oral drug absorption may be expected which may alter
the oral pharmacokinetic profiles of prescribed drugs. Table 1
summarizes these alterations, for which a distinction is made between
changes occurring upon restrictive procedures, i.e. procedures leading
to a limitation in the amount of food in the stomach such as adjustable
gastric banding and gastroplasty, or to limited digestive capacity such
as SG, versus combined restrictive/malabsorptive procedures that also
cause malabsorption of nutrients, such as Roux-en-Y gastric bypass
(RYGB). Whether or not these changes ultimately lead to altered
pharmacokinetics of a specific drug will depend on individual drug
properties. Here we discuss disintegration of the oral drug formulation,
dissolution of the drug, gastrointestinal transit time and the role of
bile acids as factors of interest for the absorption process of oral
drugs.

\emph{Disintegration of the oral drug formulation}

The first step in the absorption of solid formulations like tablets and
capsules, is disintegration in the GI tract. Disintegration is affected
by several variables, such as gastric volume and mixing, which can be
both diminished after bariatric surgery \textsuperscript{15,16}. Due to
a reduced volume, it is often assumed that tablets, may not fully
dissolve, resulting in altered exposure of the
drug\textsuperscript{17,18}. For this reason, administration of oral
liquids is often proposed after bariatric surgery, even though hard
evidence to support this statement is lacking. A disadvantage of liquid
formulations like suspensions is that these formulations may contain
sugars, which may, in large amounts, lead to the dumping
syndrome\textsuperscript{19}.

Montanha et al. investigated the effect of RYGB on the bioavailability
of amoxicillin tablets versus suspension \textsuperscript{20}. A lower
Area Under the Curve (AUC) for tablets (23.10 ± 7.41 mg.h/L) was found
as compared to the suspension (27.59 ± 8.32 mg.h/L) , corresponding to a
relative biological availability of 83\%. The higher AUC of the
suspension resulted from a higher Cmax (8.73 ± 3.26 vs 7.42 ± 2.99 mg/L)
and lower Tmax compared to tablets (1.7 ± 0.86 vs 2 ± 0.76 hours). While
no clinical outcome measures were reported, for both formulations, the
time above the minimum inhibitory concentration (MIC) for pathogens with
an MIC \textless{}4mg/l was attained, and therefore effectiveness seems
to be guaranteed for both oral drug formulations.

Schulman et al. investigated the effect of RYGB surgery on Proton Pump
Inhibitor (PPI) in Open Capsule (OC) versus Intact Capsule (IC)
form\textsuperscript{21}. They showed a significantly shorter healing
time (median healing time of 91 days vs. 342 days) in the OC PPI group
compared to the IC PPI group. There was, however, a significantly larger
percentage of sucralfate use in the OC group and a larger
non-significant percentage non-steroidal anti-inflammatory drug (NSAID)
use in the IC group, which may have contributed to the reported
difference in effect \textsuperscript{21}.

From these reports, it seems that suspensions may lead to a higher
exposure but may not always be preferable because of sugar loads, and
that open capsules may lead to more effective treatment than intact
capsules after RYGB surgery. With increased exposure upon the use of the
amoxicillin suspension, earlier and higher peak concentrations were
observed. Such early and high peak concentrations may be undesirable for
certain drugs like morphine, for which upon use of an oral solution
yielded a three-fold increased Cmax, lower Tmax and increased AUC at six
months after bariatric surgery \textsuperscript{22}. Additionally,
midazolam was reported to have an earlier and 1.5 fold higher peak
concentration after oral administration \textsuperscript{23}.

\emph{Dissolution of the drug}

After disintegration, a drug must become dissolved to be absorbed. This
dissolution process is affected by several variables, such as gastric
volume, gastric pH, and gastric transition time. After RYGB surgery,
there is limited exposure to acid, which is in contrast with a SG
procedure upon which the acid exposure time
rises\textsuperscript{12,13}. In any case, bariatric surgery patients
are generally prescribed prophylactic PPIs to reduce the risk of
gastro-intestinal complications after surgery, such as ulceration or
gastro-intestinal bleeding during the first months after
surgery\textsuperscript{24,25}. Due to this rise in pH, the solubility
of more basic drugs could decrease since they become less ionized, and
the solubility of acidic drugs could increase since they become more
ionized. Dissolution should, however, not be confused with absorption.
Ionized drugs have good solubility and show generally lower absorption
than unionized drugs, which are, in general less soluble. In healthy
subjects, the stomach is capable of absorbing most acidic drugs and the
very weakly basic drugs which are undissociated in the acidic gastric
environment \textsuperscript{26}. After surgery, the proposed rise in pH
could lead to reduced absorption of these drugs in the stomach. This
effect, however, should primarily affect the dissolution in the stomach,
where usually only a small degree of drug absorption takes place, and
the effect could, therefore, be small. In addition, there are other
factors of relevance for dissolution other than altered pH, like gastric
volume and transition time.

An example of a drug that is absorbed in the stomach is acetylsalicylic
acid, which is unionized in the acidic environment of the stomach upon
which it can be absorbed \textsuperscript{26}. Theoretically, because of
the higher pH, the absorption and exposure of acetylsalicylic acid (ASA)
could be reduced in patients after bariatric surgery. Mitrov-Winkelmolen
et al. studied the effect of RYGB on the pharmacokinetics of orally
administrated ASA before and six weeks after RYGB
surgery\textsuperscript{27}. Instead of a lower AUC, they found a
significant increase in AUC (14.1 vs. 11.4 mg h/l), an increased Cmax
(4.6 vs. 3.5 mg/l) and a significantly decreased Tmax (0.7 vs. 1 hour)
six weeks after RYGB surgery. According to the authors, the higher AUC
and Cmax suggest that absorption of acetylsalicylic acid, even when
occurring mainly in ionized form because of the elevated pH, can also
take place in the jejunum where it may even exceed absorption in the
stomach and duodenum. Regarding these results, it is unknown what the
contribution of the higher pH and/or altered gastric emptying and
transit time of the GI tract is, as all of these changes occur
simultaneously after bariatric surgery.

The weak base posaconazole is another example of a drug where the
absorption is related to the residence time in the acidic environment of
the stomach. Several studies showed the dependence of posaconazole
absorption on the pH, resulting in the avoidance of PPI in patients
using posaconazole \textsuperscript{28,29}. As in bariatric surgery
patients, a higher pH and faster gastric emptying may be expected,
Gesquiere et al. performed a single-dose pharmacokinetic study in 12
RYGB surgery patients before and 6-9 months after surgery. After
surgery, the AUC\selectlanguage{english}\textsubscript{0--[?]} was significantly reduced (9.49 vs.
4.37 ug ml/h, p\textless{}0.05), which was explained by the low
solubility of posaconazole, of which the absorption is very sensitive to
intraluminal pH and residence time in the stomach \textsuperscript{30}.
As the decrease in AUC was more extensive than would be expected based
on pH-related changes in absorption alone, the authors suggest that the
reduced residence time after RYGB surgery contributes to their findings.

From these reports, it seems that the acidic drug acetylsalicylic acid
is absorbed after RYGB surgery even when the pH in the stomach is
decreased. However, the weak base posaconazole is, as expected, not
absorbed, resulting in a lower AUC\selectlanguage{english}\textsubscript{0--[?]} in RYGB surgery
patients.

\emph{Gastro-intestinal transit time}

Besides the above-mentioned factors such as pH, gastric volume and
gastric transition time, other factors like gastric emptying and
gastro-intestinal transit time are relevant for absorption. After RYGB,
a large proportion of the stomach and intestine is bypassed, which can
result in altered gastro-intestinal transit time and gastric emptying
time. Carswell et al. studied seven obese controls, six obese
individuals undergoing adjustable gastric banding, seven subjects
undergoing RYGB surgery, and five subjects undergoing biliopancreatic
diversion with duodenal switch at 8 -- 29 months post-surgery. The
authors found no significant changes in gastro-intestinal transit time
using a sulphasalazine/sulphapyridine test with sulphapyridine detected
at 180 min in all four groups \textsuperscript{31}. Dirksen et al.
measured the transit time of water and solid nutrients through the
stomach, small intestine and colon through scintigraphy in 17 RYGB
subjects who were at least 12 months post-surgery and in nine non-obese
control subjects. In this study, RYGB subjects had faster pouch emptying
for water as well for solid nutrients but slower small intestinal
transit time and similar colonic transit time in comparison to healthy
controls \textsuperscript{32}. Nguyen et al. studied the effect of RYGB
on gastric emptying and cecal arrival time in ten RYGB subjects who
underwent surgery at least 12 months earlier in comparison to healthy
subjects \textsuperscript{33}. Compared to the healthy controls, gastric
emptying and cecal arrival time were substantially faster in RYGB
patients. Moreover, gastric emptying was faster when subjects were in a
sitting position and tended to be faster after 150 ml in comparison to
the 50 ml administration. Lastly, Wang et al. showed rapid gastric
emptying in seven patients who underwent RYGB one year after
surgery\textsuperscript{34}, where the subjects were their own controls.

The results of these studies on gastric emptying and intestinal and
colonic transit time show that gastric emptying is generally faster
after bariatric surgery compared to healthy controls and that data on
intestinal and colonic transit time is conflicting with more rapid and
even slower small intestinal transit or cecal time reported in RYGB
surgery patients.

