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. 2026 Oct 5;139(5):e70317. doi: 10.1111/bcpt.70317

Frequency of Clinically Relevant Drug–Drug Interactions Between Tyrosine Kinase Inhibitors and Proton Pump Inhibitors in Patients With Cancer Using Real‐World Data

Grietje van Elp 1,2,✉, Maikel Borg 2, Jens H J Bos 2, Catharina C M Schuiling‐Veninga 2, Katja Taxis 2, Frank G A Jansman 1,2
PMCID: PMC13639104  PMID: 42834472

ABSTRACT

Background

Proton pump inhibitors (PPIs) raise stomach pH, leading to reduced bioavailability of many tyrosine kinase inhibitors (TKIs), thereby affecting treatment outcomes. To what extent this interaction occurs in clinical practice remains underexplored.

Objective

To determine the frequency of clinically relevant interactions between TKIs and PPIs in clinical practice and the duration of concomitant prescription.

Methods

A retrospective observational study was performed using the IADB.nl prescription database. Clinically relevant drug–drug interactions between TKIs and PPIs were assessed using four drug compendia (i.e., KNMP Kennisbank, Health Base, Lexidrug and Merative Micromedex). Patients who were prescribed a TKI and PPI with a clinically relevant DDI concomitantly, between 1 January 2013 and 31 December 2024, were included. Concomitant prescription was defined as ≥ 7 days of simultaneous prescription.

Findings

In total, 60 TKIs were registered in the Netherlands; 19 TKIs had clinically relevant interactions reported by at least one compendium. Overall, 393 of 1759 (22.3%) TKI users had a clinically relevant interaction. The median duration of concomitant prescription was 43 days (IQR = 81), with 91.1% of episodes lasting at least 30 days.

Conclusion

PPIs and TKIs are frequently prescribed concomitantly in clinical practice. Prescribers should be more cautious when co‐prescribing PPIs with TKIs and adapt the dosing regimens when appropriate.

Keywords: drug–drug interactions, pharmacokinetics, proton pump inhibitors, real‐world data, tyrosine kinase inhibitors

Plain Language Summary

Acid suppressing agents like proton pump inhibitors (PPIs) can reduce absorption of oral cancer drugs named tyrosine kinase inhibitors (TKIs). Using these drugs together should be avoided. We studied how often these drugs are taken together in real‐world practice. Using a Dutch prescription database, we found that approximately one in four patients (22.3%) using a TKI also used a PPI. Most patients took both drugs together for at least 1 month. This frequent and prolonged use at the same time may reduce efficacy of cancer treatment. Prescribers should avoid this combination when possible or adjust dosing to minimize interaction.

1. Introduction

Tyrosine Kinase inhibitors (TKIs) are a cornerstone in cancer treatment. TKIs are increasingly used for a wide range of oncological and haematological indications, which increases the need to monitor occurrence of possible drug interactions in daily practice [1, 2]. Many TKIs are taken orally which enhances convenience for patients, but also poses risks of potential drug interactions [1]. Most of the TKIs are weak bases, which require an acidic environment for optimal solubility. Weak bases are ionized in the low pH of the stomach, enhancing their solubility. Once solubilized, TKIs are absorbed in the small intestine. Medication, which increases the pH of the stomach, such as proton pump inhibitors (PPIs), can reduce dissolution and thereby lower absorption of TKIs, posing a potential relevant drug–drug interaction. PPI use is common in patients with cancer to treat gastrointestinal symptoms or treatment related side effects such as dyspepsia and acid reflux [3, 4, 5]. A single dose of a PPI elevates the stomach pH for approximately 12–14 h [6]. Long‐term use (> 3 months) can decrease the time that the stomach pH is below 4 to merely 35%, hence potentially decreasing bioavailability of TKIs [7, 8].

