EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY

2022, VOL. 18, NO. 5, 337–346

https://doi.org/10.1080/17425255.2022.2098107

REVIEW

An update on drug–drug interactions associated with proton pump inhibitors

a,b a a,c
Inès Ben Ghezala , Maxime Luu and Marc Bardou
a
Centre d’Investigations Cliniques INSERM 1432 (CIC1432), Dijon Bourgogne University Hospital, Dijon, France; bOphthalmology Department, Dijon
Bourgogne University Hospital, Dijon, France; cGastroenterology and Liver Department, Dijon Bourgogne University Hospital, Dijon, France

ABSTRACT ARTICLE HISTORY

Introduction: Proton pump inhibitors (PPIs) block the gastric H/K-ATPase, therefore inhibiting acid Received 14 February 2022
gastric secretion, leading to an increased pH (>4). They account for an extremely high number of Accepted 1 July 2022
prescriptions worldwide. Numerous drug–drug interactions have been described with PPIs, but all the
KEYWORDS
described interactions do not have clinical significance.
CYP2C19; peptic ulcer;
Areas covered: This review will discuss the latest updates on drug–drug interactions with PPIs, focusing gastroesophageal reflux;
on the last 10-year publications in the following areas: anti-infective agents, anticancer drugs, anti­ Helicobacter; antifungal;
platelet agents and anticoagulants, and antidiabetics. antibiotics; antiplatelet
Expert opinion: Although pharmacokinetic interactions of PPIs have been described with many drugs, agents; antidiabetics;
their clinical relevance remains controversial. However, given the extremely high number of people oncology drugs
being treated with PPIs, clinicians should remain vigilant for interactions that may be clinically
significant and require dose adjustment or therapeutic monitoring. Interestingly, not all PPIs have the
same pharmacokinetic and pharmacodynamic profile, with some having a strong potential to inhibit
CYP2C19, such as omeprazole, esomeprazole, and lansoprazole, while others, pantoprazole, rabepra­
zole, and dexlansoprazole, are weak CYP2C19 inhibitors. These may be preferred depending on co-
prescribed treatments.
In addition, new formulations have been developed to prevent some of the gastric pH-dependent
drug interactions and should be evaluated in further large-scale prospective comparative studies.

1. Introduction years publications in the following areas: anti-infective agents,

Proton pump inhibitors (PPIs) effectively block gastric acid
secretion, therefore inhibiting gastric fluid secretion, and par­
ticularly acid secretion in the gastric parietal cells, by irrever­
sibly binding to and inhibiting the hydrogen–potassium
ATPase (H/K-ATPase) pump that resides on the luminal surface
of the parietal cell membrane. PPIs thus increase pH (>4) [1].
PPIs are weak bases (pKa between 3.8 and 4.9) which accu­
mulate in the acidic space of the secretory canaliculus of
parietal cells [2]. Through acid gastric secretion, PPIs are then
converted from prodrugs to the active sulfenamide or sulfenic
acid secretion. PPIs are indicated in multiple diseases, notably
peptic ulcers and particularly bleeding ulcers, gastroesopha­
geal reflux disease, Zollinger–Ellisvon syndrome and
Helicobacter pylori eradication therapy [3,4]. Numerous drug–
drug interactions have been described with PPIs [5,6]. By
increasing gastric pH, PPIs use may modify the absorption
and bioavailability of other drugs. They may also modify
their distribution and metabolism, especially because of meta­
bolic enzyme competition with cytochromes, mostly cyto­
chrome P450 2C19 (CYP2C19) and also but to a lesser extent,
cytochrome P450 3A4 (CYP3A4) [7,8].
All described drug–drug interactions do not have a clinical
significance. We aimed to highlight the latest updates on
drug–drug interactions with PPIs, focusing on the last 10
anticancer drugs, antiplatelet agents and anticoagulants, and
antidiabetics.
2. Anti-infective drugs
2.1. Antifungals
PPIs can reduce the bioavailability of systemic antifungals due
to their gastric acid suppressing effect [9]. For example, itra­
conazole is a broad-spectrum antifungal treatment with pH-
dependent solubility: its dissolution and absorption requires
an acidic gastric pH [10]. Omeprazole alters the dissolution
and the absorption of itraconazole (Sporanox®, Janssen
Pharmaceuticals, Inc.), reducing its total and peak plasma
exposure [11,12]. It is therefore recommended to administer
itraconazole at least 2 h before or 2 h after any PPI adminis­
tration [13]. Super bioavailability (SUBA ®) itraconazole has
been developed to enhance its bioavailability thanks to
a polymeric matrix. Coadministration of omeprazole 40 mg
induced a 22% increase in the total plasma exposure (area
under the concentration–time curve) and a 31% increase in
the peak plasma exposure of SUBA-itraconazole, which may
be confer a therapeutic benefit [14]. Controversial findings
were reported in a retrospective cohort study, which sug­
gested lower serum trough concentrations in patients

CONTACT Marc Bardou marc.bardou@u-bourgogne.fr Clinical Investigation Center, Plurithematic Unit, Dijon Bourgogne University, Hospital 14, Rue
Gaffarel, BP77908, Dijon Cedex 21079, France
© 2022 Informa UK Limited, trading as Taylor & Francis Group
338 I. BEN GHEZALA ET AL.
Article highlights
● Numerous drug–drug interactions have been reported with PPIs, the
most frequent mechanism being the increase in gastric pH, which
alters the absorption and bioavailability of numerous treatments with
pH-dependent solubility.
● Some formulations have been developed to prevent these gastric pH-
dependent drug–drug interactions. Their efficacy should be further
demonstrated large-scale comparative prospective studies.
● Another frequent mechanism is the competitive inhibition of cyto­
chromes P450, notably CYP2C19 and CYP3A4
● Some PPIs, omeprazole, esomeprazole, and lansoprazole, have high
CYP2C19 inhibitory potential. The others, pantoprazole, rabeprazole,
and dexlansoprazole, have a low CYP2C19 inhibitory potential, and
may be preferred according to the co-prescribed treatments.
● All described drug–drug interactions do not have significant clinical
impact, but clinicians should be careful with the potentially clinically
significant ones. They must also understand that because of the
retrospective nature of most of the studies assessing clinical rele­
vance, the level of evidence is quite low.
● According to the co-prescribed drugs, dose adjustment or therapeutic
drug monitoring may be required.
receiving PPIs (95% CI -0.32 to -0.05, p = 0.007) [15].
Nevertheless, in several studies, SUBA-itraconazole seems to
be overall an efficient formulation to reach therapeutic itraco­
nazole concentrations, in adults and in children as well, and its
prescription should be considered, especially with coprescrip­
tion of PPIs. Therapeutic drug monitoring should still be per­
formed [15,16].
Voriconazole is another broad-spectrum antifungal agent
with significant pharmacokinetic interpatient variability,
notably because of its hepatic metabolism by CYP2C19,
which converts it into an inactive metabolite [17]. CYP2C19
has significant genetic polymorphism and can be inhibited
by PPIs [18]. Lansoprazole and omeprazole interact with
voriconazole via CYP2C19 and CYP3A4 to increase voricona­
zole plasma concentrations [19,20]. In the Blanco Dorado’s
study [20], no significant differences were found in plasma
voriconazole concentration between patients without PPIs
and those receiving omeprazole, pantoprazole, or esomepra­
zole. Nevertheless, voriconazole plasma concentration was
lower in patients treated with pantoprazole than in those
treated with omeprazole (1.44 ± 1.22 μg/mL vs
2.67 ± 1.88 μg/mL, p = 0.013), and 44% of the patients
treated with pantoprazole, vs 22% in those receiving ome­
prazole, had a subtherapeutic voriconazole trough concen­
tration [20]. These results could be explained by the greater
cytochrome P450 inhibition capacity of omeprazole com­
pared to pantoprazole [21]. In an in vitro study in human
liver microsomes, all tested PPIs (omeprazole, lansoprazole,
pantoprazole, esomeprazole, and ilaprazole) showed inhibi­
tory effects on the voriconazole metabolism [22]. However,
only lansoprazole, omeprazole, and esomeprazole signifi­
cantly increased voriconazole plasma concentrations in vivo
[22]. Similar results were found in patients with malignant
hematological diseases [23]. Coadministration of voricona­
zole with omeprazole has also been reported to lead to
a twofold increase in maximal plasmatic concentration of
omeprazole, and it is therefore recommended to reduce
omeprazole dose by one-half [24]. It may be suggested that
pantoprazole or ilaprazole, in countries where it is already
accepted, should be prescribed preferentially in combination
with voriconazole to avoid overdose, but particular attention
should still be paid to the risk of subtherapeutic voriconazole
concentrations, and therapeutic drug monitoring is recom­
mended [22,25].
No impact of PPI co-prescription on fluconazole bioavail­
ability has been described. However, Lu et al. [26] have
shown synergistic action of PPIs and fluconazole: PPIs
could significantly decrease fluconazole minimal inhibitory
concentrations in vitro, leading to an increased sensitivity
of resistant C. albicans to fluconazole. In vivo, PPIs plus
fluconazole prolonged the survival rate of infected Galleria
mellonella larvae by two-fold compared with that for the
fluconazole monotherapy group [26]. This synergistic action
can be explained by the PPI-induced suppression of efflux
pump activity, which is one of the resistance mechanisms
of C. albicans [26].
2.2. Antibiotics
PPIs are frequently co-administered with antibiotics, particularly
for the treatment of Helicobacter pylori infection. Macrolides,
such as clarithromycin, are potent inhibitors of CYP3A4 [27].
Concomitant use of omeprazole and clarithromycin can increase
both clarithromycin and omeprazole plasmatic concentrations
[28]. Controversial interaction between PPI and macrolide have
been published. For example, whereas Saito and colleagues [29]
have reported that the bioavailability of lansoprazole might, to
some extent, be increased through inhibition of P-glycoprotein
during clarithromycin treatment, whereas Cao and colleagues
[30] found the mean Cmax was decreased by 24.9% when ila­
prazole was given in combination compared to its administration
as a single agent. However, this interaction, between ilaprazole
and clarithromycin and amoxicillin, was not any longer observed
in a more recent randomized crossover study investigating the
coadministration of ilaprazole 10 mg once or twice daily, clari­
thromycin and amoxicillin in 32 volunteers [31]. In practice, the
combination of PPI and clarithromycin has long be in the back­
bone therapy for H. pylori eradication without any particular
usage precaution [32]. It has been suggested that rabeprazole
should be preferred to omeprazole, in combination with amox­
icillin and levofloxacin, as Helicobacter pylori eradication rate
could be higher (85% vs 76.3%, p = 0.16) especially in CYP2C19
extensive metabolizers (84.6% vs 60.7%, p = 0.03) [33].
PPI-induced pH increase can not only directly affect absorp­
tion and bioavailability but also change the performance of
pH-dependent coating strategies. A common strategy to
achieve specificity of pH-dependent drug delivery systems is
coating SDFs with polymers with a pH-dependent solubility.
Soares et al. [34], showed that the PPI-induced pH increase
interferes with the release processes of tablets coated with
E100 and leads to an increased lag time, a delayed disintegra­
tion process, and a lower area under curve (AUC). In more than
a half of the volunteers, metronidazole was not detected in
plasma in the 5 h after administration [34]. More generally, pH-
dependent coating strategies should be avoided with coadmi­
nistration of PPIs.