Information on changes in the gastro-intestinal transit time as a result
of bariatric surgery may also be deduced from results on studies
evaluating the effect of bariatric surgery on the exposure of
slow-release vs. immediate-release tablets. Yska et al. studied the
effect of RYGB surgery on the exposure of metoprolol from
immediate-release (IR) and controlled-release (CR) tablets in female
patient volunteers one month before and six months after RYGB
surgery\textsuperscript{35}. The endpoint was the ratio of the
metoprolol AUC\textsubscript{after}/AUC\textsubscript{before} surgery.
For the IR tablets, no significant changes were observed, albeit with
major intraindividual and interindividual variability in AUC (range
ratio AUC\textsubscript{0--10 hours after}/AUC\textsubscript{0--10 hours
before}: 0.74--1.98). For the CR tablets, a significantly lower AUC was
observed after surgery (range ratio AUC\textsubscript{0--24 hours
after}/AUC\textsubscript{0--24 hours before}: 0.43--0.77). Based on
these results, the authors conclude that RYGB surgery may influence the
bioavailability of metoprolol from an IR tablet and that after surgery,
the dose of metoprolol CR tablets should be increased according to
clinical response \textsuperscript{35}. In contrast with these results,
another study showed no significant effect on the AUC of metoprolol
measured at 6 -- 8 months after RYGB surgery in patients receiving oral
metoprolol CR tablets \textsuperscript{36}. Also, for IR tablets, no
changes in exposure after surgery were found. Because of differences in
the volume of water used to swallow the CR tablet influencing pouch
emptying and differences between women and men (Yska et al. only
included female volunteers) as explanations for the diverging results
for CR tablets, it seems yet too early for conclusions on the use of
metoprolol CR tablets after surgery.

For venlafaxine administered as CR capsules, Krieger et al. showed no
effect on AUC of venlafaxine and its primary metabolite 3-4 months after
RYGB \textsuperscript{37}. Similarly, Hachon et al. investigated the
effect of RYGB surgery on the pharmacokinetics of morphine CR tablets in
RYGB patients (two years after surgery) and healthy controls. They found
no significant changes in the AUC or other PK parameters between studied
groups \textsuperscript{38}.

Based on the results of these studies on CR formulations, it seems that
a priori, CR formulations may not need to be discouraged in patients
after bariatric surgery.

\emph{Role of bile acids}

After bariatric surgery, the influence of digestive content is also
altered. Gastric acid secretion is significantly reduced following RYGB
surgery, leading to an increase in pH in the
stomach\textsuperscript{12,13}. The altered GI tract may also lead to a
delayed action of bile acids. Because bile salts do not reach the GI
tract before the jejunum, contact between bile acids and a drug occurs
later in comparison to normal subjects. A drug that has been
demonstrated to be dependent on bile acids is fenofibrate. Gesquiere et
al. performed a single-dose pharmacokinetic study in 12 RYGB surgery
patients before and 6-9 months after surgery and surprisingly, the
AUC\selectlanguage{english}\textsubscript{0--[?]}, Cmax, and Tmax of fenofibrate were not
altered\textsuperscript{30}. The authors hypothesize that these results
may be explained by higher fasting total serum bile acid concentration
in patients after RYGB and by faster gastric emptying that might
compensate for the delayed efflux of bile acids \textsuperscript{30}.
These study results suggest that the overall influence of altered timing
of bile acids on oral drug absorption may be minor.

\textbf{Overview of dosing information on commonly used and high-risk
drugs after bariatric surgery}

Here we provide an overview of the available literature on dosing of
commonly used oral drugs in this special population (for summary see
table 2).

\emph{Antibiotics}

Obesity is a risk factor for infections, including surgical wound
infections \textsuperscript{39--41}. It has been shown, that the
increased risk for surgical wound infections is probably due to the
decreased penetration of the prophylactic antibiotic cefazolin into the
subcutaneous tissue as a result of reduced blood flow to fatty tissue,
as similar plasma concentrations but reduced subcutaneous tissue
concentrations were found \textsuperscript{42}. Similar reduced
penetration into subcutaneous tissue and muscle was reported for
ciprofloxacin \textsuperscript{43}. With most studies evaluating
concentrations in plasma, from these results it seems that potentially
reduced perfusion into the target tissue should be considered when
deciding what drug or dose to give after bariatric surgery.

\emph{Beta-lactam antibiotics (amoxicillin, penicillin and ampicillin)}

To date, five studies have been published regarding the pharmacokinetics
of oral beta-lactam antibiotics. Two studies, i.e. Terry et al. and
Miskowiak et al., describe the pharmacokinetics of oral
phenoxymethylpenicillin after gastroplasty and jejunoileal bypass,
procedures that are to date not often applied any
more\textsuperscript{44,45}. Miskowiak et al. evaluated the effect of
gastroplasty on the absorption of phenoxymethylpenicillin when given as
a non-coated tablet or as an aqueous solution (one-week washout) in
eight female bariatric surgery patients before and three months after
gastroplasty surgery. In this study, no significant changes in plasma
concentrations, Cmax, T1/2, Tmax and AUC were found before versus after
surgery. \textsuperscript{44}. There were also no significant
differences in AUC between tablet and aqueous solution. Terry et al.
studied the oral absorption of a single administration of 1 gram
phenoxymethylpenicillin in three subjects before and three months after
jejunoileal bypass and in five subjects three months after jejunoileal
bypass \textsuperscript{45}. In the group with AUC measurements before
and after surgery, a substantially increased AUC after surgery (176.8 +-
98.1 vs. 17.1 +- 5.9 units/ml * hour) was demonstrated. However, in the
group where AUC was only measured after surgery, the AUC was 46.2 +- 30.4
units/ml * hour, illustrating a large interindividual variability in the
AUC after jejunoileal bypass surgery. Peak serum concentration also
increased significantly. The authors explained the enhanced absorption
of penicillin by the lack of degradation which generally occurs in acid
gastric contents.

The pharmacokinetics of oral amoxicillin after RYGB surgery was studied
by Rocha et al. and Montanha et al. \textsuperscript{46,47}. Rocha et
al. studied eight obese subjects receiving an amoxicillin 500mg capsule
before and two months after RYGB surgery \textsuperscript{47}. They
found a large and significant rise in AUC (7.21 +- 5.13 vs. 2.03 +- 0.77
ug.h/ml) and Cmax (1.77 +- 1.19 vs. 0.62 +- 0.22) after surgery whereas
Tmax and t1/2 were not significantly altered. All of these values were
however substantially lower compared to non-obese subjects who had
AUC\textsubscript{C0--tlast} values of 12.44 -- 12.05 ug.h/ml and a Cmax
ranging from 4.94 to 5.31 ug/ml.

As previously stated, Montanha et al. reported a higher AUC for
amoxicillin suspension compared to amoxicillin tablets in 20 RYGB
surgery patients \textsuperscript{46}. This higher AUC was predominantly
explained by the higher Cmax observed after the suspension. When
comparing these results to amoxicillin absorption rates in non-bariatric
and non-obese subjects, the total absorbed amount of amoxicillin
appeared 40\% lower the suspension group and 50\% lower for the tablets.
Even though no clinical outcome measures were reported, for both
formulations, the time above the MIC for pathogens with a MIC
\textless{}4mg/l was attained in the study of Montanha et al. Therefore,
it seems that oral amoxicillin can be used in post RYGB surgery
patients, despite the fact that the AUC is lower in comparison to normal
weight subjects.

Kampmann studied oral absorption of ampicillin in six patients with
morbid obesity undergoing jejunoileostomy \textsuperscript{48}. Before
surgery and 1-2 weeks, 6 months and 12 months postoperatively, patients
received 500 mg ampicillin intravenously and 700 mg of oral
pivampicillin (the pivaloylmethylesther of ampicillin) on separate days.
A significant decrease in bioavailability was reported at 1-2 weeks (65
+- 18\%), 6 months (66 +- 36\%) and at 12 months (41 +- 30 \%) after
surgery compared to preoperative bioavailability (109 +- 44 \%). However,
as the bioavailability in healthy normal-weight subjects was 50\%, these
lower values might not have implications for antibiotic therapy. The
authors suggest that the impeded absorption compared to pre-surgery in
morbidly obese patients which may have several explanations including: a
change in bile acid metabolism; an increased number of enterobacteriae;
premature splitting of the lipophilic part of pivampicillin; and/or an
elevated mucosal enzyme level participating in the hydrolysis of
pivampicillin \textsuperscript{48}. No explanations were given for the
higher bioavailability of pivampicillin in morbidly obese patients
before surgery compared to healthy volunteers (109 vs 50\%).

\emph{Macrolide antibiotics (azithromycin and erythromycin)}

Two studies investigating macrolide antibiotics have been published.

Prince et al. studied seven patients with morbid obesity receiving a
single dose of 250 mg erythromycin within three days before and six
weeks after surgery (one gastric bypass, six
gastroplasty)\textsuperscript{49}. Mean weight-corrected AUC was reduced
with 41\% compared to pre-surgery values, with two patients having no
detectable serum concentration after surgery. Mean peak concentration
decreased from 1.04 to 0.5 ug/ml, and Tmax increased from 3.9 +- 1.5 to
6.7 +- 2.8 hours \textsuperscript{49}.

Padwall and colleagues studied azithromycin pharmacokinetics in 14
female RYGB surgery patients, and 14 BMI matched
controls\textsuperscript{50}. Subjects were administered two 250 mg
azithromycin tablets at least three months after surgery. AUC was
reduced in the RYGB subjects by 31\%, Cmax and Tmax were not
significantly altered\textsuperscript{50}.

Since both studies showed a reduction in exposure after surgery, it
seems that the use of macrolide antibiotics should be discouraged after
bariatric surgery.

\emph{Fluoroquinolone antibiotics (ciprofloxacin and moxifloxacin)}

To date, there are two studies published investigating the effect of
bariatric surgery on oral fluoroquinolone antibiotics.

De Smet and colleagues studied the oral bioavailability of moxifloxacin
in 12 individuals after RYGB surgery \textsuperscript{51}. Each subject
received two single doses of 400 mg oral or intravenous moxifloxacin
with a washout period of seven days at least six months after surgery.
While mean oral bioavailability was 88\%, oral and intravenous exposures
were 50\% higher than those described for subjects without gastric
bypass \textsuperscript{51}. The authors suggest that differences in
percentage man/women or a higher enterohepatic recirculation of
moxifloxacin after gastric bypass may contribute to this finding.