Many TKIs are affected by concomitant use of PPIs, leading to a reduction in their maximum concentration (Cmax) and area under the curve (AUC) [9]. As a result significant effects on treatment outcomes were observed. In patients with metastatic renal cell carcinoma, concomitant use of PPIs with either pazopanib or cabozantinib decreased the progression‐free survival (PFS) (16.3 vs. 9.9 months; p < 0.001) and the overall survival (OS) (30.6 vs. 18.4 months; p = 0.013) compared to patients not using a PPI [10]. Sharma et al. found a decreased survival of 90 days (hazard ratio [HR], 1.16; 95% confidence interval [CI], 1.05–1.28) and 1 year (HR, 1.10; 95% CI, 1.04–1.18) in older adults with cancer [11].

Not all TKIs appear to be affected by concomitant PPI use. In a study conducted in healthy subjects, the effect of esomeprazole on the pharmacokinetics of a single dose of cabozantinib was evaluated. This study revealed that concomitant use of PPIs is not contraindicated, because the AUC and Cmax were significantly changed [12]. In addition, a pooled analysis showed that PPI use did not negatively affect the efficacy and safety of some vascular endothelial growth factor‐tyrosine kinase inhibitors (VEGF‐TKIs), in an analysis of sunitinib, axitinib and sorafenib users treated for metastatic renal cell carcinoma. OS was similar between PPI users and nonusers (HR, 1.051; 95% CI, 0.769–1.438; p = 0.75), as was the progression‐free survival (HR, 1.016; 95% CI, 0.793–1.301; p = 0.902) [13]. These findings suggest that the clinical relevance of the interaction between TKIs and PPIs varies between individual TKI agents.

Current guidelines emphasize caution when combining certain TKIs with PPIs and emphasize the need for a strict dosing regimen. The TKI should be taken 2 h before the PPI or they should be taken together as the onset of the PPI effect takes around one to 2 h. In case one or both of the drugs are taken multiple times a day, it is almost inevitable that the TKI is ingested when the stomach pH is elevated. This may be partially prevented by switching the PPI dosing from twice to once a day, if possible [8]. However, this interaction is difficult to prevent for TKIs, which require multiple doses per day to maintain sufficient drug exposure. Furthermore, long concomitant use of a PPI imposes an even greater risk as this will increase the time that the stomach pH is elevated and may cause longer subtherapeutic TKI concentrations [7].

The extent to which clinically relevant interactions between TKIs and PPIs occur in clinical practice has not been well described. Therefore, this study aims to provide insight into the frequency of clinically relevant interactions between TKIs and PPIs using real‐world data. Furthermore, the duration of concomitant prescription and dosage of both drugs during concomitant prescription is evaluated.

2. Materials and Methods

2.1. Study Design and Data Source

A retrospective observational study was conducted using the prescription database IADB.nl, from University Groningen [14]. This database includes prescription data of 3 million patients of 155 community and five outpatient pharmacies in the Netherlands. Due to specific Dutch reimbursement regulations, TKIs are primarily dispensed by outpatient pharmacies and not available through community pharmacies. The database is representative for the Dutch primary care population with regards to age, gender and prescription patterns [15]. IADB.nl contains detailed anonymized prescription records including dispensing dates, quantities dispensed, dosage regimens, prescription durations, prescribing physicians and Anatomical Therapeutic Chemical (ATC) codes. The database does not include data on over the counter (OTC) drugs and medication dispensed during hospitalization.

The study was conducted in accordance with the Basic and Clinical Pharmacology and Toxicology policy for experimental and clinical studies [16].

2.2. Clinically Relevant DDIs

Information on the clinical relevance of interactions between TKIs and PPIs was extracted from four drug compendia for decision support, that is, the Dutch KNMP Kennisbank (KB) and Health Base (HB) and the American UpToDate Lexidrug (LD) and Micromedex (MM) [17, 18, 19, 20]. The analyses included all TKIs approved by the European Medicines Agency (EMA) and registered in the Netherlands in the period between 2013 and 2024, according to the Dutch Medicines Evaluation Board (CBG medicines information database) [21, 22, 23]. In order to search for interactions, the general class of PPIs was used for compendia KB and HB. For compendia LC and MM, only interactions with omeprazole and pantoprazole were evaluated. The TKIs were categorized into three groups (Table 1): TKIs for which no interaction with PPIs was mentioned in any of the four compendia (not interacting [NI]), TKIs for which at least one compendium reported a clinically relevant interaction, while at least one other compendium reported no interaction (conflicting information [CI]) and TKIs with a clinically relevant interaction with PPIs reported in all four compendia (interacting [IA]). Subsequently, the group of not‐interacting TKIs was not further considered. The categorization of the interactions per compendium is provided in Appendix S1.