2.3. Antivirals
Doravirine is a novel non-nucleoside reverse transcriptase
inhibitor for the treatment of patients with human immuno­
deficiency virus infection, on the market since 2018 [35,36]. In
a three-period open-label trial conducted in healthy volun­
teers, coadministration of pantoprazole lead to a 12%
decrease in doravirine maximum plasma concentration,
which was not clinically meaningful [37]. These results support
the use of acid-reducing agents with doravirine [37].
Ritonavir is an HIV protease inhibitor often used in combi­
nation with other protease inhibitors, marketed since 1999. It
is a lipophilic base (pKa 2.6) with pH-dependent solubility,
formulated as a solid dispersion [7]. Van den Abeele et al.
[38] showed in a crossover study that pretreatment with PPIs
lead to a drop in ritonavir gastric solubility, with a tenfold
lower median drug solubility and persistence of solid drug
material in the stomach. However, duodenal concentrations
remained unaffected. In another crossover study, de Waal
et al. [7] showed that, in healthy volunteers, a three-day pre-
treatment with the PPI esomeprazole reduced ritonavir plasma
concentrations by 40%. The gastric residual volume and gas­
tric fluid volume decreased by 41% and 44%, respectively,
while the duodenal fluid volume was reduced by 33%, and
authors suggest it may limit the amount of ritonavir that can
be absorbed [7]. Further studies are needed to investigate this
potential interaction and its clinical implications.
The treatment of hepatitis C has been dramatically chan­
ged by the arrival in 2016 of new treatments combining
molecules that act directly on viral replication. These include
elbasvir/grazoprevir, a combined therapy recently approved to
treat patients infected with genotype 1 or 4 viruses.
Grazoprevir is a potent once-daily nonstructural protein 3/4A
protease inhibitor, and elbasvir a potent once-daily nonstruc­
tural protein 5A protein inhibitor. Elbasvir is a basic com­
pound, and increasing gastric pH may decrease its solubility.
Some studies showed a slightly increased plasmatic concen­
tration of elbasvir and grazoprevir when co-administered with
PPIs [39]. However, a pooled analysis of six phase 3 studies
reported that, in 162 patients who were co-prescribed PPIs
and elbasvir/grazoprevir 12-week sustained viral response
(SVR12) was 96%, not statistically different from the 97% in
the 1160 patients not self-reporting PPI use [40]. Area under
the plasma concentration–time curve within 24 h and max­
imum plasma concentrations for elbasvir were similar between
patients with and without reported PPI use [40]. Elbasvir/gra­
zoprevir summary of pharmacological characteristics (SPC)
states that PPI co-prescription does not require any dose
adjustment.
Glecaprevir is a potent pangenotypic nonstructural protein
3/4A protease inhibitor and pibrentasvir a potent pangenoty­
pic NS5A inhibitor. Glecaprevir/pibrentasvir has been
approved for the treatment of chronic genotypes 1–6 HCV
infections. Omeprazole has been shown to reduce the max­
imum plasma concentration and the AUC of glecaprevir from
22% to 64% [41]. An integrated analysis of nine phase 2 and 3
studies, including 2369 patients infected with HCV genotypes
1–6 and compensated liver disease treated with an all-oral
regimen of glecaprevir/pibrentasvir for 8–16 weeks, evaluated
EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY 339
the impact of concomitant PPI use on efficacy and pharmaco­
kinetics of glecaprevir/pibrentasvir in 263 patients taking PPIs
[42]. Rates of SVR12 were 97.0% among patients who used
acid-reducing agents and 97.5% among those not using acid-
reducing agents (P = 0.6), and was not different in those
taking low dose (97.4%) vs high dose (96.3%, daily dose
greater than 20 mg omeprazole or equivalent) of PPIs [42].
Of note, high-dose PPI use significantly decreased glecaprevir
bioavailability (P < 0.001) with a mean 41% decrease in AUC
[42]. No dose adjustment is recommended when PPIs are co-
prescribed with glecaprevir/pribrentasvir.
2.4. Antiparasitics
Hydroxychloroquine is used in the treatment of malaria and
inflammatory rheumatic diseases. It was also considered
a potentially effective medication for coronavirus disease
(COVID-19) at the beginning of the pandemic in 2020.
Hydroxychloroquine is a weak base with high solubility in an
acidic environment. Significant inter-individual variability in
relative bioavailability has been reported [43]. A randomized,
parallel drug–drug interaction trial in healthy volunteers found
that hydroxychloroquine AUC0-72h and Cmax did not differ
between groups without and with pantoprazole (arithmetic
mean; AUC0-72h, 7649 ng/ml • h, and 8429 ng/ml • h, P = .50;
Cmax, 448 and 451.5 ng/mL, P = .96, respectively) [44]. These
results are consistent with those of a randomized double-blind
placebo-controlled trial on patients with systemic lupus trea­
ted with hydroxychloroquine, which described that PPI use
had no significant impact on blood hydroxychloroquine con­
centrations [45]. Therefore, PPIs and hydroxychloroquine can
be co-prescribed if needed, without any dose adjustment.
3. Antiplatelet agents and anticoagulants
3.1. Antiplatelet agents
Clopidogrel is an antiplatelet agent. CYP2C19 has to convert
clopidogrel to an active metabolite for clopidogrel to be
effective [46]. Some studies have shown that PPIs could
reduce the platelet inhibitory effects of clopidogrel, tested
by vasodilator-stimulated phosphoprotein phosphorylation,
through a competitive effect on CYP2C19 [47,48]. Hence,
this reduced anti-aggregation effect could increase the risk
of cardiovascular ischemic events. Ho et al. [49] reported, in
a retrospective cohort study on patients who had an acute
coronary syndrome (ACS), that use of clopidogrel plus PPI
was associated with a 25% increased risk of death or rehos­
pitalization for ACS compared with use of clopidogrel with­
out PPI (adjusted odds ratio [AOR], 1.25; 95% confidence
interval [CI], 1.11–1.41). Same findings were reported in
a multi-ethnic Asian population study where clopidogrel
with omeprazole was found to be associated with an
increased risk of MI (16% vs 3.8%; AHR 2.03: 95%CI 1.70–
2.44), but not mortality or stroke [50]. The inconsistency of
the increase in risk (from 25% to 200%) is noteworthy, as it
highlights the lack of robustness of these pharmaco-
epidemiological findings. However, clopidogrel SPC states
that administration of omeprazole 80 mg once daily, either
340 I. BEN GHEZALA ET AL.