Rivas et al. evaluated the pharmacokinetic parameters of ciprofloxacin
in 17 RYGB patients before, one month, and six months after surgery
compared to 17 matched controls \textsuperscript{52}. AUC was 9737.2 +-
2717.6 h.ng/ml in the control and 9141.3 +- 1774.0 h.ng/ml at baseline in
the surgery group. One month after surgery, AUC decreased to 7581.4 +-
1511.1 h.ng/ml and returned to presurgical baseline values at 6 months
after surgery (9067.6 +- 3880.2 h.ng/ml).

\emph{Failure of oral antibiotic therapy after bariatric surgery}

Roy et al. investigated the association between the history of RYGB and
increased treatment failure in patients who received oral
antibiotics\textsuperscript{53}. Treatment failure was defined as any
prescription change that resulted in an increased daily dose, frequency
or duration of current oral antibiotics, substitution or addition of
another oral, intramuscular, or intravenous antibiotic for the same
indication, any surgical intervention for current infection, emergency
room or outpatient visit for current infection and hospitalization for
current infection. In their study, 186 patients were included (58 RYGB
patients and 128 controls). There was no significant difference in
composite therapeutic failure rates by time since RYGB surgery (24.1\%,
n=14) compared to the control group (15.6\% n=20). However, in the
subgroup treated with fluoroquinolones (31.6 vs. 7.1 \%, n= 6 and 2
respectively) and with sulfamethoxazole/trimethoprim (40 vs. 7.1\%, n=4
and 2 respectively) more therapeutic failure rates were reported
compared to controls.

Summarizing, for beta-lactam antibiotics, similar, increased or
decreased exposure can be anticipated after surgery, however as
concentrations seem overall high enough, these antibiotics can generally
be applied. For macrolide antibiotics, a reduced exposure up to 30-40\%
after surgery has been reported and therefore the use of these
antibiotics should be discouraged. While fluoroquinolones did show some
reduction in exposure after surgery, the overall bioavailability seems
adequate. In general, it seems that bariatric surgery patients treated
with oral antibiotics should be monitored closely for therapy failure
and side effects. When prescribing antibiotics to bariatric surgery
patients, several factors should be considered including , the site and
severity of infection, route of administration and potential toxicity.

\emph{Antihormones}

Tamoxifen is widely used in the treatment of estrogen receptor-positive
breast cancer and is known for its inter-individual variability in
pharmacokinetics. Previously, a minimal concentration threshold of 5.9
mg/ml of the active metabolite (Z)-endoxifen for the recurrence of
breast cancer has been identified \textsuperscript{54}. Therefore,
Therapeutic Drug Monitoring (TDM) has been recommended for tamoxifen to
prevent under-treatment based on the (Z)-endoxifen
concentration\textsuperscript{55,56}.

In patients after RYGB surgery, reduced absorption of tamoxifen has been
described in three women after RYGB \textsuperscript{57} with tamoxifen
blood concentrations below the therapeutic level of 5.9 mg/ml. For one
patient, the time between RYGB and measured tamoxifen concentration was
described and was four years. Because of the established relation
between (Z)-endoxifen and the recurrence of breast cancer, particularly
for patients after bariatric surgery, it seems advisable to apply TDM of
(Z)-endoxifen over time after bariatric surgery. The monitoring of side
effects can be included in determining the effectiveness/absorption of
the therapy, however, because hot flashes are not predictive for serum
concentrations of tamoxifen and its metabolites \textsuperscript{58}, it
can not replace TDM. To our best knowledge, there are no known data from
other antihormones in patients with bariatric surgery. Tamoxifen seems
to be the preferred antihormone therapy because of routine TDM.

\emph{Direct Acting Anticoagulants (DOACs)}

In recent years, direct-acting anticoagulants (DOACs) have emerged as
alternatives for vitamin K antagonists to be used for stroke prevention
in atrial fibrillation and for the prevention and treatment of venous
thromboembolism. Currently, four DOACs are available, of which apixaban,
rivaroxaban, edoxaban are direct factor Xa inhibitors, and dabigatran is
a direct thrombin inhibitor. In the general population, these drugs have
a predictable pharmacokinetic profile, which enables fixed dosing
without routine coagulation additional monitoring and consequently,
DOACs may have a profound benefit over the vitamin K antagonists
(VKAs)\textsuperscript{59}. However, in patients undergoing bariatric
surgery, these pharmacokinetic profiles may be aberrant. This may
particularly apply to rivaroxaban of which oral absorption is linear
until a dose of 15 mg, while in higher doses the bioavailability is
reduced and becomes dependent on co-administration with food
\textsuperscript{59}. For rivaroxaban 20-mg tablets, AUC and Cmax were
reported to increase by 39\% and 76\% when administered with food,
respectively\textsuperscript{60}. Also, dabigatran, which requires an
acid environment for absorption for which tartaric acid is added to the
tablet, the reduced volume for gastric acid secretion leading to a more
alkaline pH in the gastric pouch, may be subject to altered
absorption\textsuperscript{61,62}. Since all DOACs are absorbed in the
first part of the gastro-intestinal tract, surgery-related changes in
the absorptive surface could alter the absorption of all these
drugs\textsuperscript{63}.

Only limited information is available about the absorption of DOACs
after bariatric surgery. Kroll et al. measured the rivaroxaban AUC after
a single dose of 10 mg rivaroxaban in 12 patients with obesity one day
before and three days after RYGB / SG surgery \textsuperscript{64}. In
this study, no significant changes in pharmacokinetic profile were
reported. In an extension study, Kroll and colleagues investigated a
single dose of oral rivaroxaban of 10 mg 6 to 8 months after SG or
RYGB\textsuperscript{65}. While the AUC and T1/2 were not significantly
altered 6-8 months after surgery, Tmax was increased after RYGB and SG,
and Cmax was lower and not altered in RYGB and SG patients,
respectively\textsuperscript{64,65}. Given the known nonlinear
absorption of rivaroxaban, it is unknown whether these results can be
extrapolated to 15 or 20 mg tablets.

Rottenstreich et al. matched 18 patients who underwent bariatric surgery
(12 SG, four adjustable bands, and two RYGB) to 18 obese control
subjects. They were receiving DOACs (9 apixaban 5 mg BID, 7 rivaroxaban
15 mg OD and 20 mg OD and 2 dabigatran 110 mg and 150 mg BID) for atrial
fibrillation, pulmonary embolism or deep vein thrombosis. The median
time elapsed from surgery until study inclusion was 4.9 years. Peak
concentrations were within the normal range in all apixaban and
dabigatran patients; however, five of the seven patients receiving
rivaroxaban had significantly lower peak concentrations than the control
group \textsuperscript{66}. The authors conclude that all DOACs,
particularly rivaroxaban, should be used cautiously after bariatric
surgery if used at all given that VKAs can be easily monitored. In two
case reports, thromboembolic events related to possible impaired
dabigatran absorption have been published \textsuperscript{67,68}.

Based on the above reports, it seems that until more data on DOAC use is
available, VKAs or low molecular weight heparins are to be preferred of
DOACs. Measuring DOAC \textsuperscript{69--71} or
anti-Xa\textsuperscript{72,73} concentrations has been suggested when
applied in special patient groups, however as there is no hard evidence
on the relation between peak, trough or AUC of these measures with
outcome, it seems yet too early to use TDM as guidance for DOAC use in
postbariatric surgery patients. In another special patient population
(i.e. children), anti-Xa measurement for monitoring of the effect of
rivaroxaban was regarded as inferior compared to measurement of
rivaroxaban concentration. The reasons for this conclusion, is that the
anti-Xa assay result may be falsely high or low because the assay can be
influenced by pre-processing procedures (e.g., blood draw technique,
extended time until measurement) \textsuperscript{74}.

\emph{Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)}

The most common postoperative complications of bariatric surgery are
related to the GI tract, such as bleeding and
ulceration\textsuperscript{75,76}. Depending on the definition, the
reported incidence of ulceration ranges from 1 --
20\%\textsuperscript{75,77--84}. It is demonstrated that the use of
NSAIDs is an independent risk factor for the development of
ulcerations\textsuperscript{85--87}. Although NSAIDs after bariatric
surgery are often proclaimed to be life-long
contraindicated\textsuperscript{24,2524,25}, NSAIDs are commonly used in
bariatric surgery patients \textsuperscript{86--88}. Studies show that
the majority of the ulcerations occur within the first year after
surgery\textsuperscript{78,79,81}, and therefore it can be speculated
that the risk might thereafter be the same for bariatric surgery
patients and other subjects. For now, it seems reasonable to conclude
that NSAIDs are contraindicated in the first six months after bariatric
surgery and that until there is more evidence, after these six months,
the use of NSAIDS should be discouraged. There are no studies on the
pharmacokinetics of NSAIDS before versus after bariatric surgery.

\emph{Oral contraceptives}

Obesity is associated with infertility in women by various
mechanisms\textsuperscript{89}, which seems to be (totally or partially)
reversible after bariatric surgery \textsuperscript{90}. As
reproductive-aged women are advised to avoid pregnancy twelve to
twenty-four months after bariatric surgery, contraceptives are
recommended \textsuperscript{91--93}. An anticipated reduction in
absorption area, residence time and enterohepatic circulation after
bariatric surgery may potentially decrease the reliability of oral
contraceptives. There is however limited information on the use of oral
contraceptives after bariatric surgery. Victor et al. showed that
norethisterone and levonorgestrel levels were lower after jejunoileal
bypass at 1-8 hours after ingestion even though at 24 hours, there was
no difference \textsuperscript{94}. Furthermore a reduced effect of oral
contraceptives after biliopancreatic bypass was
described\textsuperscript{95}. Two of the nine patients who used oral
contraceptives postoperatively were unexpectedly pregnant. These two
patients suffered from chronic diarrhea. No unexpected pregnancies were
reported among users of non-oral contraceptives \textsuperscript{95}.
Ciangura et al. showed reduced norgestrel levels six months after RYGB,
however, these values were considered sufficiently high for a
contraceptive effect \textsuperscript{96}.