TABLE 1.

Categorization of registered tyrosine kinase inhibitors (TKIs) with regard to a potential interaction with a proton pump inhibitor (PPI).

Not interacting Abemaciclib, acalabrutinib, afatinib, alectinib, asciminib, avapritinib, axitinib, binimetinib, brigatinib, cabozantinib, capmatinib, cobimetinib, crizotinib, encorafenib, entrectinib, erdafitinib, fruquintinib, futibatinib, gilteritinib, ibrutinib, imatinib, larotrectinib, lenvatinib, lorlatinib, midostaurine, nintedanib, osimertinib, ponatinib, pralsetinib, quizartinib, regorafenib, ribociclib, ripretinib, ruxolitinib, selumetinib, tepotinib, tivozanib, trametinib, tucatinib, vandetanib, vemurafenib, zanubrutinib.
Conflicting information Ceritinib, dabrafenib, fedratinib, lapatinib, nilotinib, palbociclib, pemigatinib, pirtobrutinib, selpercatinib, sorafenib, sunitinib.
Interacting Acalabrutinib (capsule), bosutinib, dacomitinib, dasatinib, erlotinib, gefitinib, neratinib, pazopanib.
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2.3. Patient Population and Outcome Measures

Patients from the IADB database were included when they had a prescription of a potential interacting TKI (IA and CI) for at least 7 days between January 2013 and December 2024. For those patients, data on prescriptions of PPIs were extracted.

The main outcome measure was the frequency of interaction episodes defined as the concomitant prescription of a TKI and a PPI (omeprazole, esomeprazole, pantoprazole, lansoprazole and rabeprazole) for at least 7 days. Secondary outcome measures were the mean daily doses of both the TKI and the PPI expressed as defined daily doses (DDDs), the duration of concomitant prescriptions and the frequency of interaction episodes per individual TKI, distinguishing between TKIs given once daily and TKIs that were dosed more than once daily (acalabrutinib, dabrafenib, nilotinib, selpercatinib and sorafenib [24, 25, 26, 27, 28]).

2.4. Data Analysis

Episodes were determined based on the first recorded dispensing date of the medication (TKI or PPI). The end date of an episode was defined as the last day covered by the prescribed amount of medication, followed by a 30‐day clearance period in which no subsequent prescription was recorded. If a new prescription was issued within this 30‐day window, the episode was extended accordingly. The number of patients with overlapping episodes of treatment with a TKI and PPI was determined at a patient level, with each TKI user counted only once, even if they received multiple TKIs. The duration and average daily doses, expressed as DDD, were determined at an episode level, allowing individual patients to be included with multiple episodes. The duration of each prescription was calculated by dividing the total number of units dispensed by the DDD. The number of users per individual TKI was determined at a patient level, with patients who used multiple TKIs counted separately for each TKI they received.

Frequency outcomes and population characteristics were determined using descriptive statistics. Statistical tests were performed using SPSS. Normality of the average daily dose for both TKI‐only users and patients with concomitant prescription was evaluated using the Kolmogorov–Smirnov test (p < 0.05). Differences in DDD of the TKI between episodes with and without concomitant PPI prescriptions were assessed using the Mann–Whitney U test.

3. Results

In total, 60 TKIs were registered for use in the Netherlands up to 2024. Of those, 19 TKIs had clinically relevant interactions or conflicting information. Table 1 summarizes the clinically relevant interactions between TKIs and PPIs and shows how they are categorized based on the level of agreement between compendia.