at the same time as clopidogrel or 12 h apart, decreased the 3.2. Anticoagulants

exposure to the active metabolite by 45% (loading dose) and
PPIs are often co-prescribed with anticoagulants to reduce the
40% (at the maintenance dose). Inhibition of platelet aggre­
risk of gastrointestinal (GI) bleeding [61]. Warfarin is commonly
gation was also reduced, by 39% (loading dose) and 21%
used but requires a careful monitoring of the International
(maintenance dose). A similar interaction is expected with
Normalized Ratio [62], as it has a narrow therapeutic index
esomeprazole and, as a precaution, the association of ome­
and numerous potential drug-drug interactions, especially via
prazole or esomeprazole with clopidogrel is not advised
cytochromes P450. Coprescription of warfarin with PPIs has
[51,52].
been shown to be very frequent, especially in the elderly, and
Controversy exists regarding this reported interaction,
an Australian study reported a 43% rate of coprescription of
which has mainly been described in retrospective studies,
PPI in patients under warfarin for atrial fibrillation [63].
whereas the results from randomized controlled trials evaluat­
A recently published meta-analysis of 72 studies reporting
ing omeprazole compared with placebo showed no difference
on 3,735,775 patients including 11 randomized clinical trials
in ischemic outcomes, despite a reduction in upper gastroin­
and 61 observational studies found a protective effect of PPIs
testinal bleeding with omeprazole [53]. This was later con­
against warfarin-related GI bleeding (OR = 0.69; 95% CI 0.64–
firmed in two meta-analyses of randomized controlled trials
0.73), without significant effect on thromboembolic events or
or propensity scores matched studies [54,55].
mortality [64]. Controversy exists regarding the possible clini­
In a retrospective study on Asian patients receiving clopidogrel,
cally significant interaction between warfarin and PPIs.
platelet inhibition levels did not differ between patients taking or
A retrospective Australian study on 4494 patients receiving
not PPIs, except for dexlansoprazole which induced a decreased
warfarin reported that patients taking warfarin plus PPI had
level of platelet inhibition (25.7% ± 24.3% vs 14.0% ± 21.6%,
a lower mean percentage time in therapeutic range (TTR) than
P = .0297) [56]. In a retrospective study of more than 300,000
patients without PPIs (78.5 ± 9.7% vs 81.7 ± 10.2%, respec­
concomitant PPIs and clopidogrel users, esomeprazole, lansopra­
tively, p < 0.0001) [65]. Patients with PPIs also had a higher
zole, omeprazole, and rabeprazole were not associated with an
incidence of minor bleeds vs patients without PPIs (32.4% vs
increased risk of stroke compared to pantoprazole, which, not
26.1%, respectively, P = 0.0487), but not for major bleeds,
being a strong inhibitor of CYP2C19, is not considered for drug–
questioning the clinical relevance of the statistically significant
drug interactions with clopidogrel [57]. A meta-analysis of 28
difference in TTR [65]. In patients under warfarin, the PPI
studies focusing on major adverse cardiovascular endpoints
prescription should be done after cautiously evaluating the
(MACE), myocardial infarction (MI), cardiovascular death, and gas­
risk–benefit balance and should lead to a careful and regular
trointestinal bleeding and totaling 131,412 patients, found that
INR monitoring.
the pooled HR of adjusted events for MACEs showed that the
Drug–drug interactions between PPIs and factor Xa inhibitors
increased risk of MACEs was similar for 4 classes of PPIs but not for
have also been described. Co-treatment with PPIs was associated
rabeprazole (HR: 1.32; 95% CI 0.69–2.53, P = .40). This was consis­
with a very significant decrease in dabigatran trough and peak
tent with the findings by Shi et al. [58], who reported a twofold
levels (through: 83 ± 42.3 vs 55.5 ± 24.6 ng/mL; and peak:
increased risk of stroke during the 2-year follow-up (HR 2.1,
184.1 ± 107.7 vs 124 ± 59.2 ng/mL, without and with PPI, respec­
p < 0.001) and a 1.6-fold increased risk of myocardial infarction
tively; P < 0.003), probably because of a decrease of its solubility
after 6 months (HR 1.6, p = 0.01). But the same group, working on
due to raised gastric pH [66,67]. A study assessing the bioequiva­
the same database, the China Acute Myocardial Infarction (CAMI)
lence of a newly developed dabigatran tablet showed that at high
registry, found that PPIs in combination with clopidogrel was
gastric pH, a mean gastric pH of 5.3, bioavailability of the tablet was
associated with decreased risk for MACCE in AMI patients [59].
reduced by approximately 70%, which may lead to reduced effi­
In a retrospective cohort study, Muthiah et al. [50] found
cacy [68]. This effect being reversible 2 weeks after PPI withdrawal
that the concomitant use of clopidogrel with omeprazole was
[69]. Further studies investigating clinical potential consequences
associated with an increased risk of myocardial infarction,
of this interaction are required. Of interest, patients treated with
especially in Chinese and Malay patients, but not mortality
anticoagulants are at increased risk of gastrointestinal bleeding,
or stroke. A retrospective cohort study on the Korean
which can be severe and life-threatening. Patients benefitting from
National Health Insurance Database found an increased risk
a coprescription of anticoagulants and PPIs have a 34–47% lower
of major thrombotic events in patients under clopidogrel and
incidence of hospitalization for upper gastrointestinal tract bleed­
PPIs compared with clopidogrel only (HR 1.27, 95% CI 1.12–
ing, so this coprescription should not be discouraged [70,71].
1.45) [60]. The study also reported that the risk was higher
with PPIs with high CYP2C19 inhibitory potential (omeprazole,
esomeprazole, and lansoprazole, HR 1.28, 95% CI 1.02–1.61)
4. Antidiabetics
than PPI of low CYP2C19 inhibitory potential (pantoprazole,
rabeprazole, and dexlansoprazole) [60]. Metformin is a first-line treatment for patients with type 2
These recent data tend to question the existence of diabetes. In vitro studies have shown that PPIs were potent
a clinically significant interaction between PPI and clopidogrel. organic cation transporters inhibitors, therefore limiting active
As a precaution PPIs should still be used cautiously in associa­ transport of metformin into its target cells [72]. A randomized
tion with clopidogrel. Low CYP2C19-inhibitory potential PPIs crossover study found that PPIs induced a slight increase in
such as pantoprazole or rabeprazole may be preferred in metformin concentration (+15% and +22% with pantoprazole
association with clopidogrel. and rabeprazole, respectively) [73]. A retrospective cohort