In conclusion, the absorption of oral contraceptives may be reduced,
particularly in the event of chronic diarrhea following restrictive and
malabsorptive bariatric surgery. Oral contraceptives should be
discouraged or alternative contraception should be used. Of note, Damhof
et al. showed that 16\% of the women undergoing bariatric surgery are
using potentially unsafe contraception postoperatively warranting the
attention of the health care professional for this
problem\textsuperscript{97}.

\emph{Platelet aggregation inhibitors}

Platelet aggregation inhibitors such as acetylsalicylic acid (ASA),
clopidogrel, prasugrel, and ticagrelor are frequently prescribed for the
prevention of (recurrent) thrombotic disease in high-risk patients.
Clopidogrel and prasugrel, both thienopyridines, and ticagrelor, a
cyclopentyltriazolopyrimidine, are oral P2Y\textsubscript{12} receptor
antagonists. While clopidogrel and prasugrel both need metabolic
activation, ticagrelor acts directly on the
P2Y\textsubscript{12}receptor. ASA, which is also a prodrug, exerts its
effects by irreversible COX inhibition, which in turn leads to a
reduction in the production of prostaglandin thromboxane
A\textsubscript{2} and inhibition of platelet aggregation.

Several studies have shown that elevated bodyweight results in higher
platelet reactivity, and therefore altered regimens for
ASA\textsuperscript{98--103} and clopidogrel
\textsuperscript{98,105--107}have been explored that might provide a
more optimal platelet inhibition in obese patients. The relevance of the
higher platelet reactivity in obese patients and its consequence for
dosing of platelet inhitibitors is unknown.

To date, four studies have investigated the effect of bariatric surgery
on the pharmacokinetic profile of platelet aggregation inhibitors. Three
studies describe the effect on ASA \textsuperscript{27,102,108}. The
other study investigates the effect of surgery on the pharmacodynamics
on ticagrelor \textsuperscript{109}.

As previously described, Mitrov-Winkelmolen et al. studied in an
open-label longitudinal repeated-measure study the effect of RYGB on ASA
pharmacokinetics. In their study, Tmax was shorter, and both Cmax and
AUC\textsubscript{0-24} (14.1 and 11.4 mg/l respectively
p\textless{}0.001) higher after surgery. Although statistically
significant, the authors argue that there are no clinically relevant
changes in ASA pharmacokinetics since the changes are still within the
recommended dosing range for platelet aggregation
inhibition\textsuperscript{27}.

Norgard and colleagues studied the effect of bariatric surgery on the
aspirin-induced platelet inhibition and subsequent platelet
aggregability \textsuperscript{102}. Ten patients undergoing bariatric
surgery (8 RYGB and 2 SG) were administrated two 7-day courses of ASA,
before and three months after surgery. After the last dose, platelet
reactivity expressed as aspirin reaction units (ARU) was tested and
compared to data of normal-weighted subjects. They showed that before
surgery, the platelet reactivity was significantly higher in patients
with obesity compared to normal-weight subjects (469 +- 60 vs. 419 +- 52
ARU p=0.016) when using ASA. After surgery, the platelet reactivity was
significantly reduced (432 +- 143 vs. 469 +- 60 ARU p=0.03), which was
also seen in RYGB patients who did not use ASA (602 +- 59 vs. 531 +- 78
ARU p=0.035). This shows that the reduced reactivity after surgery
compared to preoperative values may not be solely related to
ASA\textsuperscript{102}.

The safety of low-dose ASA was studied by Kang and
colleagues\textsuperscript{108}. They followed a group of 1016 patients
undergoing RYGB surgery, of whom 145 used ASA. The incidence of
ulceration was not significantly different between the two treatment
groups. Although it was a small study, the authors conclude that
patients were not at increased bleeding risk when using low-dose ASA
\textsuperscript{108}. In contrast, Caruana et al. reported an overall
rate of upper gastrointestinal bleeding of 4 of 11 bariatric surgery
patients within 2-3.5 weeks after starting clopidogrel (25-234 days
after surgery)\textsuperscript{110}. As such, it seems that prophylactic
PPIs are indicated for at least six months after bariatric surgery when
platelet inhibitors are given.

Ma et al. measured the influence of ticagrelor on whole blood impedance
platelet aggregability induced by adenosine in obese patients undergoing
bariatric surgery and in healthy normal weighted control
subjects\textsuperscript{109}. The half-maximal inhibitory concentration
(IC\textsubscript{50}) value was 34.0 nM six weeks before bariatric
surgery, which reduced to 23.1 nM 12 weeks after surgery whereas in
controls, the IC\textsubscript{50} level of ticagrelor was 14.5 nM. This
suggests that bariatric surgery improves the ticagrelor pharmacodynamic
response that was blunted by obesity, which is also showed in the study
of Norgard described above \textsuperscript{102}.

In conclusion, although obese patients seem to differ from non-obese
patients with respect to platelet activity, it seems that platelet
aggregation inhibitors do exert an effect after bariatric surgery.
However, it is difficult to distinguish between the influence of the
reduction of obesity versus the effect of the platelet inhibitor. From
the available results, it seems that there is no indication for dose
adjustments of platelet inhibitors after bariatric surgery.

\emph{Proton Pump Inhibitors (PPIs)}

According to many local protocols, PPIs are frequently prescribed after
bariatric surgery for the prevention of ulceration, even though the
duration of prophylactic PPI use seems to vary. In an internet-based
survey among members of the International Federation for the Surgery of
Obesity and Metabolic Disorders (IFSO) on the management of anastomotic
ulcers after RYGB surgery, 88\% of the 189 participants reported the
prescription of prophylactic medication of which 91\% preferred proton
pump inhibitors \textsuperscript{111}. The prophylactic medication was
prescribed for a period of one month in 25\% of the cases, for a period
of three months in 37\% of the cases, for a period of six months in 28\%
of the cases, for more than six months in 4\% of the cases and lifelong
for 5\% of the cases with a median of three months\textsuperscript{111}.
Even though the majority (\textasciitilde{}75\%) of ulceration appears
to occur in the first year after surgery with the steepest increase in
the first six months (\textasciitilde{}60\%)\textsuperscript{78}, the
available literature regarding this subject is not conclusive on the
duration of prophylaxis in this
population\textsuperscript{78--80,82,84,112}.

Since the prescription and usage of PPIs is widespread, information on
the absorption and dose is of relevance. Mitrov-winkelmolen et al.
studied the pharmacokinetics of omeprazole in 34 patients with morbid
obesity the months -- two weeks before and more than six weeks after
RYGB. Tmax after surgery was 0.9 h compared to 2.1h before surgery, Cmax
was higher (958.6+-300.8 \selectlanguage{greek}μ\selectlanguage{english}g/l vs. (731.1\selectlanguage{ngerman}±339.0 \selectlanguage{greek}μ\selectlanguage{english}g/l) and
AUC\textsubscript{0--12} was lower (2834.1\selectlanguage{ngerman}±1560.4 vs. 3737.4±21932 \selectlanguage{greek}μ\selectlanguage{english}g
h/l) after surgery \textsuperscript{27}. Another study in 18 RYGB
subjects one year after surgery also showed a reduced Tmax (0.75h vs.
4h) but no alterations in other PK parameters compared to matched
controls \textsuperscript{113}. This discrepancy might be explained by
differences in study design (matched vs. repeated measure design) and/or
large inter-individual variability in omeprazole PK. Also, the timing of
the study in relation to surgery, can be relevant.

Another factor that might contribute to therapy failure of PPIs is the
dissolution of the capsule, which was investigated by Schulman et al.,
reporting shorter healing time when the capsule was opened (as described
under Disintegration of the oral drug formulation) \textsuperscript{21}.
Therefore, in case an inadequate response is observed, opening the PPI
capsule can be advised provided that PPIs do not get in contact with
acid to prevent degradation \textsuperscript{114}. Therefore, PPI
capsules can only be opened when this is allowed according to the SmPC.

\emph{Psychotropic drugs}

Morbid obesity has been linked to different psychiatric disorders.
Depression is the most common psychiatric disorder in the obese
population with reported odds ratios (OR) ranging from 1.21 -- 5.8 with
a stronger association in women \textsuperscript{115}. There is also a
higher risk of anxiety disorders in the obese population (OR 1.27 --
1.40) \textsuperscript{115}. The prescription of psychotropic drugs is,
therefore, relatively common in the bariatric surgery population.

In an in-vitro model studying the dissolution of common psychotropic
drugs, ten of 22 psychiatric drugs had a significantly lower dissolution
fraction and two had significantly higher dissolution after RYGB
compared to preoperatively \textsuperscript{116}.

Hamad et al. investigated the effect of RYGB on the pharmacokinetics of
Serotonin Reuptake Inhibitors (SRI). Patients were taking venlafaxine
(N=5), citalopram (N=2), escitalopram (N=2), sertraline (N=2), or
duloxetine (N=1) \textsuperscript{117}. AUC values decreased with 54\%
(36 -- 80\%) one month after surgery in comparison with pre-operative
levels. In most patients AUC values returned to baseline or exceeded
baseline at six months after surgery \textsuperscript{117}.

Marzinke et al. measured escitalopram plasma levels in four subjects two
weeks before versus two and six weeks after RYGB. Two weeks after
surgery, escitalopram plasma levels decreased by 4 -- 71\%. Samples
collected six weeks after surgery showed a further decrease with 16 --
19\% \textsuperscript{118}.

Roerig et al. measured the AUC of duloxetine and sertraline in RYGB
patients and matched controls \textsuperscript{119,120}. For sertraline
both the AUC\textsubscript{0-10,5} (124.4 +/- 55.5 ng-hr/ml vs 314.8 +/-
129.6 ng-hr/ml) and Cmax (19.0 +/- 7.8 ng/ml vs 48.7 +/- 19.1 ng/ml)
were significantly lower 9-15 months after RYGB
surgery\textsuperscript{119}. For duloxetine, AUC\textsubscript{0-[?]}
(646.74 +/- 79.7 vs 1119.91 +/- 593.40) and Tmax (2.2 +/- 0.86 vs 6.0
+/- 2.17) were significantly lower in the RYGB group 9 -- 15 months
after surgery \textsuperscript{120}.