A total of 1759 users of TKIs corresponding to categories IA and CI, were identified, of which 393 patients (22.3%) used a PPI concomitantly. There were 284 patients from category CI and 119 patients from category IA, including 10 patients who used two TKIs. TKI users without concomitant PPI prescription were prescribed a median of 0.97 DDD. TKI users with concomitant prescriptions of PPIs were prescribed a median of 0.97 DDD (Table 2). This difference was not statically significant. PPI prescriptions represented a median of 1.00 DDD. The median duration of concomitant prescription of a PPI and a TKI was 43 days (IQR = 81). The distribution of this duration is also shown in Table 2. In our dataset, concomitant prescriptions of at least 30 days were registered in 522 of the 573 episodes, which accounts for 91.1%.

TABLE 2.

Median defined daily doses (DDDs) of episodes of Tyrosine Kinase Inhibitors (TKIs) with (TKI + PPI) and without (TKI) concomitant Proton Pump Inhibitor (PPI) prescription, duration of concomitant prescription and DDD distribution.

TKI (n = 2431) TKI + PPI (n = 573) p
Median DDD (IQR)
TKI 0.97 (0.35) 0.244
PPI 0.97 (0.34) 1.00 (0.86)
Duration of concomitant prescription (days)
Q1 28
Median 43
Q3 109
IQR 81
PPI prescriptions over the years (n;%)
2013 68 (11.9)
2014 46 (8.0)
2015 48 (8.4)
2016 52 (9.1)
2017 53 (9.2)
2018 47 (8.2)
2019 56 (9.8)
2020 41 (7.2)
2021 57 (9.9)
2022 42 (7.3)
2023 25 (4.4)
2024 38 (6.6)
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Note: The median DDD of a TKI between the two groups was tested using a Mann–Whitney U test.

Dabrafenib was the most frequently prescribed TKI in the database with 515 (29.1%) users, followed by palbociclib with 339 (19.2%) users. Pemigatinib, neratinib and dacomitinib had no recorded users. Erlotinib was the most frequently used TKI in combination with a PPI (n = 22; 27.2%) (Table 3). Lapatinib (n = 25; 89.3%) was used relatively frequently without concomitant PPI prescriptions (Table 3), against three (10.7%) patients with concomitant PPI prescriptions. Pirtobrutinib was not prescribed concomitantly with a PPI, but only three users were included. Six hundred eighty‐one patients used a TKI commonly prescribed more than once daily of which 146 (21.4%) patients had a concomitant prescription of a PPI, which amounts to 37.2% of the TKI users with a concomitant PPI prescription (n = 393).

TABLE 3.

Users of tyrosine kinase inhibitors (TKIs) with (TKI + PPI) and without (TKI) concomitant proton pump inhibitor (PPI) prescription. Patients who used multiple TKIs are counted separately for each TKI used.

TKI, n (%) TKI + PPI, n (%)
Conflicting 984 (77.6) 284 (22.4)
Interacting 465 (79.6) 119 (20.4)
Acalabrutinib 7 (87.5) 1 (12.5)
Bosutinib 37 (86.0) 6 (14.0)
Ceritinib 26 (81.3) 6 (18.8)
Dabrafenib 405 (78.6) 110 (21.4)
Dacomitinib 0 (0) 0 (0)
Dasatinib 136 (83.4) 27 (16.6)
Erlotinib 59 (72.8) 22 (27.2)
Fedratinib 8 (88.9) 1 (11.1)
Gefitinib 45 (73.8) 16 (26.2)
Lapatinib 25 (89.3) 3 (10.7)
Neratinib 0 (0) 0 (0)
Nilotinib 69 (76.7) 21 (23.3)
Palbociclib 251 (74.0) 88 (26.0)
Pazopanib 181 (79.4) 47 (20.6)
Pemigatinib 0 (0) 0 (0)
Pirtobrutinib 3 (100.0) 0 (0)
Selpercatinib 8 (88.9) 1 (11.1)
Sorafenib 46 (78.0) 13 (22.0)
Sunitinib 146 (78.1) 41 (21.9)
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4. Discussion

This study identified 1759 patients with a concomitant prescription of a TKI and PPI with interacting potential within the IADB database in the period 2013–2024. For 393 patients (22.3%), PPIs were prescribed concomitantly for at least 7 days with these TKIs. In 37.2% of the TKI users with a concomitant PPI prescription, TKIs were routinely dosed more than once daily, which means that a clinically relevant interaction cannot be avoided [24, 25, 26, 27, 28]. The average daily TKI intake did not differ significantly between the groups, while the median daily PPI intake among TKI users was 1.00 DDD.