study, using the Health Improvement Network database in the
United Kingdom, reported a minimally, and not clinically rele­
vant, better glycemic control exhibited by a − 0.06% decrease
in HbA1C 3–9 months after the start of metformin in those
also taking PPIs (−1.69% vs −1.63%, respectively, p = 0.01) [74].
A low-quality (small sample-size, bias not discussed) case–
control study found that the prescription of PPIs in addition
to metformin was associated with better glycemic control as
expressed by mean HbA1C, which was 8.15% for patients
treated with metformin only and 6.01% with patients treated
with metformin and PPIs (p = 0.002) [75]. A meta-analysis of
seven studies (n = 342) for glycemic control and 5 studies
(n = 244 439) for risk of incident diabetes, found that com­
pared with standard therapy, add-on PPI was associated with
a significant decrease in HbA1c (−0.36%; −0.68 to −0.05;
P = 0.025) and Fasting Blood glucose (−10.0 mg/dL; −19.4 to
−0.6; P = 0.037). PPI use did not reduce the risk of incident
diabetes [76]. This could be explained by a PPI-induced
increase in gastrin levels [75,76]. Further large-scale prospec­
tive studies are required to investigate this hypothesis. As of
now, no clear clinically significant interaction between PPIs
and metformin has been demonstrated, and PPIs and metfor­
min may be co-prescribed if needed.
An oral glucagon-like peptide-1 analog, semaglutide
(Rybelsus®, Novo Nordisk A/S), has been approved by health
authorities in 2019–2020 [77,78]. Oral semaglutide has been
formulated with an absorption enhancer, sodium
N-(8-[2-hydroxylbenzoyl] amino) caprylate (SNAC), which
increases gastric pH. However, in a randomized open-label
trial, the coprescription of omeprazole with oral semaglutide
was associated with a non-statistically significant, and not
clinically relevant, increase in semaglutide exposure
(AUC0-24h,semaglutide,Day10, estimated treatment ratio 1.13;
0.88–1.45, and Cmax,semaglutide,Day10, estimated treatment ratio
1.16; 90% CI 0.90, 1.49) [79]. Semaglutide and PPIs can be co-
prescribed without any dose adjustment.
5. Oncology drugs
PPIs are widely used in cancer patients to manage anticancer
drug-related gastrointestinal symptoms. At least a fifth of
patients treated for a cancer are taking PPIs at normal dose,
but this estimation is likely to be largely underestimated in
countries where the over-the-counter use may be substantial
[80]. Additionally, the recent development of oral cancer
therapies has increased their potential indirect drug interac­
tion with PPIs, mainly due to the absorption alteration.
5.1. Tyrosine kinase inhibitors (TKI)
There are numerous publications on the interactions between
TKI and PPI, and we do not present here a systematic review of
all available evidences. Interactions between PPI and Tyrosine
Kinase Inhibitors are mainly of pharmacokinetic nature. TKIs
are weak bases that require a low pH in order to be fully
solubilized for an optimal absorption [81–83]. PPIs by their
strong anti-acid effect decrease absorption of TKIs, potentially
EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY 341
impairing their efficacy, and consequently the patient’s
prognosis.
5.1.1. EGFR inhibitors
Erlotinib is a TKI targeting specifically the epidermal growth
factor receptor (EGFR). The interaction between PPI and erlo­
tinib in non-small cell lung cancer (NSCLC) has been demon­
strated in several studies [82,84,85]. PPI intake significantly
lowers the plasma concentration-to-dose ratio of erlotinib by
23% (in µg·mL·mg·kg: 0.39; 0.08–0.76 vs 0.51; 0.28–1.28 in PPI
users and non-users respectively, p < 0.05], and its oral clear­
ance by 28% (in L/h: 5.55; 3.36–14.52, vs 3.95; 2.01–10.44 in PPI
users and non-users, respectively, p < 0.05) [85].
Same drug–drug interaction has been described gefitinib,
another EGFR-TKI, with a significant decrease of AUC0-24 (med­
ian AUC0-24 values: 8542 vs 13,103 ng.h/mL, in PPI users and
non-users respectively; P = 0.005) [86].
If publications are quite consistent on the PK consequences of
PPI-TKI drug–drug interaction, that is much less the case for the
clinical relevance of this interaction. A meta-analysis published in
2021, including 45,626 patients from 7 RCTs and 18 observational
studies, with esophageal/gastric, colorectal, pancreatic, lung,
breast, prostate, kidney, and other cancers, and found
a significantly worse prognosis (worse PFS, HR 1.64; 1.14–2.37,
and OS, HR 1.13; 1.05–1.21) only for patients with lung cancer
[87]. No association was found with any of the other cancer
assessed [87]. Data from a cohort of 12,538 patients with cancer,
from the Medicare database, showed that prevalence of TKI-PPI
use was 22.7% and that TKI-PPI use decreased survival (HR = 1.16;
95% CI = 1.05, 1.28) at 90 days and 1 year (median survival time
260 days vs 306 days, HR = 1.10; 95% CI = 1.04,1.18) [88]. In a recent
meta-analysis on 1,114 patients from 14 studies treated with EGFR-
TKIs for a non-small cell lung cancer, Sim et al. [89] showed that TKI
users alone had more favorable survival outcomes than TKI-PPIs
users, with a better overall survival (OS) rate at 1.98 (95% CI: 1.33–
2.94, P = 0.0007), and progression-free survival (PFS) rate
(HR = 3.39, 95% CI: 2.18–5.26, P < 0.00001). Nevertheless, it remains
unclear whether this negative impact on survival is exclusively due
to the drug–drug interactions or if the pro-carcinogenic effect of
long-term PPI use can play a role.
5.1.2. VEGF inhibitors
The interaction between molecules targeting the vascular
endothelial growth factor (VEGF) and PPI has now been stu­
died now for a decade, but findings are still contradictory. In
a pooled analysis of 10 phase II and III trials, totaling 2,188
patients, treated with sunitinib (n = 952), axitinib (n = 626) or
sorafenib (n = 610) for metastatic renal cell carcinoma, the PPI
users (n = 120) showed similar OS, PFS and objective response
rates than non-PPI users [90]. But the number of patients
receiving PPI may be too small to find a statistical difference.
On the contrary, in a retrospective review on 231 patients
treated by sunitinib for metastatic renal cell carcinoma (45
with concomitant PPI use), median PFS and OS were shorter
in patients who received continuous acid suppression (mPFS
18.9 weeks, 11.0–23.7 vs 23.6 weeks, 19.0–31.9 weeks and
mOS 40.9 weeks, 26.1–74.4 vs 62.4 weeks, 42.0–82.7 weeks
for PPI users and non-users respectively) [91]. This
342 I. BEN GHEZALA ET AL.
Pazopanib targets VEGFR1, VEGFR12, VEGFR3, PDGFRα and
β, and c-KIT. Two trials conducted in patients with soft-tissue
sarcoma – the single-arm, phase 2, EORTC 62043 trial and the
placebo-controlled, phase 3, EORTC 62072 (PALETTE) trial –
were pooled in a post hoc analysis to evaluate the impact of
concomitant acid-suppressive (AS) treatment, mainly PPI (93/
117; 79.5%), on OS and PFS [92]. At a median follow-up of
27.6 months (IQR 22.9–35.4), patient with concomitant AS
treatment had a significant worse median PFS of 2.8 months
versus 4.6 months, respectively (HR 1.49; 1.11–1.99; p = 0.008).
Median OS was also shorter in patients receiving AS,
8.0 months versus 12.6 months (1.81, 1.31–2.49; p < 0.001)
[93]. Unfortunately, no PPI-only subgroup analysis was per­
formed to corroborate these results. Nonetheless, in a recent
monocentric retrospective study, no negative impact of PPI on
clinical outcome was observed [94].
It is worth noticing that even with a 1-h delay interval
between pazopanib and PPI intake, pazopanib trough concen­
tration (Cmin) remains significantly lowered, whether pazopa­
nib is taken fasted at 800 mg or with food at 600 mg. This
reduction of pazopanib exposure seems to be stronger with
omeprazole (−20% fasted, p = 0.038; −31.6% with food,
p = 0.003), than with pantoprazole (−5.6% fasted; p = 0.8,
−11.1% with food, p = 0.5) [95].
Once again, data come mostly from retrospective or post
hoc analysis and the strength of the evidences is very low.
5.1.3. Other TKIs
Bcr-Abl (Bcr [Breakpoint Cluster Region]-Abl) TKI is indicated
for chronic myeloid leukemia in chronic phase (CP-CML) and
does not seem to be affected by the concomitant use of PPIs.
In a retrospective analysis on 748 patients with CP-CML (with
256 imatinib-resistant or – intolerant patients), the molecular
response at 12 months of nilotinib, was similar AS users com­
pared to those without AS treatment (49.6% vs 41.0%,
p = 0.13) [96]. Interestingly, in a more recent study on dasati­
nib, another Bcr-Abl TKI, in 73 patients with CP-CML, AS users
had a better compliance to treatment, with no interruption at
18 months, while nearly half of non-AS users (18/25, 43.9%)
had to stop because of adverse events [97]. Here also no
specific PPI user group analysis was done.
Apart from the molecules detailed upper, there is no signal
of concern regarding PPI interaction with the other TKI.
Regorafenib, a multikinase inhibitor (VEGFR, KIT, B-Raf,
PDGFR, and FGRF) proved in a randomized crossover pharma­
cokinetic trial to be unaffected by concomitant or subsequent
(3 h later) omeprazole intake [93]. Co-administration of PPI
with lenvatinib, sorafenib, vandetanib for example is consid­
ered safe by the FDA and EMA [98].
A retrospective review of a prospectively collected electro­
nic database identified 99 patients treated with cabozantinib,
including 43 patients being PPI users, found that, after
a median follow-up of 30.3 months, PPI users showed similar
progression-free survival and overall survival outcomes com­
pared with PPI nonusers [99]. In the independent pharmaco­
kinetic cohort, of whom 21 received PPI concomitantly,
Ctrough was similar between the two groups of patients
with mRCC who received cabozantinib [99]. Nevertheless,
prescribers should remain cautious and be aware that these
recommendations are mainly based on physiologically based
pharmacokinetic (PBPK) models. Clinical data are currently
inexistent or sparse for the newest TKIs.
5.2. Immunotherapies
Immune checkpoint inhibitors (ICPI) got a renewed interest in
the last years, but few data exist yet on their interaction with
PPI in case of co-medication. The main hypothesis is an indir­
ect interaction throughout the gut microbiome modification.
Several preclinical works have shown an impaired immune
response when the microbiome is altered [100,101]. PPIs are
known to alter the microbiome and are regularly accused of
increasing the risk of Clostrium difficile infection, but the level
of evidence is very low [102,103]. In a retrospective study on
the Japanese adverse Drug Event Report (JADER) database,
concomitant use of PPI with ICPI was strongly associated with
an increased risk of nephritis, but only for male patients
treated with ipilimumab (OR, 3.88; 1.63–9.04, p = 0.001)
[104]. However, considering the overall very low number of
cases of nephritis reported with PPI use in this study, and the
non-capture of other possible confounding factors (antibio­
tics), this observed association needs to be further confirmed.
In a pooled post-hoc analysis of the phase II POPLAR and
phase III OAK trials, patients with NSCLC were randomized to
receive atezolizumab (n = 757) or docetaxel (n = 755) [105].
Within the atezolizumab population, PFS and OS were signifi­
cantly shorter in patients who received PPI (1.9 vs 2.8 months,
HR 1.30, 95% CI 1.10–1.53, P = 0.001, and 9.6 vs 14.5 months,
HR 1.45, 95% CI 1.20–1.75, P = 0.0001 respectively). No asso­
ciation between antibiotics and PPI was observed, which
strongly support independence of the PPI effect. In brief, the
link between PPI and immunotherapy is still uncertain, and in
the hypothesis of a gut microbiome involvement, future stu­
dies must take in account antibiotics co-medication in their
analyses. Table 1 is a brief summary of the main drug-to-drug
interactions discussed above with their clinical relevance and
potential preventive measures.
6. Conclusion
Many drug–drug interactions have been described with PPIs,
involving different mechanisms, the first one being the
increase in gastric pH, i.e. The principal pharmacodynamic
action of PPIs. The absorption and bioavailability of treatments
with ph-dependent solubility are often decreased by PPIs
concomitant PPI usefor example, with itraconazole. When
PPIs are co-administered, clinicians should pay particular
attention to any treatments involving ph-dependent coating
strategies, as described for example with metronidazole-
coated magnetic tablets. Second, many interactions involve
cytochromes P450, notably CYP2C19 and CYP3A4, via compe­
titive inhibition, as for example with clopidogrel.
Finally, drug interactions with ppis may involve some less
known mechanismsfor example, via inhibition of organic
cation transporters, which reduces the uptake of metformin
by its target cells.
 EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY 343