These studies suggest that health care professionals should be aware of
decreased serum concentrations when prescribing anti-depressants and
anti-psychotics drugs to bariatric surgery patients, especially in the
first few weeks and months after surgery \textsuperscript{117--120}.
Although no information was provided on the mental status of patients in
the above mentioned reports, prescribers should, monitor patients for
signs of therapy failure, particularly in the first year after bariatric
surgery.

\emph{Vitamin K antagonists (VKAs)}

VKAs such as acenocoumarol, fenprocoumon, and warfarin, inhibit the
carboxylation of the vitamin K-dependent coagulation factors II, VII,
IX, and X in the liver necessary for coagulation and thus indirectly
inhibit the coagulation process. VKAs are used for the prophylaxis and
treatment of VTE and stroke prevention in atrial fibrillation. As VKAs
are absorbed in the proximal intestine, bariatric surgery could have an
impact on the absorption of VKAs.

Several studies investigated the effect of bariatric surgery on the
daily dose of warfarin

\textsuperscript{121--124}. All studies demonstrated that the warfarin
dose was significantly reduced after RYGB surgery, especially in the six
month postoperatively. After the direct postoperative phase, the
required dose tended to gradually go back up to pre-surgical levels at
six months to one year after surgery \textsuperscript{121--124}. It is
not yet entirely clear why a lower dose is needed shortly after the
operation. While it can be hypothesized that absorption may be increased
because of crushing the tablets by patients directly after surgery,
another explanation may lie in the changes that are associated with
bariatric surgery that are to date not fully understood, such as
metabolic changes \textsuperscript{4}. Also changes in diet during the
first months after surgery may play a role. Similar to the results of
platelet aggregation inhibitors, it seems that bariatric surgery may
improve the response on VKAs compared to obese subjects, especially in
the first months after surgery \textsuperscript{121,122}. It is known
that compared to normal weight patients, obese patients require a higher
average daily dose and also require more time to achieve therapeutic
international normalized ratio (INR) \textsuperscript{125}. While no
studies have been conducted on acenocoumarol and fenprocoumon after
bariatric surgery, it may seem that these results also apply to these
drugs. Overall, more frequent monitoring of the INR seems appropriate in
the first year after bariatric surgery.

\textbf{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 \textsuperscript{37,38,46,64,65},
lower\textsuperscript{30,46,50,52,117,119} or
higher\textsuperscript{27,45,47} 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 \textsuperscript{44,45}. Also for controlled
release formulations, conflicting results were obtained in different
studies \textsuperscript{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 AUC\textsubscript{0-24h} (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
morphine\textsuperscript{22} or midazolam \textsuperscript{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).

\textbf{Conclusions}

Bariatric surgery is increasingly employed for (morbid) obesity because
it improves long-term morbidity and mortality. As a result of changes in
the gastrointestinal tract that subsequently result in major weight
loss, the pharmacokinetics of drugs in patients after bariatric surgery
may be subject to alterations in the absorption, distribution,
metabolism, and/or elimination. Due to an increased absorption rate
after bariatric surgery, the time at maximum concentration is often
earlier and the maximum concentration may be higher with less consistent
effects on trough concentrations and exposure or area under the curve
upon oral drug administration. We conclude that based on current
literature an advice can be proposed in many cases but also that there
is insufficient evidence for general dosing recommendations for oral
drug therapy after bariatric surgery implying a risk assessment on a
case by case basis.

\textbf{References}

1. World Health Organisation. Fact sheet - Obesity and overweight.
Published 2020. Accessed May 20, 2020.
https://www.who.int/en/news-room/fact-sheets/detail/obesity-and-overweight

2. Adams K, Schatzkin A, Harris T, et al. Overweight, obesity, and
mortality in a large prospective cohort of persons 50 to 71 years
old.\emph{N Engl J Med} . 2006;(355):763-778. doi:10.1056/NEJMoa1109071

3. Bogers R, Bemelmans W, Hoogenveen R, et al. Association of Overweight
With Increased Risk of Coronary Heart Disease Partly Independent of
Blood Pressure and Cholesterol Levels. \emph{Arch Intern Med} .
2007;167(16):1720-1728.

4. Sj\selectlanguage{ngerman}öström L. Review of the key results from the Swedish Obese Subjects
(SOS) trial - a prospective controlled intervention study of bariatric
surgery. \emph{J Intern Med} . 2013;273(3):219-234.
doi:10.1111/joim.12012

5. Sjöström L, Lindroos AK, Peltonen M, et al. Lifestyle, diabetes, and
cardiovascular risk factors 10 years after bariatric surgery. \emph{N
Engl J Med} . Published online 2003:1695-1702.

6. Colquitt JL, Pickett K, Loveman E, Frampton GK. Surgery for weight
loss in adults. Cochrane Database of Systematic Reviews. \emph{Cochrane
Collab} . 2014;(8):244.
doi:10.1002/14651858.CD003641.pub4.www.cochranelibrary.com

7. Mechanick JI, Apovian C, Brethauer S, et al. Clinical Practice
Guidelines for the Perioperative Nutrition, Metabolic, and Nonsurgical
Support of Patients Undergoing Bariatric Procedures - 2019 Update:
Cosponsored By American Association of Clinical
Endocrinologists/American College of Endocrinology,. \emph{Endocr Pract}
. 2019;25(12):1346-1359. doi:10.4158/GL-2019-0406

8. Zenténius E, Andersson-Assarsson JC, Carlsson LMS, Svensson PA,
Larsson I. Self-Reported Weight-Loss Methods and Weight Change: Ten-Year
Analysis in the Swedish Obese Subjects Study Control
Group.\emph{Obesity} . 2018;26(7):1137-1143. doi:10.1002/oby.22200

9. Reges O, Greenland P, Dicker D, et al. Association of bariatric
surgery using laparoscopic banding, roux-en-y gastric bypass, or
laparoscopic sleeve gastrectomy vs usual care obesity management with
all-cause mortality. \emph{JAMA - J Am Med Assoc} . 2018;319(3):279-290.
doi:10.1001/jama.2017.20513

10. Lindekilde N, Gladstone BP, Lübeck M, et al. The impact of bariatric
surgery on quality of life: A systematic review and
meta-analysis.\emph{Obes Rev} . 2015;16(8):639-651.
doi:10.1111/obr.12294

11. Angrisani L, Santonicola A, Iovino P, et al. IFSO Worldwide Survey
2016: Primary, Endoluminal, and Revisional Procedures. \emph{Obes Surg}
. 2018;28(12):3783-3794. doi:10.1007/s11695-018-3450-2

12. Smith C, Herkes S, Behrn K, Fairbanks V, Kelly K, Sarr M. Gastric
acid secretion and vitamin B12 absorption after vertical Roux-en-Y
gastric bypass for morbid obesity. \emph{Ann Surg} . 1993;218:91-96.

13. Tolone S, Savarino E, de Bortoli N, et al. Esophageal
High-Resolution Manometry Can Unravel the Mechanisms by Which Different
Bariatric Techniques Produce Different Reflux Exposures. \emph{J
Gastrointest Surg} . 2020;24(1):1-7. doi:10.1007/s11605-019-04406-7

14. Yska JP, Van Der Meer DH, Dreijer AR, et al. Influence of bariatric
surgery on the use of medication. \emph{Eur J Clin Pharmacol} .
2016;72(2):203-209. doi:10.1007/s00228-015-1971-3

15. Johnson TN, Bonner JJ, Tucker GT, Turner DB, Jamei M. Development
and applications of a physiologically-based model of paediatric oral
drug absorption. \emph{Eur J Pharm Sci} . 2018;115(December 2017):57-67.
doi:10.1016/j.ejps.2018.01.009

16. Kostewicz ES, Aarons L, Bergstrand M, et al. PBPK models for the
prediction of in vivo performance of oral dosage forms. \emph{Eur J
Pharm Sci} . 2014;57(1):300-321. doi:10.1016/j.ejps.2013.09.008

17. Darwich AS, Henderson K, Burgin A, et al. Trends in oral drug
bioavailability following bariatric surgery: Examining the variable
extent of impact on exposure of different drug classes. \emph{Br J Clin
Pharmacol} . 2012;74(5):774-787. doi:10.1111/j.1365-2125.2012.04284.x

18. Azran C, Wolk O, Zur M, et al. Oral drug therapy following bariatric
surgery: an overview of fundamentals, literature and clinical
recommendations. \emph{Obes Rev} . 2016;17(11):1050-1066.
doi:10.1111/obr.12434

19. van Beek AP, Emous M, Laville M, Tack J. Dumping syndrome after
esophageal, gastric or bariatric surgery: pathophysiology, diagnosis,
and management. \emph{Obes Rev} . 2017;18(1):68-85.
doi:10.1111/obr.12467

20. Montanha MC, Santos Magon TF, Souza Alcantara C, et al. Reduced
bioavailability of oral amoxicillin tablets compared to suspensions in
Roux\selectlanguage{english}-en\selectlanguage{english}-Y gastric bypass bariatric subjects. \emph{Br J Clin Pharmacol}
. 2019;85(9):2118-2125. doi:10.1111/bcp.14023

21. Schulman AR, Chan WW, Devery A, Ryan MB, Thompson CC. Opened Proton
Pump Inhibitor Capsules Reduce Time to Healing~Compared With Intact
Capsules for Marginal Ulceration~Following Roux-en-Y Gastric
Bypass.\emph{Clin Gastroenterol Hepatol} . 2017;15(4):494-500.e1.
doi:10.1016/j.cgh.2016.10.015

22. Lloret-Linares C, Luo H, Rouquette A, et al. The effect of morbid
obesity on morphine glucuronidation. \emph{Pharmacol Res} .
2017;118:64-70. doi:10.1016/j.phrs.2016.08.031

23. Brill MJ, Van Rongen A, Van Dongen EP, et al. The Pharmacokinetics
of the CYP3A Substrate Midazolam in Morbidly Obese Patients before and
One Year after Bariatric Surgery. \emph{Pharm Res} .
2015;32(12):3927-3936. doi:10.1007/s11095-015-1752-9

24. Mechanick JI, Youdim A, Jones DB, T G, L HD, Mcmahon M. Clinical
Practice Guidelines for the Perioperative Nutritional. \emph{Obesity} .
2013;21(0 1):S1-27. doi:10.1002/oby.20461.Clinical

25. Carr WRJ, Mahawar KK, Balupuri S, Small PK. An evidence-based
algorithm for the management of marginal ulcers following Roux-en-Y
gastric bypass. \emph{Obes Surg} . 2014;24(9):1520-1527.
doi:10.1007/s11695-014-1293-z

26. Hogben CAM, Schanker LS, Tocco DJ, Brodie BB. ABSORPTION OF DRUGS
FROM THE STOMACH. II. THE HUMAN. \emph{J Pharmacol Exp Ther} .
1957;120(4).