Our study suggests that PPI co‐prescription is common among TKI users. Buti et al. found an even higher frequency of 43.9% (132 of 301 patients) in patients with renal cell carcinoma receiving pazopanib or cabozantinib [10]. This difference may be due to the fact that we did not classify concomitant prescription of cabazantinib and PPIs as an interaction. A retrospective study conducted between 2007 and 2012, including patients treated with TKIs for lung cancer, renal cell carcinoma, chronic myeloid leukaemia, hepatocellular carcinoma and pancreatic cancer, found concomitant PPI use in 22.7% (2843 of 12 538) of patients, which is similar to our study [11]. In this study also imatinib and sunitinib users were included, whereas we did not classify those drugs as interacting with PPIs. Nevertheless, a substantial proportion of patients in our study probably had clinically relevant drug–drug interactions. This comparison with information from literature also shows the discrepancies in classifying the clinical relevance of interactions with TKIs.

The duration of concomitant prescribing was highly variable, with a median of 43 days and some episodes extending to several years. 91.1% of patients received concomitant prescriptions for at least 30 days. In previous studies, concomitant use for at least 30 days has been shown to decrease the time per day that gastric pH is below 4 and was associated with a 16% increased risk of death in older patients within 90 days [7, 11]. Data on OS are not available for shorter concomitant use (< 30 days). Nonetheless, a pharmacokinetic study with erlotinib showed a 61% reduction in plasma concentration and a 46% reduction in overall exposure after only 7 days of PPI use [29]. Together, these findings suggest a high risk for a clinically relevant drug–drug interaction in most patients with concomitant prescribing in our dataset.

The clinically relevant TKI‐PPI interactions identified in 393 patients are defined as those classified as relevant in at least one of the four compendia. Two hundred eighty‐four patients were prescribed TKIs concomitantly with PPIs for which the information of the interaction was conflicting. This demonstrates the substantial inconsistency in both the inclusion and the severity grading of DDIs across compendia. Although such discrepancies have been reported previously, they remain evident in current clinical practice. [30] Furthermore, prior research has shown that drug‐interaction specialists employ diverse strategies to identify potential DDIs [31].

A major strength of this study is the assessment of the frequency of relevant drug–drug interactions between TKIs and PPIs in a large real‐world population. The IADB database contains prescriptions of 3 million patients and is representative for the outpatient population of the Netherlands [15]. Furthermore, the daily dose and the duration of prescribing were considered, which affect the impact of the drug interaction. This study has some limitations. We had no information about the proportion of TKIs, which were dosed based on therapeutic drug monitoring. The average daily dose and duration of treatment were estimated using the total number of DDDs and the total number of tablets dispensed which may not accurately reflect the actual dosage used. Furthermore, patient adherence to medication use and time of drug administration could not be retrieved from the database. Because this information was not available, we could not assess clinical consequences of the drug interactions, like the extent of the reduction in plasma concentrations, as they partly depend on the timing of administration of the interacting drugs [6]. Additionally, we could not determine whether patients took the medication with food. For some TKIs, such as selpercatinib and erlotinib, the pH‐elevating effect of PPIs has no or only minimal effect on TKI absorption when the TKI is taken with food [27, 32]. In this case the interaction is not considered clinically relevant. Furthermore, our dataset did not contain information on OS, progression‐free survival or treatment‐related toxicity. Consequently, we were unable to assess the clinical impact of the drug–drug interactions on such patient outcomes. Due to the lack of detailed clinical data, our study is limited to describing the frequency of co‐prescriptions and we cannot draw conclusions about the consequences of these interactions for patients. In addition, indications of the TKI prescriptions could not be retrieved from the database. Therefore, we could not assess whether frequencies of interactions differ across tumour types. Furthermore, we observed a low frequency of use for some TKIs (acalabrutinib and selpercatinib) and no use of dacomitinib, neratinib, pemigatinib and pirtobrutinib. This may be due to the Dutch ‘lock procedure.’ Under this procedure, newly approved high‐cost medicines may not be immediately reimbursed or reimbursed at all [33]. This may delay or limit their availability in clinical practice and, consequently, their use in our study population, as is the case for instance for acalabrutinib. Lastly, PPI use, and consequently the frequency of this drug–drug interaction, may be underestimated due to the lack of information on over‐the‐counter (OTC) PPI use. In particular, TKIs are known to cause gastrointestinal side effects, which are often managed using PPIs that are readily available without prescription in local drugstores [2]. However, data from Germany indicate that less than 15% of total PPI use is based on OTC purchases, which suggests that this may not have a major impact on our results [34]. Furthermore, hospital prescriptions for PPIs were not included in our study, but we also expect that the impact on our results is small, given the majority of prescribing of PPIs is in primary care [35].