Table 1. drug-drug interactions associated with proton pump inhibitors.

Class of
medications Effect of the drug-to-drug interaction Clinical consequence. Clinical relevance/action
Anti-infectives, antifungeal
-Itraconazole Decreased total and peak plasma exposure Decreased efficacy Uncertain/no simultaneous intake
Increased plasma concentration. Increased antifungeal activity Uncertain/Reduce PPI dose
-Voriconazole No impact /suppression of efflux pump Uncertain/none
-Fluconasole activity
Antibiotics
-Macrolides Increased blood levels Synergistic effect Uncertain/none
Antivirals
-Doravirine 12% decreased blood levels Reduced efficacy No/None
-Ritonavir 40% decreased blood levels Reduced efficacy Possible/ avoid co-prescription
-elbasvir/ Increased blood level None No/No dose adjustment
grazoprevir 22-64% decreased blood level None No/No dose adjustment
-Glecaprevir
Antiplatelet agents
-clopidogrel Reduced conversion into the active Reduced antiplatelet activity/increased Uncertain/prefer other antiplatelet agents or use
metabolite risk for MI rabeprazole
Anticoagulants
-warfarin Reduced proportion of time in therapeutic Controversial effect on bleeding Uncertain/INR monitoring at PPI initiation or
range No clear signal cessation
-Factors Xa decrease in trough and peak levels No/None
inhibitors
Antidiabetics
-Metformin Reduced transport to target cells Better glycaemic control Uncertain/No adaptation
-Semaglutide Increase in blood levels Better glycaemic control Uncertain/No adaptation
Increased plasmatic exposure
Oncology medications
-TKI
-Immunotherapies Decreased absorption, reduced AUC Reduced PFS & OS Possible/ no simultaneous intake
Interaction with gut microbiome Reduced PFS & OS Uncertain/none