27. Mitrov-Winkelmolen L, van Buul-Gast MCW, Swank DJ, Overdiek HWPM,
van Schaik RHN, Touw DJ. The Effect of Roux-en-Y Gastric Bypass Surgery
in Morbidly Obese Patients on Pharmacokinetics of (Acetyl)Salicylic Acid
and Omeprazole: the ERY-PAO Study. \emph{Obes Surg} .
2016;26(9):2051-2058. doi:10.1007/s11695-016-2065-8

28. Walravens J, Brouwers J, Spriet I, Tack J, Annaert P, Augustijns P.
Effect of pH and Comedication on Gastrointestinal Absorption of
Posaconazole. \emph{Clin Pharmacokinet} . 2011;50(11):725-734.
doi:10.2165/11592630-000000000-00000

29. Krishna G, Moton A, Lei M, Medlock MM, McLeod J. Pharmacokinetics
and absorption of posaconazole oral suspension under various gastric
conditions in healthy volunteers. \emph{Antimicrob Agents Chemother} .
2009;53(3):958-966. doi:10.1128/AAC.01034-08

30. Gesquiere I, Hens B, Van der Schueren B, et al. Drug disposition
before and after gastric bypass: fenofibrate and posaconazole. \emph{Br
J Clin Pharmacol} . 2016;60:1325-1332. doi:10.1111/bcp.13054

31. Carswell KA, Vincent RP, Belgaumkar AP, et al. The Effect of
Bariatric Surgery on Intestinal Absorption and Transit Time. \emph{Obes
Surg} . 2014;24(5):796-805. doi:10.1007/s11695-013-1166-x

32. Dirksen C, Damgaard M, Bojsen-Moller KN, et al. Fast pouch emptying,
delayed small intestinal transit, and exaggerated gut hormone responses
after Roux-en-Y gastric bypass. \emph{Neurogastroenterol Motil} .
2013;25(4). doi:10.1111/nmo.12087

33. Nguyen NQ, Debreceni TL, Burgstad CM, et al. Effects of Posture and
Meal Volume on Gastric Emptying, Intestinal Transit, Oral Glucose
Tolerance, Blood Pressure and Gastrointestinal Symptoms After Roux-en-Y
Gastric Bypass. \emph{Obes Surg} . 2015;25(8):1392-1400.
doi:10.1007/s11695-014-1531-4

34. Wang G, Agenor K, Pizot J, et al. Accelerated Gastric Emptying but
No Carbohydrate Malabsorption 1 Year After Gastric Bypass Surgery
(GBP).\emph{Obes Surg} . 2012;22(8):1263-1267.
doi:10.1007/s11695-012-0656-6

35. Yska JP, Wanders JTM, Odigie B, et al. Effect of Roux-en-Y gastric
bypass on the bioavailability of metoprolol from immediate and
controlled release tablets: A single oral dose study before and after
surgery. \emph{Eur J Hosp Pharm} . Published online 2019:1-6.
doi:10.1136/ejhpharm-2018-001804

36. Gesquiere I, Darwich AS, Van der Schueren B, et al. Drug disposition
and modelling before and after gastric bypass: immediate and
controlled-release metoprolol formulations. \emph{Br J Clin Pharmacol} .
2015;80(5):1021-1030. doi:10.1111/bcp.12666

37. Krieger CA, Cunningham JL, Reid JM, et al. Comparison of
Bioavailability of Single-Dose Extended-Release Venlafaxine Capsules in
Obese Patients Before and After Gastric Bypass
Surgery.\emph{Pharmacotherapy} . 2017;37(11):1374-1382.
doi:10.1002/phar.2022

38. Hachon L, Reis R, Labat L, et al. Morphine and metabolites plasma
levels after administration of sustained release morphine in Roux-en-Y
gastric bypass subjects versus matched control subjects. \emph{Surg Obes
Relat Dis} . 2017;13(11):1869-1874. doi:10.1016/j.soard.2017.07.030

39. Dobner J, Kaser S. Body mass index and the risk of infection - from
underweight to obesity. \emph{Clin Microbiol Infect} . 2018;24(1):24-28.
doi:10.1016/j.cmi.2017.02.013

40. Huttunen R, Syrjanen J. Obesity and the risk and outcome of
infection. \emph{Int J Obes} . 2013;37(3):333-340.
doi:10.1038/ijo.2012.62

41. Falagas ME, Kompoti M. Obesity and infection. \emph{Lancet Infect
Dis} . 2006;6(7):438-446. doi:10.1016/S1473-3099(06)70523-0

42. Brill MJE, Houwink API, Schmidt S, et al. Reduced subcutaneous
tissue distribution of cefazolin in morbidly obese versus non-obese
patients determined using clinical microdialysis. \emph{J Antimicrob
Chemother} . 2014;69(3):715-723. doi:10.1093/jac/dkt444

43. Hollenstein UM, Brunner M, Schmid R, Muller M. Soft tissue
concentrations of ciprofloxacin in obese and lean subjects following
weight-adjusted dosing. \emph{Int J Obes} . 2001;25(3):354-358.
doi:10.1038/sj.ijo.0801555

44. Miskowiak J, Andersen B, Nielsen VG. Absorption of oral penicillin
before and after gastroplasty for morbid obesity. \emph{Pharmacology} .
1985;31(2):115-120. doi:10.1159/000138106

45. Terry SI, Gould JC, McManus JPA, Prescott LF. Absorption of
penicillin and paracetamol after small intestinal bypass
surgery.\emph{Eur J Clin Pharmacol} . 1982;23(3):245-248.
doi:10.1007/BF00547562

46. Montanha MC, dos Santos Magon TF, de Souza Alcantara C, et al.
Reduced bioavailability of oral amoxicillin tablets compared to
suspensions in Roux-en-Y gastric bypass bariatric subjects. \emph{Br J
Clin Pharmacol} . 2019;85(9):2118-2125. doi:10.1111/bcp.14023

47. Rocha MBS, De Nucci G, Lemos FN, et al. Impact of Bariatric Surgery
on the Pharmacokinetics Parameters of Amoxicillin. \emph{Obes Surg} .
2019;29(3):917-927. doi:10.1007/s11695-018-3591-3

48. Kampmann JP, Klein H, Lumholtz B, Hansen JEM. Ampicillin and
Propylthiouracil Pharmacokinetics in Intestinal Bypass Patients Followed
Up to a Year after Operation. \emph{Clin Pharmacokinet} .
1984;9(2):168-176. doi:10.2165/00003088-198409020-00004

49. Prince RA, Pincheira JC, Mason EE, Printen KJ. Influence of
bariatric surgery on erythromycin absorption. \emph{J Clin Pharmacol} .
1984;24(11-12):523-527. doi:10.1002/j.1552-4604.1984.tb02762.x

50. Padwal RS, Ben-Eltriki M, Wang X, et al. Effect of gastric bypass
surgery on azithromycin oral bioavailability. \emph{J Antimicrob
Chemother} . 2012;67(9):2203-2206. doi:10.1093/jac/dks177

51. De Smet J, Colin P, De Paepe P, et al. Oral bioavailability of
moxifloxacin after Roux-en-Y gastric bypass surgery. \emph{J Antimicrob
Chemother} . 2012;67(1):226-229. doi:10.1093/jac/dkr436

52. Rivas AB, Lopez-Picado A, Salas-Butron M del R, et al. Effect of
Roux-en-Y gastric surgery on ciprofloxacin pharmacokinetics: an obvious
effect? \emph{Eur J Clin Pharmacol} . 2019;75(5):647-654.
doi:10.1007/s00228-018-02623-8

53. Roy DJ, Langworthy DR, Thurber KM, Lorentz PA, Dierkhising RA, Mundi
MS. Comparison of oral antibiotic failure rates in post-Roux-en-Y
gastric bypass patients versus controls. \emph{Surg Obes Relat Dis} .
2017;13(9):1524-1529. doi:10.1016/j.soard.2017.03.026

54. Madlensky L, Natarajan L, Tchu S, et al. Tamoxifen metabolite
concentrations, CYP2D6 genotype, and breast cancer outcomes. \emph{Clin
Pharmacol Ther} . 2011;89(5):718-725. doi:10.1038/clpt.2011.32

55. Jager NGL, Rosing H, Schellens JHM, Linn SC, Beijnen JH. Tamoxifen
dose and serum concentrations of tamoxifen and six of its metabolites in
routine clinical outpatient care. \emph{Breast Cancer Res Treat} .
2014;143(3):477-483. doi:10.1007/s10549-013-2826-1

56. Binkhorst L, Van Gelder T, Mathijssen RHJ. Individualization of
tamoxifen treatment for breast carcinoma. \emph{Clin Pharmacol Ther} .
2012;92(4):431-433. doi:10.1038/clpt.2012.94

57. Wills SM, Zekman R, Bestul D, Kuwajerwala N, Decker D. Tamoxifen
Malabsorption after Roux-en-Y Gastric Bypass Surgery: Case Series and
Review of the Literature. \emph{Pharmacotherapy} . 2010;30(2):217.
doi:10.1592/phco.30.2.217

58. Jager NGL, Koornstra RHT, Vincent AD, et al. Hot flashes are not
predictive for serum concentrations of tamoxifen and its
metabolites.\emph{BMC Cancer} . 2013;13. doi:10.1186/1471-2407-13-612

59. Bauer KA. Pros and cons of new oral anticoagulants. \emph{Hematol am
soc hematol educ Progr} . Published online 2013:464-470.

