Oral chemotherapy agents often are used in patients with concomitant medications that may interact with the anti-cancer treatment, and successful management of the interaction is needed for optimal treatment. The most common types of interactions include CYP3A4 inhibitors and inducers, anticoagulants, agents that prolong the QTc interval of the ECG, and gastric acid suppressing medications. Some methods of managing drug-drug interactions (DDIs) include stopping or changing the interacting medication, increased monitoring for toxicity or efficacy, changing the dose of the oral chemotherapy agent, or in rare circumstances, changing to a different chemotherapy treatment.
Gastric acid suppressing (GAS) medications are commonly prescribed for patients receiving cancer treatment. GAS agents include proton pump inhibitors (PPIs), histamine-2 receptor antagonists (H2RAs), and antacid liquids/tabs. In addition, all of these GAS agents are available over-the-counter, and patients might not always report this usage. Hard indications for use of GAS medications include: 1) peptic ulcer disease, 2) gastroesophageal reflux disease (GERD) both as higher dose initial treatment and lower dose maintenance treatment, 3) Barrett's esophagus, 4) Zollinger-Ellison syndrome, 5) NSAID-associated ulcers, and 6) eradication of Helicobacter pylori infections.
In addition, these agents are also used for softer indications, such as 1) prevention of gastritis in those receiving corticosteroids or NSAIDs, 2) stress ulcer prophylaxis after discharge from hospital, 3) endoscopy-negative reflux symptoms, and 4) symptoms of laryngopharyngeal reflux such as hoarse voice or coughing.
Based on data from several surveys, as many as 20-55 percent of people with cancer are taking GAS agents. The actual rate may be higher, because as these agents are available over the counter, the oncology team may not be aware of this usage.
Most orally available tyrosine kinase inhibitor (TKI) anticancer treatments exhibit incomplete and variable absorption. This stems, in part, from incomplete dissolution and thus can be the rate-limiting factor for absorption. As weakly basic molecules, the dissolution is improved in acidic gastric fluids. When the stomach pH is increased up over 4, the TKI absorption is reduced, resulting in a lower Cmax and AUC of the TKI. Therapy with GAS agents increases the gastric pH, contributing to lower TKI absorption. With some TKIs, this change in absorption is inconsequential, but is very large with other agents.
Different GAS agents have different potencies and durations of effect on the gastric pH. Oral antacids, such as magnesium/aluminum hydroxide, change the pH for a couple of hours. The effects of H2RAs, such as ranitidine and famotidine, have an onset of about 30-60 minutes and a duration of about 10-12 hours. PPIs, such as omeprazole and pantoprazole, show a variable and delayed increase in the gastric pH (to >4) of about 3-4 hours. Although the half-lives are about 1-2 hours, the duration of significant effects on the stomach pH is about 12-14 hours assuming once daily administration. Twice daily administration of PPIs often result in pH elevations during most of the day. A summary of PPI and H2RA medications is shown in Table 1.
Increasing the dose of the TKI to overcome the reduced dissolution/absorption would be successful if there is saturable absorption. In addition, the effect of food intake on the TKI absorption as well as the gastric pH is complicated.
A further complexity in the dosing of TKIs is the concept of “therapeutic range.” For most medications, it is not clear what would be the ideal blood level of the TKI that would ensure optimal anti-cancer effects. The intent of most phase I drug trials is to determine the maximum-tolerated dose, not the minimally effective dose. As such, the recommended dose of a TKI might be higher than actually required. Only more complex studies could show the effect of a DDI on actual patient outcomes. In addition, studies of DDIs are highly dependent on the actual trial design. Such factors of when the GAS agent and TKI were given in relation to each other, the actual dose and schedule of the PPI or H2RA, and the duration of the study period all could contribute to conflicting results.
Sharma and associates reviewed SEERs and Medicare data of over 12, 000 patients between 2007 and 2012 who received a TKI (erlotinib, sunitinib, imatinib, dasatinib, lapatinib, sorafenib, or nilotinib) and who were diagnosed with lung cancer, renal cell cancer, CML, pancreatic cancer, or liver cancer. The primary exposure variable was the concurrent receipt of a TKI and a PPI with at least 30 days of overlap in the first 90 days of TKI treatment. In this study, the prevalence of overlapping use of TKI and PPI was a little over 22 percent of people. One of the outcome measures, death in 90 days, showed an adjusted hazard ratio of 1.16 (95% CI 1.05-1.28). In addition, there was an increased risk of death at 1 year with a hazard ratio of 1.10 (95% CI 1.04-1.17). The increased risk of death was particularly striking for patients with lung cancer receiving erlotinib. The authors concluded that PPI use with one of these TKIs impacted survival, and PPI used should be reassessed when TKIs are started (Cancer 2019;125:1155-1162).