7. Expert opinion prescribed or self-medicated. Attention should be paid to the

net effect of PPIs on cancer treatment, as the deleterious effect
PPIs are one of the most prescribed drug classes in the world, due
on plasma exposure may be offset, at least in part, by
to their high efficacy and safety profile perceived as very favorable.
improved compliance because preventive effect on che­
However, many potential adverse effects of PPIs have been
motherapy-induced side effects.
reported in the literature, particularly through drug–drug
In addition, some formulations of cancer treatments have
interactions. Not all of the drug–drug interactions described
been developed to limit gastric pH-dependent drug interac­
have a significant clinical impact, and many remain controver­
tions. The impact of interaction with PPIs may be less with
sial, nevertheless clinicians should routinely question the risk
these new formulations. This still needs to be convincingly
of interactions, which may require dose adjustment or specific
demonstrated by experimental and real-life data.
therapeutic monitoring.
Clinicians should systematically, and carefully, assess
the benefit/risk ratio before introducing a new treatment Funding
with a potential interaction with PPIs. This paper was not funded.
While the clinical response profile induced by different PPIs,
at equivalent doses, can be considered equivalent, this is not
exactly the same for the pharmacokinetic profile. Declaration of interest
Knowledge of the pharmacokinetic profile may be of The authors have no relevant affiliations or financial involvement with any
particular interest when a potentially problematic interac­ organization or entity with a financial interest in or financial conflict with
tion is due to competitive inhibition of hepatic cyto­ the subject matter or materials discussed in the manuscript. This includes
chrome P450. Indeed, some PPIs have a high potential employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
for CYP2C19 inhibition, namely omeprazole, esomeprazole,
and lansoprazole, whereas the others, pantoprazole, rabe­
prazole, and dexlansoprazole, have a much lower potential
Reviewer disclosures
for CYP2C19 inhibition. These may be preferred depending
on co-prescribed treatments. Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
Assessment of the interaction of PPIs with cancer treat­
ments remains too fragmented, mostly based on low-quality
studies, which is problematic given its potential negative ORCID
impact on disease outcomes. As a substantial proportion of
Inès Ben Ghezala http://orcid.org/0000-0002-4002-7414
patients receive PPIs, it is very important that future clinical Maxime Luu http://orcid.org/0000-0002-9024-293X
trials rigorously and systematically collect PPI use, whether Marc Bardou http://orcid.org/0000-0003-0028-1837
344 I. BEN GHEZALA ET AL.
References
Papers of special note have been highlighted as either of interest (•) or of
considerable interest (••) to readers.
1. Shin JM, Sachs G. Pharmacology of proton pump inhibitors. Curr
Gastroenterol Rep. 2008 Dec;10(6):528–534.
2. Shin JM, Kim N. Pharmacokinetics and pharmacodynamics of the
proton pump inhibitors. J Neurogastroenterol Motil. 2013 Jan;19
(1):25–35.
• A very clear description of PPIs’ pharmacology.
3. Scarpignato C, Gatta L, Zullo A, et al. Effective and safe proton
pump inhibitor therapy in acid-related diseases - a position paper
addressing benefits and potential harms of acid suppression. BMC
Med. 2016 Nov 9;14(1):179.
4. Barkun AN, Almadi M, Kuipers EJ, et al. Management of nonvariceal
upper gastrointestinal bleeding: guideline recommendations from
the international consensus group. Ann Intern Med. 2019 Dec
3;171(11):805–822.
•• These are one of the most complete guidelines on the manage­
ment of gastrointestinal bleeding issued by a group of world­
wide experts.
5. Johnson DA, Katz PO, Armstrong D, et al. The safety of appropriate
use of over-the-counter proton pump inhibitors: an
evidence-based review and Delphi consensus. Drugs. 2017 Apr;77
(5):547–561.
6. Patel D, Bertz R, Ren S, et al. A systematic review of gastric
acid-reducing agent-mediated drug-drug interactions with orally
administered medications. Clin Pharmacokinet. 2020 Apr;59
(4):447–462.
7. de Waal T, Rubbens J, Grimm M, et al. Exploring the effect of
esomeprazole on gastric and duodenal fluid volumes and absorp­
tion of ritonavir. Pharmaceutics. 2020 Jul 17; 12(7):670
8. El Rouby N, Lima JJ, Johnson JA. Proton pump inhibitors: from
CYP2C19 pharmacogenetics to precision medicine. Expert Opin
Drug Metab Toxicol. 2018 Apr;14(4):447–460.
9. Albengres E, Le Louët H, Tillement JP. Systemic antifungal agents.
drug interactions of clinical significance. Drug Saf. 1998 Feb;18
(2):83–97.
10. Fotaki N, Klein S. Mechanistic understanding of the effect of PPIs
and acidic carbonated beverages on the oral absorption of itraco­
nazole based on absorption modeling with appropriate in vitro
data. Mol Pharm. 2013 Nov 4;10(11):4016–4023.
11. Jaruratanasirikul S, Sriwiriyajan S. Effect of omeprazole on the
pharmacokinetics of itraconazole. Eur J Clin Pharmacol. 1998
Apr;54(2):159–161.
12. Abuhelwa AY, Mudge S, Upton RN, et al. Mechanistic assessment of
the effect of omeprazole on the in vivo pharmacokinetics of itra­
conazole in healthy volunteers. Eur J Drug Metab Pharmacokinet.
2019 Apr;44(2):201–215.
13. Hilton JF, Tu D, Seymour L, et al. An evaluation of the possible
interaction of gastric acid suppressing medication and the EGFR
tyrosine kinase inhibitor erlotinib. Lung Cancer. 2013 Oct;82
(1):136–142.
14. Lindsay J, Mudge S, and Thompson GR 3rd. Effects of food and
omeprazole on a novel formulation of super bioavailability itraco­
nazole in healthy subjects. Antimicrob Agents Chemother. 2018;62
(12):e01723–18.
15. Nield B, Larsen SR, van Hal SJ. Clinical experience with new for­
mulation SUBA(R)-itraconazole for prophylaxis in patients under­
going stem cell transplantation or treatment for haematological
malignancies. J Antimicrob Chemother. 2019 Oct 1;74
(10):3049–3055.
16. Abbotsford J, Foley DA, Goff Z, et al. Clinical experience with
SUBA-itraconazole at a tertiary paediatric hospital. J Antimicrob
Chemother. 2021 Jan 1;76(1):249–252.
17. Zonios D, Yamazaki H, Murayama N, et al. Voriconazole metabo­
lism, toxicity, and the effect of cytochrome P450 2C19 genotype.
J Infect Dis. 2014 Jun 15;209(12):1941–1948.
18. Modak AS, Klyarytska I, Kriviy V, et al. The effect of proton pump
inhibitors on the CYP2C19 enzyme activity evaluated by the
pantoprazole-(13)C breath test in GERD patients: clinical relevance
for personalized medicine. J Breath Res. 2016 Dec 17;10(4):046017.
19. Wood N, Tan K, Purkins L, et al., Effect of omeprazole on the
steady-state pharmacokinetics of voriconazole. Br J Clin
Pharmacol. 2003;56(1): 56–61.
• A clear explanation PPI and antifugeal drug-to-drug intera
ction.
20. Blanco Dorado S, Maronas Amigo O, Latorre-Pellicer A, et al.
A multicentre prospective study evaluating the impact of
proton-pump inhibitors omeprazole and pantoprazole on vorico­
nazole plasma concentrations. Br J Clin Pharmacol. 2020 Aug;86
(8):1661–1666.
•• This is a prospective study.
21. Zvyaga T, Chang SY, Chen C, et al. Evaluation of six proton pump
inhibitors as inhibitors of various human cytochromes P450: focus
on cytochrome P450 2C19. Drug Metab Dispos. 2012 Sep;40
(9):1698–1711.
22. Yan M, Wu ZF, Tang D, et al. The impact of proton pump inhibitors
on the pharmacokinetics of voriconazole in vitro and in vivo.
Biomed Pharmacother. 2018 Dec;108:60–64.
23. Huang Q, Liu Q, Yin T, et al. Effect of proton pump inhibitors on
voriconazole concentrations in Chinese patients with malignant
hematological diseases. Eur J Clin Pharmacol. 2020 Jun;76
(6):833–842.
24. Marsot A, Goirand F, Milesi N, et al. Interaction of thiopental with
esomeprazole in critically ill patients. Eur J Clin Pharmacol. 2013
Sep;69(9):1667–1672.
25. Ashbee HR, Barnes RA, Johnson EM, et al. Therapeutic drug mon­
itoring (TDM) of antifungal agents: guidelines from the British
Society for Medical Mycology. J Antimicrob Chemother. 2014
May;69(5):1162–1176.
26. Lu M, Yan H, Yu C, et al. Proton pump inhibitors act synergistically
with fluconazole against resistant Candida albicans. Sci Rep. 2020
Jan 16;10(1):498.
27. Kapetas AJ, Abuhelwa AY, Sorich MJ, et al. Evidence-based guide­
lines for drug interaction studies: model-informed time course of
intestinal and hepatic CYP3A4 inhibition by clarithromycin. AAPS J.
2021 Aug 31;23(5):104.
28. Calabresi L, Pazzucconi F, Ferrara S, et al. Pharmacokinetic interac­
tions between omeprazole/pantoprazole and clarithromycin in
health volunteers. Pharmacol Res. 2004 May;49(5):493–499.
29. Saito M, Yasui-Furukori N, Uno T, et al. Effects of clarithromycin on
lansoprazole pharmacokinetics between CYP2C19 genotypes. Br
J Clin Pharmacol. 2005 Mar;59(3):302–309.
30. Cao S, Zhou G, Ou-Yang DS, et al. Pharmacokinetic interactions
between ilaprazole and clarithromycin following ilaprazole, clari­
thromycin and amoxicillin triple therapy. Acta Pharmacol Sin. 2012
Aug;33(8):1095–1100.
31. Jin BH, Yoo BW, Park J, et al. Pharmacokinetic drug interaction and
safety after coadministration of clarithromycin, amoxicillin, and
ilaprazole: a randomised, open-label, one-way crossover, two par­
allel sequences study. Eur J Clin Pharmacol. 2018 Sep;74
(9):1149–1157.
32. Georgopoulos S, Papastergiou V. An update on current and advan­
cing pharmacotherapy options for the treatment of H. pylori
infection. Expert Opin Pharmacother. 2021 Apr;22(6):729–741.
33. Lin YA, Wang H, Gu ZJ, et al. Effect of CYP2C19 gene polymorph­
isms on proton pump inhibitor, amoxicillin, and levofloxacin triple
therapy for eradication of Helicobacter pylori. Med Sci Monit. 2017
Jun 3;23:2701–2707.
34. Soares GA, Pires DW, Pinto LA, et al. The influence of omeprazole
on the dissolution processes of pH-dependent magnetic tablets
assessed by pharmacomagnetography. Pharmaceutics. 2021 Aug
17; 13(8):1274.
35. Offman E, Schobelock MJ, Brickl R, et al. Pharmacokinetics and
pharmacodynamics of the antiplatelet combination aspirin
(acetylsalicylic acid) plus extended-release dipyridamole are
not altered by coadministration with the potent CYP2C19 inhi­
bitor omeprazole. Am J Cardiovasc Drugs. 2013 Apr;13
(2):113–120.