60. Kubitza D, Becka M, Zuehlsdorf M, Mueck W. Effect of food, an
antacid, and the H2 antagonist ranitidine on the absorption of BAY
59-7939 (rivaroxaban), an oral, direct factor Xa inhibitor, in healthy
subjects. \emph{J Clin Pharmacol} . 2006;46(5):549-558.
doi:10.1177/0091270006286904

61. Dewald TA, Becker RC. The pharmacology of novel oral
anticoagulants.\emph{J Thromb Thrombolysis} . 2014;37(2):217-233.
doi:10.1007/s11239-013-0967-z

62. Stangier J, Eriksson BI, Dahl OE, et al. Pharmacokinetic Profile of
the Oral Direct Thrombin Inhibitor Dabigatran Etexilate in Healthy
Volunteers and Patients Undergoing Total Hip Replacement. \emph{J Clin
Pharmacol} . 2005;45(5):555-565. doi:10.1177/0091270005274550

63. Martin KA, Lee CR, Farrell TM, Moll S. Oral Anticoagulant Use After
Bariatric Surgery: A Literature Review and Clinical Guidance. \emph{Am J
Med} . 2017;130(5):517-524. doi:10.1016/j.amjmed.2016.12.033

64. Kroll D, Stirnimann G, Vogt A, et al. Pharmacokinetics and
pharmacodynamics of single doses of rivaroxaban in obese patients prior
to and after bariatric surgery. \emph{Br J Clin Pharmacol} .
2017;83(7):1466-1475. doi:10.1111/bcp.13243

65. Kroll D, Nett PC, Borbely YM, et al. The effect of bariatric surgery
on the direct oral anticoagulant rivaroxaban: the extension
study.\emph{Surg Obes Relat Dis} . 2018;14(12):1890-1896.
doi:10.1016/j.soard.2018.08.025

66. Rottenstreich A, Barkai A, Arad A, Raccah BH, Kalish Y. The effect
of bariatric surgery on direct-acting oral anticoagulant drug
levels.\emph{Thromb Res} . 2018;163:190-195.
doi:10.1016/j.thromres.2017.11.006

67. Lachant DJ, Uraizee I, Gupta R, Pedulla AJ. IJCRI International
Journal of Case Reports and Images. \emph{Int J Case Reports Images
Cover} . 2015;6(11):663-664. doi:10.1681/ASN.2014100997

68. Lee D, DeFilipp Z, Judson K, Kennedy M. Subtherapeutic
anticoagulation with dabigatran following Roux-en-Y gastric bypass
surgery. \emph{J Cardiol Cases} . 2013;8(1):e49-e50.
doi:10.1016/j.jccase.2013.03.013

69. Mikli\selectlanguage{polish}č \selectlanguage{english}M, Mavri A, Vene N, et al. Intra- and inter- individual
rivaroxaban concentrations and potential bleeding risk in patients with
atrial fibrillation. \emph{Eur J Clin Pharmacol} . 2019;75(8):1069-1075.
doi:10.1007/s00228-019-02693-2

70. Ruff CT, Giugliano RP, Braunwald E, et al. Association between
edoxaban dose, concentration, anti-Factor Xa activity, and outcomes: An
analysis of data from the randomised, double-blind ENGAGE AF-TIMI 48
trial. \emph{Lancet} . 2015;385(9984):2288-2295.
doi:10.1016/S0140-6736(14)61943-7

71. Reilly PA, Lehr T, Haertter S, et al. The effect of dabigatran
plasma concentrations and patient characteristics on the frequency of
ischemic stroke and major bleeding in atrial fibrillation patients: The
RE-LY trial (Randomized Evaluation of Long-Term Anticoagulation
Therapy). \emph{J Am Coll Cardiol} . 2014;63(4):321-328.
doi:10.1016/j.jacc.2013.07.104

72. Gosselin R, Grant RP, Adcock DM. Comparison of the effect of the
anti-Xa direct oral anticoagulants apixaban, edoxaban, and rivaroxaban
on coagulation assays. \emph{Int J Lab Hematol} . 2016;38(5):505-513.
doi:10.1111/ijlh.12528

73. Cini M, Legnani C, Padrini R, et al. DOAC plasma levels measured by
chromogenic anti-Xa assays and HPLC-UV in apixaban- and
rivaroxaban-treated patients from the START-Register. \emph{Int J Lab
Hematol} . 2020;42(2):214-222. doi:10.1111/ijlh.13159

74. Kubitza D, Willmann S, Becka M, et al. Exploratory evaluation of
pharmacodynamics, pharmacokinetics and safety of rivaroxaban in children
and adolescents: An EINSTEIN-Jr phase i study. \emph{Thromb J} .
2018;16(1):1-13. doi:10.1186/s12959-018-0186-0

75. Kassir R, Debs T, Blanc P, et al. Complications of bariatric
surgery: Presentation and emergency management. \emph{Int J Surg} .
2016;27:77-81. doi:10.1016/j.ijsu.2016.01.067

76. Thereaux J, Lesuffleur T, Czernichow S, et al. Long-term adverse
events after sleeve gastrectomy or gastric bypass: a 7-year nationwide,
observational, population-based, cohort study. \emph{Lancet Diabetes
Endocrinol} . 2019;7(10):786-795. doi:10.1016/S2213-8587(19)30191-3

77. Dallal RM, Bailey LA. Ulcer disease after gastric bypass
surgery.\emph{Surg Obes Relat Dis} . 2006;2(4):455-459.
doi:10.1016/j.soard.2006.03.004

78. D'Hondt MA, Pottel H, Devriendt D, Van Rooy F, Vansteenkiste F. Can
a short course of prophylactic low-dose proton pump inhibitor therapy
prevent stomal ulceration after laparoscopic Roux-en-Y gastric
bypass?\emph{Obes Surg} . 2010;20(5):595-599.
doi:10.1007/s11695-009-0062-x

79. Gumbs AA, Duffy AJ, Bell RL. Incidence and management of marginal
ulceration after laparoscopic Roux-Y gastric bypass. \emph{Surg Obes
Relat Dis} . 2006;2(4):460-463. doi:10.1016/j.soard.2006.04.233

80. Wu Chao Ying V, Song SH, J. Khan K, et al. Prophylactic PPI help
reduce marginal ulcers after gastric bypass surgery: a systematic review
and meta-analysis of cohort studies. \emph{Surg Endosc} .
2015;29(5):1018-1023. doi:10.1007/s00464-014-3794-1

81. Garrido AB, Rossi M, Lima SE, Brenner AS, Gomes CAR. Early marginal
ulcer following Roux-en-Y gastric bypass under proton pump inhibitor
treatment - Prospective multicentric study. \emph{Arq Gastroenterol} .
2010;47(2):130-134. doi:10.1590/S0004-28032010000200003

82. Kang X, Zurita-Macias L, Hong D, Cadeddu M, Anvari M, Gmora S. A
comparison of 30-day versus 90-day proton pump inhibitor therapy in
prevention of marginal ulcers after laparoscopic Roux-en-Y gastric
bypass. \emph{Surg Obes Relat Dis} . 2016;12(5):1003-1007.
doi:10.1016/j.soard.2015.11.010

83. Coblijn UK, Lagarde SM, De Castro SMM, Kuiken SD, Van Tets WF, Van
Wagensveld BA. The influence of prophylactic proton pump inhibitor
treatment on the development of symptomatic marginal ulceration in
Roux-en-Y gastric bypass patients: A historic cohort study. \emph{Surg
Obes Relat Dis} . 2016;12(2):246-252. doi:10.1016/j.soard.2015.04.022

84. Plaeke P, Ruppert M, Hubens G. Benefits of prophylactic proton pump
inhibitors after Roux-en-Y gastric bypass surgery a retrospective
study.\emph{Acta Chir Belg} . 2015;115(4):273-278.
doi:10.1080/00015458.2015.11681111

85. Hakkarainen TW, Steele SR, Bastaworous A, et al. Nonsteroidal
anti-inflammatory drugs and the risk for anastomotic failure A report
from Washington State's Surgical Care and Outcomes Assessment Program
(SCOAP). \emph{JAMA Surg} . 2015;150(3):223-228.
doi:10.1001/jamasurg.2014.2239

86. Sasse KC, Ganser J, Kozar M, et al. Seven cases of gastric
perforation in Roux-en-Y gastric bypass patients: What lessons can we
learn? \emph{Obes Surg} . 2008;18(5):530-534.
doi:10.1007/s11695-007-9335-4

87. Wendling MR, Linn JG, Keplinger KM, et al. Omental patch repair
effectively treats perforated marginal ulcer following Roux-en-Y gastric
bypass. \emph{Surg Endosc} . 2013;27(2):384-389.
doi:10.1007/s00464-012-2492-0

88. Yska JP, Gertsen S, Flapper G, Emous M, Wilffert B, van Roon EN.
NSAID Use after Bariatric Surgery: a Randomized Controlled Intervention
Study. \emph{Obes Surg} . 2016;26(12):2880-2885.
doi:10.1007/s11695-016-2218-9

89. Gambineri A, Laudisio D, Marocco C, Radellini S, Colao A, Savastano
S. Female infertility: which role for obesity? \emph{Int J Obes Suppl} .
2019;9(1):65-72. doi:10.1038/s41367-019-0009-1

90. Merhi ZO. Impact of bariatric surgery on female
reproduction.\emph{Fertil Steril} . 2009;92(5):1501-1508.
doi:10.1016/j.fertnstert.2009.06.046

91. Dao T, Kuhn J, Ehmer D, Fisher T, McCarty T. Pregnancy outcomes
after gastric-bypass surgery. \emph{Am J Surg} . 2006;192(6):762-766.
doi:10.1016/j.amjsurg.2006.08.041

92. Wittgrove AC, Jester L, Wittgrove P, Clark W. Pregnancy following
gastric by-pass for morbid obesity. \emph{Obes Surg} . 1998;8:461-464.

