Long-Term Use of Proton Pump Inhibitors in Cancer Patients: An Opinion Paper

Abstract

Multikinase inhibitors (MKIs), and particularly tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (CPIs), are currently some of the major breakthroughs in cancer treatment. Proton pump inhibitors (PPIs) revolutionised the treatment of acid-related diseases, but are frequently overused for epigastric pain or heartburn. However, long-term acid suppression from using PPIs may lead to safety concerns, and could have a greater impact in cancer patients undergoing therapy, like bone fractures, renal toxicities, enteric infections, and micronutrient deficiencies (iron and magnesium). Moreover, acid suppression may also affect the pharmacokinetics of drugs (at least during acid suppression) and decrease the absorption of many molecularly-targeted anticancer therapies, which are mostly weak bases with pH-dependent absorption. This type of drug-drug interaction may have detrimental effects on efficacy, with major clinical impacts described for some orally administrated targeted therapies (erlotinib, gefitinib, pazopanib, palbociclib), and conflicting results with many others, including capecitabine. Furthermore, the long-term use of PPIs results in severe alterations to the gut microbiome and recent retrospective analyses have shown that the benefit of using CPIs was suppressed in patients treated with PPIs. These very expensive drugs are of great importance because of their efficacy. As the use of PPIs is not essential, we must apply the precautionary principle. All these data should encourage medical oncologists to refrain from prescribing PPIs, explaining to patients the risks of interaction in order to prevent inappropriate prescription by another physician.

Prevalence of Proton Pump Inhibitor Use Among Patients With Cancer

“…The long-term use of PPIs is a problem in the population of patients with cancer, who may have various comorbidities, such as kidney dysfunction, anemia, infection, or hypomagnesemia. 5 Moreover, indirect drug-drug interactions (eg, lower absorption of TKIs and capecitabine and gut microbiome changes) are associated with a decrease in survival benefit for some of these drugs. [1][2][3][4] PPIs should be actively identified and substituted.…”

Evaluation of gastric pH-dependent drug interaction between famitinib and the commonly used proton pump inhibitor omeprazole in healthy subjects

“…The oral administration route of TKIs offers logistic flexibility and is convenient for the patients, however, despite these advantages, it also causes a highly relevant new problem. Of recently approved orally administered cancer therapeutics, >50% are characterized as having pH-dependent solubility [4][5][6] . The poor and variable pH-dependent solubility, together with other variable pharmacokinetic factors, contribute to a significant patient variability in plasma levels and exposure.…”

“…Next to other factors, TKI therapy is associated with a higher risk for gastrointestinal disorders. A majority of cancer patients frequently take acid-reducing agent (ARA) to alleviate gastroesophageal symptoms, thereby raising the potential for a gastric pH-dependent drug interaction 4 . This type of DDI may have detrimental effects on the efficacy of TKIs, with major clinical impacts described for some orally administrated targeted therapies (erlotinib, gefitinib, pazopanib, palbociclib), and conflicting results with many others, including nilotinib or dasatinib 4,7,8 .…”

“…A majority of cancer patients frequently take acid-reducing agent (ARA) to alleviate gastroesophageal symptoms, thereby raising the potential for a gastric pH-dependent drug interaction 4 . This type of DDI may have detrimental effects on the efficacy of TKIs, with major clinical impacts described for some orally administrated targeted therapies (erlotinib, gefitinib, pazopanib, palbociclib), and conflicting results with many others, including nilotinib or dasatinib 4,7,8 . Longterm suppression of gastric acidity could decrease the absorption of certain major oral anticancer drugs with pH-dependent solubility and result in subsequent failure of therapy.…”

“…Famitinib fits both of these criteria, so it is necessary to explore the effects of pH on the PK of famitinib, including maximum plasma concentration (C max ), area under the curve (AUC), and other PK parameters. Among all therapeutic agents, PPIs are the most prevalent and most potent ARAs and with daily use produce a marked and sustained duration of acid suppression 4,5 . A prospective study in four French Comprehensive Cancer Centers, more than a quarter of cancer patients used PPIs, mostly on a daily basis and in the long term 23 .…”