36. Colombier MA, Molina JM. Doravirine: a review. Curr Opin HIV AIDS.
2018 Jul;13(4):308–314.
37. Khalilieh SG, Yee KL, Sanchez RI, et al. A study to evaluate doravir­
ine pharmacokinetics when coadministered with acid-reducing
agents. J Clin Pharmacol. 2019 Aug;59(8):1093–1098.
38. Van Den Abeele J, Kostantini C, Barker R, et al. The effect of
reduced gastric acid secretion on the gastrointestinal disposition
of a ritonavir amorphous solid dispersion in fasted healthy volun­
teers: an in vivo - in vitro investigation. Eur J Pharm Sci. 2020 Aug;1
(151):105377.
39. Pohl O, Osterloh I, Lecomte V, et al. Changes in gastric pH and in
pharmacokinetics of ulipristal acetate - a drug-drug interaction
study using the proton pump inhibitor esomeprazole. Int J Clin
Pharmacol Ther. 2013 Jan;51(1):26–33.
40. Reau N, Robertson MN, Feng HP, et al. Concomitant proton pump
inhibitor use does not reduce the efficacy of elbasvir/grazoprevir:
a pooled analysis of 1,322 patients with hepatitis C infection.
Hepatol Commun. 2017 Oct 1;1(8):757–764.
•• Clinical assessment of the clinical consequences of drug-to-
drug interaction.
41. Trifiro G, Corrao S, Alacqua M, et al. Interaction risk with proton
pump inhibitors in general practice: significant disagreement
between different drug-related information sources. Br J Clin
Pharmacol. 2006 Nov;62(5):582–590.
42. Flamm S, Reddy KR, Zadeikis N, et al. Efficacy and pharmacokinetics
of glecaprevir and pibrentasvir with concurrent use of
acid-reducing agents in patients with chronic HCV infection. Clin
Gastroenterol Hepatol. 2019 Feb;17(3):527–535 e6.
43. Tett S, Day R, Cutler D. Hydroxychloroquine relative bioavailability:
within subject reproducibility. Br J Clin Pharmacol. 1996 Mar;41
(3):244–246.
44. Stoll F, Blank A, Mikus G, et al. Effect of pantoprazole on the
absorption of hydroxychloroquinea a randomized drug-drug inter­
action trial in healthy adults. Clin Pharmacol Drug Dev. 2022 Feb;11
(2):285–290.
•• A randomised PK study.
45. Jallouli M, Galicier L, Zahr N, et al. Determinants of hydroxy­
chloroquine blood concentration variations in systemic lupus
erythematosus. Arthritis Rheumatol. 2015 May;67(8):2176–2184.
46. Dean L. Clopidogrel therapy and CYP2C19 genotype. In: Pratt VM,
Scott SA, Pirmohamed M, et al., editors. Medical genetics summa­
ries. Bethesda (MD): National Center for Biotechnology Information
(US); 2012.
47. Gilard M, Arnaud B, Le Gal G, et al. Influence of omeprazol on the
antiplatelet action of clopidogrel associated to aspirin. J Thromb
Haemost. 2006 Nov;4(11):2508–2509.
48. Gilard M, Arnaud B, Cornily JC, et al. Influence of omeprazole on
the antiplatelet action of clopidogrel associated with aspirin: the
randomized, double-blind OCLA (Omeprazole clopidogrel aspirin)
study. J Am Coll Cardiol. 2008 Jan 22;51(3):256–260.
• A well-conduced randomized clinical trial. Unfortunately, the
primary outcome is not a clinical event.
49. Ho PM, Maddox TM, and Wang L, et al. Risk of adverse outcomes
associated with concomitant use of clopidogrel and proton pump
inhibitors following acute coronary syndrome. JAMA. 2009 Mar
4;301(9):937–944.
•• One of the leading studies on the topic.
50. Muthiah MD, Zheng H, Chew NWS, et al. Outcomes of a
multi-ethnic Asian population on combined treatment with clopi­
dogrel and omeprazole in 12,440 patients. J Thromb Thrombolysis.
2021 Oct;52(3):925–933.
51. Lau WC, Gurbel PA. The drug-drug interaction between proton
pump inhibitors and clopidogrel. Cmaj. 2009 Mar 31;180
(7):699–700.
52. Moreira Dias L. Pantoprazole: a proton pump inhibitor. Clin Drug
Investig. 2009;29(2):3–12.
53. Melloni C, Washam JB, Jones WS, et al. Conflicting results between
randomized trials and observational studies on the impact of pro­
ton pump inhibitors on cardiovascular events when
EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY 345
coadministered with dual antiplatelet therapy: systematic review.
Circ Cardiovasc Qual Outcomes. 2015 Jan;8(1):47–55.
54. Demcsák A, Lantos T, Bálint ER, et al. PPIs are not responsible for
elevating cardiovascular risk in patients on clopidogrel-a systematic
review and meta-analysis. Front Physiol. 2018;9:1550.
55. Farhat N, Fortin Y, Haddad N, et al. Systematic review and
meta-analysis of adverse cardiovascular events associated with
proton pump inhibitors used alone or in combination with anti­
platelet agents. Crit Rev Toxicol. 2019 Mar;49(3):215–261.
56. Lin SF, Lin PC, Chang CC, et al. Investigation of the interaction
between proton pump inhibitors and clopidogrel using VerifyNow
P2Y12 assay. Medicine (Baltimore). 2020 Dec 11;99(50):e23695.
57. Leonard CE, Bilker WB, Brensinger CM, et al. Comparative risk of
ischemic stroke among users of clopidogrel together with indivi­
dual proton pump inhibitors. Stroke. 2015 Mar;46(3):722–731.
58. Shi W, Ni L, Yang J, et al. The clinical impact of proton pump
inhibitors when co-administered with dual antiplatelet therapy
in patients having acute myocardial infarction with low risk of
gastrointestinal bleeding: insights from the China acute myo­
cardial infarction registry. Front Cardiovasc Med.
2021;8:685072.
59. Shi WC, Gao SD, Yang JG, et al. Impact of proton pump inhibitors
on clinical outcomes in patients after acute myocardial infarction:
a propensity score analysis from China Acute Myocardial Infarction
(CAMI) registry. J Geriatr Cardiol. 2020 Nov 28;17(11):659–665.
60. Kim MS, Song HJ, Lee J, et al. Effectiveness and safety of clopido­
grel co-administered with statins and proton pump inhibitors:
a Korean national health insurance database study. Clin
Pharmacol Ther. 2019 Jul;106(1):182–194.
61. Bang CS, Joo MK, Kim BW, et al. The role of acid suppressants in the
prevention of anticoagulant-related gastrointestinal bleeding:
a systematic review and meta-analysis. Gut Liver. 2020 Jan 15;14
(1):57–66.
62. Cole JA, Taylor JS, Hangartner TN, et al. Reducing selection bias in
case-control studies from rare disease registries. Orphanet J Rare
Dis. 2011 Sep;12(6):61.
63. Gadzhanova SRE. Co-prescribing of warfarin with statins and pro­
ton pump inhibitors in elderly Australians. Adv Pharmacoepidemiol
Drug Saf. 2014;3:3.
64. Wang M, Zeraatkar D, Obeda M, et al. Drug-drug interactions with
warfarin: a systematic review and meta-analysis. Br J Clin
Pharmacol. 2021 Nov;87(11):4051–4100.
65. Bertram V, Yeo K, Anoopkumar-Dukie S, et al. Proton pump inhibi­
tors co-prescribed with warfarin reduce warfarin control as mea­
sured by time in therapeutic range. Int J Clin Pract. 2019 Nov;73
(11):e13382.
66. Kuwayama T, Osanai H, Ajioka M, et al. Influence of proton pump
inhibitors on blood dabigatran concentrations in Japanese patients
with non-valvular atrial fibrillation. J Arrhythm. 2017 Dec;33
(6):619–623.
67. Bolek T, Samos M, Stanciakova L, et al. The impact of proton pump
inhibition on dabigatran levels in patients with atrial fibrillation.
Am J Ther. 2019 May;26(3):e308–e313.
68. Harada A, Ikushima I, Haranaka M, et al. Bioequivalence of a newly
developed dabigatran etexilate tablet versus the commercial cap­
sule and impact of rabeprazole-induced elevated gastric ph on
exposure in healthy subjects. Am J Cardiovasc Drugs. 2020 Jun;20
(3):249–258.
69. Schnierer M, Samos M, Bolek T, et al. The effect of proton pump
inhibitor withdrawal on dabigatran etexilate plasma levels in
patients with atrial fibrillation: a washout study. J Cardiovasc
Pharmacol. 2020 Apr;75(4):333–335.
70. Ray WA, Chung CP, Murray KT, et al. Association of oral antic­
oagulants and proton pump inhibitor cotherapy with hospitaliza­
