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Dr. Jack West is a medical oncologist and thoracic oncology specialist, and Executive Director of Employer Services at the City of Hope Comprehensive Cancer Center in Duarte, CA.

EGFR inhibitors (Tarceva, Iressa) and Stomach Acid
Thu, 05/24/2007 - 21:21

Please Note: New Treatments Have Emerged Since this Original Post
Author
Howard (Jack) West, MD, Associate Clinical Professor, Medical Oncology, Executive Director, Employer Services, Founder, President and CEO of GRACE

Several members have raised questions in the last several weeks around the question of whether antacids like garden variety Rolaids or Tums, a class of drugs called histamine H2 blockers like zantac and tagamet, and also proton pump inhibitors (PPIs) like prilosec (the "magic purple pill"), protonix, nexium, etc. that effectively shut down stomach acid may actually be problematic if taken in combination with Iressa or Tarceva (I'm going to focus primarily on Tarceva here, since that's the drug marketed in the US right now). This issue isn't one that has been highlighted in the general research and teaching about these oral agents. We do know that absorption is variable, but the reason it is recommended that they be taken on an empty stomach is that it's more predictable in that setting. Taking these agents with food tends to increase absorption, but unpredictably, so the best way to have a good idea of what's going into the body is to take the recommended amount (or a dose reduction, as needed) on an empty stomach. It's certainly understandable that the absorption from the stomach and gastrointestinal tract be moderated in part by stomach acid or lack thereof, since it's the job of stomach acid to help digest food (it's not just to cause heartburn), but there has never been any instruction on having antacids and/or PPIs be considered contra-indicated medicines (advised to not be taken at the same time). In fact, the Iressa package insert does mention that zantac and sodium bocarbonate (antacids), given to keep the pH above 5 (outside of the highly acidic range, which is the low numbers like 1-2), reduce Iressa absorption by 44% in one of the studies by the manufacturer (AstraZeneca). Member NeilB was kind enough to e-mail me this link to a chart in a summary article about the EGFR inhibitors, which notes some of the key drug interactions observed with EGFR tyrosine kinase inhibitors like Iressa and Tarceva. Another official document summarizing extensive pharmacologic information on Tarceva tablets (here) also documents that tarceva absorption appears to be diminished in the absence of an acidic stomach environment and suggests that "caution should be exercised when these medicinal products are prescribed with erlotinib" (Tarceva) (page 19 of this pdf document).

Unfortunately, while I can't exactly call this a state secret, this potentially important issue hasn't been highlighted at all. Part of the issue is that nobody has produced any evidence yet that it's associated with worse outcomes. The big trials with Iressa and Tarceva didn't restrict drugs for gastro-esophageal reflux disease (GERD, a fancy diagnostic term for heartburn), so the survival benefits of tarceva in the Br.21 trial, for example (abstract here, in case you missed it the first 25 times it's appeared in a post) were shown in a general population regardless of whether people took zantac or prilosec or whatever. Ideally, this would give us the opportunity to look back at the patient files, see who was taking drugs that inhibit stomach acid production, and see if those patients had a lower response rate and less of a survival benefit compared with a placebo than the patients who weren't on these -- these trials routinely monitor the medications participants are on during treatment. So I asked a former colleague from medical training who now works at Genentech (which co-markets Tarceva with OSI Pharmaceuticals, who actually developed the drug and ran the BR.21 Study with the National Cancer Institute of Canada) about what they know about Tarceva and stomach acid. She was kind enough to get back to me to report that following the approval of Tarceva in the European Union, there has been a formal request to do a "post-marketing study" by Roche, which markets Tarceva outside of the US (Genentech in the US only), to assess the interaction between antacids, H2 blockers, or PPIs and Tarceva. "The final study is being completed as we speak", she tells me, and it will be included in the next version of official Tarceva documentation to regulatory bodies like the FDA, at which point it should become publically available. She also informed me that, unfortunately, they couldn't uncover enough good data on these drugs in BR.21 to learn anything conclusive. It's clear that this information would be helpful for everyone. Any patient would want to know if their over-the-counter or prescription medication for heartburn is reducing the potential effectiveness of their cancer medication. As doctors, we'd want to provide good advice to give our patients the best chance to benefit from these treatments. And the companies selling EGFR inhibitors would definitely want to not shortchange their potentially favorable results by under-dosing some patients because they were taking medications that reduced the uptake of tarceva or iressa. Perhaps we could improve the response rate by 5 or 10%, and improve the survival benefit by a few weeks on average, by optimizing the right amount getting into the bloodstream. There are lots of variables here -- we use the same dose for a frail, thin 80 year old never-smoking woman and a 275 pound, 52 year old chain-smoking man. I can only hope that we can improve our results by refining our use of these tools as we learn more about these other potentially important variables like absorption and metabolism rates (recall my prior post on current smokers and tarceva). Before people ask, let me say that I really don't know whether there would be any value in re-trying tarceva in someone who progressed on it while taking zantac or nexium, and I don't think anyone knows that right now. To me, it's not a tempting prospect in someone who progressed quickly after their first couple of months on it, but it would be quite tempting to restart in someone who responded for 6 months, then started a PPI, and had slow progression of their disease after that. And I suspect there are a lot of patients in between. I hope to report more information soon. In the meantime, thanks to everyone who raised this issue, because it's been relayed to the companies as a high priority to disseminate this kind of information in teaching for doctors offices and directly to patients.

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