The substantial co‐prescribing of clinically relevant interacting drugs indicates that stricter medication surveillance is needed. Our results also underscore the ongoing need for a standardized evaluation framework or uniform selection criteria to harmonize the definition and classification of drug–drug interactions, as there is limited consistency across the different compendia. It is important that prescribers and pharmacists are aware that knowledge resources vary considerably and evaluations cannot be considered definite, as has been suggested by others [36]. Therefore, in case of conflicting information between compendia for a certain interaction, health care professionals are advised for safety reasons to consider this interaction as relevant. Furthermore, pharmacists should also proactively communicate with prescribing physicians to verify whether TKI and PPI combinations were intentionally prescribed. Prescribers must consider whether multiple daily dosing of TKI and PPI is applicable as this increases the risk of subtherapeutic TKI concentrations. Finally, the duration of concomitant use should be taken into account because prolonged co‐medication is likely to further increase the cumulative risk of the interaction.

Therapeutic drug monitoring (TDM) can possibly be an alternative strategy to minimize clinically relevant interactions. By adjusting TKI dosing based on measured plasma concentrations, the risk of subtherapeutic exposure can be reduced while minimizing toxicity. TDM is currently recommended for gefitinib, pazopanib and sunitinib, but it might be beneficial for other TKIs in the presence of clinically relevant interactions [37]. Reduced TKI absorption due to PPI use may necessitate dose escalation to achieve adequate exposure, resulting in inefficient drug utilization in a drug class that is already known for its high costs [38]. Moreover, TDM is not routinely implemented in clinical practice for TKIs [39, 40].

Future research is warranted to evaluate the effect of short‐term PPI use (< 30 days) on TKI plasma levels and OS, as short‐term PPI co‐medication may also have a relevant impact on treatment outcomes.

5. Conclusions

This large real‐world prescription database showed that almost a quarter of TKI users are prescribed a PPI concomitantly. A considerable proportion of patients with a concomitant prescription used a TKI that requires twice daily dosing and the vast majority of episodes of concomitant prescribing lasted at least 30 days. Prescribers need to be more cautious in co‐prescribing PPIs especially when TKIs or PPIs are dosed multiple times per day and long‐term use is intended. More proactive medication surveillance is needed to identify interactions between PPIs and TKIs and patients should be encouraged to report medication use to prevent or manage relevant interactions.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Appendix S1A: Categorization of drug–drug interactions between TKIs and PPIs per compendium.

Appendix S1B: Explanation of the colours used for classification of the drug–drug interaction in Appendix 1A.

BCPT-139-0-s001.docx (26.8KB, docx)

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Appendix S1A: Categorization of drug–drug interactions between TKIs and PPIs per compendium.

Appendix S1B: Explanation of the colours used for classification of the drug–drug interaction in Appendix 1A.

BCPT-139-0-s001.docx (26.8KB, docx)

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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