tion for upper gastrointestinal tract bleeding. Jama. 2018 Dec 4;320
(21):2221–2230.
71. Chan EW, Lau WC, Leung WK, et al. Prevention of dabigatran-related
gastrointestinal bleeding with gastroprotective agents: a
population-based study. Gastroenterology. 2015 Sep;149(3):586–95.e3.
346 I. BEN GHEZALA ET AL.
72. Nies AT, Hofmann U, Resch C, et al. Proton pump inhibitors inhibit
metformin uptake by organic cation transporters (OCTs). PLoS One.
2011;6(7):e22163.
73. Kim A, Chung I, Yoon SH, et al. Effects of proton pump inhibitors on
metformin pharmacokinetics and pharmacodynamics. Drug Metab
Dispos. 2014 Jul;42(7):1174–1179.
74. Flory J, Haynes K, Leonard CE, et al. Proton pump inhibitors do not
impair the effectiveness of metformin in patients with diabetes. Br
J Clin Pharmacol. 2015 Feb;79(2):330–336.
75. Al-Bachaji IN, Al-Buhadiliy AK, Al-Kuraishy HM, et al. Proton pump
inhibitors regulate metabolic profile and glycaemic indices in
patients with type 2 diabetes mellitus: a rising dawn of a new
therapeutic concept. J Pak Med Assoc. 2019 Aug;69(8):S31–S35.
76. Peng CC, Tu YK, Lee GY, et al. Effects of proton pump inhibitors on
glycemic control and incident diabetes: a systematic review and
meta-analysis. J Clin Endocrinol Metab. 2021 Oct 21;106
(11):3354–3366.
• A well-conducted meta-analysis.
77. Ginanneschi F, Volpi N, Giannini F, et al. Rhabdomyolysis in an
elderly multitreated patient: multiple drug interactions after statin
withdrawal. J Neurol Sci. 2014 Jan 15;336(1–2):284–287.
78. Kashour T, Al-Tannir M, Bahamid R. Changing prescription pattern
of omeprazole among patients receiving clopidogrel. Int Heart J.
2014;55(2):93–95.
79. Baekdal TA, Breitschaft A, Navarria A, et al. A randomized study
investigating the effect of omeprazole on the pharmacokinetics of
oral semaglutide. Expert Opin Drug Metab Toxicol. 2018 Aug;14
(8):869–877.
80. Raoul JL, Guerin-Charbonnel C, Edeline J, et al. Prevalence of pro­
ton pump inhibitor use among patients with cancer. JAMA
Network Open. 2021 Jun 1;4(6):e2113739.
81. Budha NR, Frymoyer A, Smelick GS, et al. Drug absorption interac­
tions between oral targeted anticancer agents and PPIs: is
pH-dependent solubility the Achilles heel of targeted therapy?
Clin Pharmacol Ther. 2012 Aug;92(2):203–213.
82. Peters S, Zimmermann S, Adjei AA. Oral epidermal growth factor
receptor tyrosine kinase inhibitors for the treatment of non-small
cell lung cancer: comparative pharmacokinetics and drug-drug
interactions. Cancer Treat Rev. 2014 Sep;40(8):917–926.
83. van Leeuwen RW, van Gelder T, Mathijssen RH, et al. Drug-drug
interactions with tyrosine-kinase inhibitors: a clinical perspective.
Lancet Oncol. 2014 Jul;15(8):e315–26.
•• A comprehensive overview of known or suspected drug–drug
interactions between tyrosine-kinase inhibitors and other
drugs.
84. Veerman GDM, Hussaarts K, Peric R, et al. Influence of cow’s milk
and esomeprazole on the absorption of erlotinib: a randomized,
crossover pharmacokinetic study in lung cancer patients. Clin
Pharmacokinet. 2021 Jan;60(1):69–77.
85. Ohgami M, Kaburagi T, Kurosawa A, et al. Effects of proton pump
inhibitor coadministration on the plasma concentration of erlotinib
in patients with non-small cell lung cancer. Ther Drug Monit. 2018
Dec;40(6):699–704.
86. Yokota H, Sato K, Okuda Y, et al. Effects of histamine 2-receptor
antagonists and proton pump inhibitors on the pharmacokinetics
of gefitinib in patients with non-small-cell lung cancer. Clin Lung
Cancer. 2017 Nov;18(6):e433–e439.
87. Song HJ, Rhew K, Lee YJ, et al. Acid-suppressive agents and survival
outcomes in patients with cancer: a systematic review and
meta-analysis. Int J Clin Oncol. 2021 Jan;26(1):34–50.
88. Sharma M, Holmes HM, Mehta HB, et al. The concomitant use of
tyrosine kinase inhibitors and proton pump inhibitors: prevalence,
predictors, and impact on survival and discontinuation of therapy
in older adults with cancer. Cancer. 2019 Apr 1;125(7):1155–1162.
View publication stats
89. Sim W, Jain SR, Lim WH, et al. Interactions between epidermal
growth factor receptor tyrosine kinase inhibitors and
proton-pump inhibitors/histamine type-2 receptor antagonists in
non-small cell lung cancer: a systematic review and meta-analysis.
Transl Lung Cancer Res. 2021 Aug;10(8):3567–3581.
90. Lalani AA, McKay RR, Lin X, et al. Proton pump inhibitors and
survival outcomes in patients with metastatic renal cell
carcinoma. Clin Genitourin Cancer. 2017 Dec;15(6):724–732.
91. Ha VH, Ngo M, Chu MP, et al. Does gastric acid suppression
affect sunitinib efficacy in patients with advanced or meta­
static renal cell cancer? J Oncol Pharm Pract. 2015 Jun;21
(3):194–200.
92. Mir O, Touati N, Lia M, et al. Impact of concomitant adminis­
tration of gastric acid-suppressive agents and pazopanib on
outcomes in soft-tissue sarcoma patients treated within the
EORTC 62043/62072 trials. Clin Cancer Res. 2019 Mar 1;25
(5):1479–1485.
93. de Man FM, Hussaarts K, de With M, et al. Influence of the proton
pump inhibitor esomeprazole on the bioavailability of regorafenib:
a randomized crossover pharmacokinetic study. Clin Pharmacol
Ther. 2019 Jun;105(6):1456–1461.
94. Van De Sijpe G, Beuselinck B, Van Nieuwenhuyse T, et al. Impact of
concomitant acid suppressive therapy on pazopanib efficacy and
dose reductions in patients with metastatic renal cell carcinoma.
Eur J Clin Pharmacol. 2020 Sep;76(9):1273–1280.
95. Krens SD, Lubberman FJE, van Egmond M, et al. The impact of a
1-hour time interval between pazopanib and subsequent intake of
gastric acid suppressants on pazopanib exposure. Int J Cancer.
2021 Jun 1;148(11):2799–2806.
96. Yin OQ, Giles FJ, Baccarani M, et al. Concurrent use of proton pump
inhibitors or H2 blockers did not adversely affect nilotinib efficacy
in patients with chronic myeloid leukemia. Cancer Chemother
Pharmacol. 2012 Aug;70(2):345–350.
97. Koutake Y, Taniguchi J, Yasumori N, et al. Influence of proton pump
inhibitors and H2-receptor antagonists on the efficacy and safety of
dasatinib in chronic myeloid leukemia patients. Int J Hematol. 2020
Jun;111(6):826–832.
98. Hussaarts K, Veerman GDM, Jansman FGA, et al. Clinically relevant
drug interactions with multikinase inhibitors: a review. Ther Adv
Med Oncol. 2019;11:1758835918818347.
99. Rassy E, Cerbone L, Auclin E, et al. The effect of concomitant proton
pump inhibitor and cabozantinib on the outcomes of patients with
metastatic renal cell carcinoma. Oncologist. 2021 May;26
(5):389–396.
100. Gopalakrishnan V, Spencer CN, Nezi L, et al. Gut microbiome mod­
ulates response to anti-PD-1 immunotherapy in melanoma
patients. Science. 2018 Jan 5;359(6371):97–103.
101. Viaud S, Saccheri F, Mignot G, et al. The intestinal microbiota
modulates the anticancer immune effects of cyclophosphamide.
Science. 2013 Nov 22;342(6161):971–976.
102. Trifan A, Stanciu C, Girleanu I, et al. Proton pump inhibitors therapy
and risk of Clostridium difficile infection: systematic review and
meta-analysis. World J Gastroenterol. 2017 Sep 21;23
(35):6500–6515.
103. Weersma RK, Zhernakova A, Fu J. Interaction between drugs and
the gut microbiome. Gut. 2020 Aug;69(8):1510–1519.
104. Kato K, Mizuno T, Koseki T, et al. Concomitant proton pump
inhibitors and immune checkpoint inhibitors increase nephritis
frequency. Vivo. 2021 Sep–Oct;35(5):2831–2840.
105. Chalabi M, Cardona A, Nagarkar DR, et al. Efficacy of chemotherapy
and atezolizumab in patients with non-small-cell lung cancer
receiving antibiotics and proton pump inhibitors: pooled post
hoc analyses of the OAK and POPLAR trials. Ann Oncol. 2020
Apr;31(4):525–531.