93. Patel JA, Patel NA, Thomas RL, Nelms JK, Colella JJ. Pregnancy
outcomes after laparoscopic Roux-en-Y gastric bypass. \emph{Surg Obes
Relat Dis} . 2008;4(1):39-45. doi:10.1016/j.soard.2007.10.008

94. Victor A, Odlind V, Kral J. Oral contraceptive absorption and sex
hormone binding globulins in obese women: effects of jejunoileal
bypass.\emph{Gastroenterol Clin North Am} . 1987;(16(3)):483-491.

95. Gerrits E, Ceulemans R, van Hee R, Hendrickx L, Tott\selectlanguage{ngerman}é E. Materials
and MethoContraceptive Treatment after Biliopancreatic Diversion Needs
Consensusds. \emph{Obes Surg} . 2003;13:378-382.

96. Ciangura C, Corigliano N, Basdevant A, et al. Etonorgestrel
concentrations in morbidly obese women following Roux-en-Y gastric
bypass surgery: Three case reports. \emph{Contraception} .
2011;84(6):649-651. doi:10.1016/j.contraception.2011.03.015

97. Damhof MA, Pierik E, Krens LL, Vermeer M, van Det MJ, van Roon EN.
Assessment of Contraceptive Counseling and Contraceptive Use in Women
After Bariatric Surgery. \emph{Obes Surg} . 2019;29(12):4029-4035.
doi:10.1007/s11695-019-04084-z

98. Gremmel T, Steiner S, Seidinger D, Koppensteiner R, Panzer S, Kopp
CW. Obesity is associated with poor response to clopidogrel and an
increased susceptibility to protease activated receptor-1 mediated
platelet activation. \emph{Transl Res} . 2013;161(5):421-429.
doi:10.1016/j.trsl.2012.12.015

99. Tamminen M, Lassila R, Westerbacka J, Vehkavaara S, Yki-Järvinen H.
Obesity is associated with impaired platelet-inhibitory effect of
acetylsalicylic acid in nondiabetic subjects. \emph{Int J Obes} .
2003;27(8):907-911. doi:10.1038/sj.ijo.0802312

100. Bordeaux BC, Qayyum R, Yanek LR, et al. Effect of obesity on
platelet reactivity and response to low-dose aspirin. \emph{Prev
Cardiol} . 2010;13(2):56-62. doi:10.1111/j.1751-7141.2009.00058.x

101. Larsen SB, Grove EL, Neergaard-Petersen S, Würtz M, Hvas AM,
Kristensen SD. Determinants of reduced antiplatelet effect of aspirin in
patients with stable coronary artery disease. \emph{PLoS One} .
2015;10(5):1-14. doi:10.1371/journal.pone.0126767

102. Norgard NB, Monte S V., Fernandez SF, Ma Q. Aspirin responsiveness
changes in obese patients following bariatric surgery. \emph{Cardiovasc
Ther} . 2017;35(4):2-6. doi:10.1111/1755-5922.12268

103. Norgard NB. Obesity and Altered Aspirin Pharmacology. \emph{Clin
Pharmacokinet} . 2018;57(6):663-672. doi:10.1007/s40262-017-0611-8

104. Cohen HW, Crandall JP, Hailpern SM, Billett HH. Aspirin resistance
associated with HbA1c and obesity in diabetic patients. \emph{J Diabetes
Complications} . 2008;22(3):224-228. doi:10.1016/j.jdiacomp.2007.05.002

105. Darlington A, Tello-Montoliu A, Rollini F, et al. Pharmacodynamic
effects of standard dose prasugrel versus high dose clopidogrel in
non-diabetic obese patients with coronary artery disease. \emph{Thromb
Haemost} . 2013;111(2):258-265. doi:10.1160/TH13-07-0529

106. Bonello-Palot N, Armero S, Paganelli F, et al. Relation of Body
Mass Index to High On-Treatment Platelet Reactivity and of Failed
Clopidogrel Dose Adjustment According to Platelet Reactivity Monitoring
in Patients Undergoing Percutaneous Coronary Intervention. \emph{Am J
Cardiol} . 2009;104(11):1511-1515. doi:10.1016/j.amjcard.2009.07.015

107. Sibbing D, von Beckerath O, Schömig A, Kastrati A, von Beckerath N.
Impact of Body Mass Index on Platelet Aggregation After Administration
of a High Loading Dose of 600 mg of Clopidogrel Before Percutaneous
Coronary Intervention. \emph{Am J Cardiol} . 2007;100(2):203-205.
doi:10.1016/j.amjcard.2007.02.081

108. Kang X, Hong D, Anvari M, Tiboni M, Amin N, Gmora S. Is Daily
Low-Dose Aspirin Safe to Take Following Laparoscopic Roux-en-Y Gastric
Bypass for Obesity Surgery? \emph{Obes Surg} . 2017;27(5):1261-1265.
doi:10.1007/s11695-016-2462-z

109. Ma Q., Norgard N. MS. Abstract, ACCP Annual Meeting 2017.
Pharmacotherapy 2017 37:12 (e142-). \emph{Pharmacother J Hum Pharmacol
Drug Ther} . 2017;37(12):e124-e238. doi:10.1002/phar.2052

110. Caruana JA, McCabe MN, Smith AD, Panemanglore VP, Sette Camara D.
Risk of massive upper gastrointestinal bleeding in gastric bypass
patients taking clopidogrel. \emph{Surg Obes Relat Dis} .
2007;3(4):443-445. doi:10.1016/j.soard.2006.12.008

111. Steinemann DC, Bueter M, Schiesser M, Amygdalos I, Clavien PA,
Nocito A. Management of anastomotic ulcers after Roux-en-Y gastric
bypass: Results of an international survey. \emph{Obes Surg} .
2014;24(5):741-746. doi:10.1007/s11695-013-1152-3

112. Wilson JA, Romagnuolo J, Byrne TK, Morgan K, Wilson FA. Predictors
of endoscopic findings after Roux-en-Y gastric bypass. \emph{Am J
Gastroenterol} . 2006;101(10):2194-2199.
doi:10.1111/j.1572-0241.2006.00770.x

113. Tandra S, Chalasani N, Jones DR, Mattar S, Hall SD, Vuppalanchi R.
Pharmacokinetic and pharmacodynamic alterations in the Roux-en-Y gastric
bypass recipients. \emph{Ann Surg} . 2013;258(2):262-269.
doi:10.1097/SLA.0b013e31827a0e82

114. Strand DS, Kim D, Peura DA. 25 years of proton pump inhibitors: A
comprehensive review. \emph{Gut Liver} . 2017;11(1):27-37.
doi:10.5009/gnl15502

115. Rajan TM, Menon V. Psychiatric disorders and obesity: A review of
association studies. \emph{J Postgrad Med} . 2017;63(3):182-190.
doi:10.4103/jpgm.JPGM\_712\_16

116. Seaman JS, Bowers SP, Dixon P, Schindler L. \emph{Dissolution of
Common Psychiatric Medications in a Roux-En-Y Gastric Bypass Model} .
Vol 46.; 2005.

117. Hamad GG, Helsel JC, Perel JM, et al. The Effect of Gastric Bypass
on the Pharmacokinetics of Serotonin Reuptake Inhibitors. \emph{Am J
Psychiatry} . 2012;169(3):256-263. doi:10.1176/appi.ajp.2011.11050719

118. Marzinke MA, Petrides AK, Steele K, et al. Decreased Escitalopram
Concentrations Post-Roux-en-Y Gastric Bypass Surgery. \emph{Ther Drug
Monit} . 2015;37:408-412.

119. Roerig JL, Steffen K, Zimmerman C, Mitchell JE, Crosby RD, Cao L.
Preliminary comparison of sertraline levels in postbariatric surgery
patients versus matched nonsurgical cohort. \emph{Surg Obes Relat Dis} .
2012;8(1):62-66. doi:10.1016/j.soard.2010.12.003

120. Roerig JL, Steffen KJ, Zimmerman C, Mitchell JE, Crosby RD, Cao L.
A comparison of duloxetine plasma levels in postbariatric surgery
patients versus matched nonsurgical control subjects. \emph{J Clin
Psychopharmacol} . 2013;33(4):479-484. doi:10.1097/JCP.0b013e3182905ffb

121. Strong AT, Sharma G, Nor Hanipah Z, et al. Adjustments to warfarin
dosing after gastric bypass and sleeve gastrectomy. \emph{Surg Obes
Relat Dis} . 2018;14(5):700-706. doi:10.1016/j.soard.2017.12.021

122. Steffen KJ, Wonderlich JA, Erickson AL, Strawsell H, Mitchell JE,
Crosby RD. Comparison of warfarin dosages and international normalized
ratios before and after Roux-en-Y gastric bypass
surgery.\emph{Pharmacotherapy} . 2015;35(9):876-880.
doi:10.1002/phar.1632

123. Schullo-Feulner AM, Stoecker Z, Brown GA, Schneider J, Jones TA,
Burnett B. Warfarin dosing after bariatric surgery: a retrospective
study of 10 patients previously stable on chronic warfarin
therapy.\emph{Clin Obes} . 2014;4(2):108-115. doi:10.1111/cob.12046

124. Irwin AN, McCool KH, Delate T, Witt DM. Assessment of warfarin
dosing requirements after bariatric surgery in patients requiring
long-term warfarin therapy. \emph{Pharmacotherapy} .
2013;33(11):1175-1183. doi:10.1002/phar.1307

125. Wallace JL, Reaves AB, Tolley EA, et al. Comparison of initial
warfarin response in obese patients versus non-obese patients. \emph{J
Thromb Thrombolysis} . 2013;36(1):96-101. doi:10.1007/s11239-012-0811-x

\selectlanguage{english}
\FloatBarrier
\end{document}