Mir and associates performed a retrospective review of participants in two trials of pazopanib treatment in patients with soft tissue sarcoma. The first trial, EORTC 62043, was a single-arm study and the second, EORTC 62072, was a placebo controlled phase III trial. Of the 333 evaluable patients, nearly 18 percent received concurrent GAS agents for ≥ 80 percent of the treatment duration. The median PFS was shorter in those receiving GAS agents (2.8 months) compared to those who did not (4.6 months) [HR, 1.49; 95% CI 1.11-1.99; p=0.01]. In addition, a shorter overall survival was seen in those with concomitant GAS usage (8.0 months) compared to those without GAS agent usage (12.6 months [HR, 1.81; 95% CI 1.31-2.49; p=0.01]. To control for the possible confounder of presence of GI disease, they studied the participants in the placebo arm of the controlled trial, and there was no observable difference in survival between those who did take GAS agents and those that did not. The authors concluded that administration of long-term GAS medications was associated with shortened survival in these patients. (Clin Cancer Res 2019;25:1479-1485)
In caring for a patient already on a PPI or H2RA about to start an affected TKI, the clinician should start by determining the indication for the GAS agent, the length of treatment, and whether the person has attempted to stop the GAS agent in the past. When PPIs are abruptly discontinued, especially in those on a PPI for a long time, the gastric acid output may rebound significantly, due to hypergastrinemia. This often leads to rebound symptoms, making PPI discontinuation very difficult. To avoid this, one or more methods of deprescribing can be recommended.
One method is to step down to “on demand” or PRN dosing, in which the person takes the PPI only when significant symptoms (unresolved by OTC AAs) are present. Unfortunately, this could still lead to erratic TKI absorption.
Another two-step method is to first reduce the PPI dose to once daily administration of the lowest available dosage for a few days, then switch to a once daily H2RA dose. This would allow for some GAS therapy while initiating TKI treatment in most cases. There would still be a DDI, but this might be mitigated through us of the less potent H2RA.
The ideal method, if there's enough time, is the tapering and complete discontinuation of the PPI. One way is to 1) reduce the PPI dose to the lowest dosage given once daily for 1-2 weeks, 2) then change to every-other-day dosing for about 2 weeks, 3) then change to two times per week dosing for about 2 weeks, and 4) then discontinue. Residual symptoms can be managed with OTC AAs. Non-drug remedies for symptoms include elevation of the head of the bed, avoidance of meals for 2-3 hours prior to bedtime, and avoidance of dietary triggers of symptoms.
One of the first steps in managing patients about to start TKI treatment is to check for DDIs. A DDI check is only as good as the accuracy of the medication list, and patients should be specifically asked about the use of GAS agents. If a clinically significant DDI is found, then it should be determined if a deprescribing/step-down method would be appropriate based on the indication for GAS treatment. For example, if the patient has Zollinger-Ellison syndrome, then deprescribing would be inappropriate, and an alternate cancer treatment might be necessary, depending on the cancer diagnosis. However, this situation is rare and for most patients a deprescribing/step-down approach will likely be successful, allowing for TKI treatment to start.
Specific DDI management recommendations are found in Table 2, for those TKIs agents with likely clinically significant absorption changes when used with GAS medications.
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- Targownik L. Discontinuing long-term PPI therapy: Why, With Whom, and How? Am J Gastroenterol 2018; 113:529–528.
- van Leeuwen RWF, Jansman FGA, Hunfeld NG, et al. Tyrosine kinase inhibitors and proton pump inhibitors: an evaluation of treatment options. Clin Pharmacokinet 2017; 56:683–688.
LISA LOHR, PHARMD, BCOP, BCPS, is Clinical Oncology Specialist/MTM provider at Masonic Cancer Clinic Fairview/University of Minnesota Health, Minn.