Erlotinib:  Things to Consider
Jacob Schor, ND
Fellow American Board of Naturopathic Oncology

www. DenverNaturopathic.com       
March 25, 2012
 
The contents of this article are probably only relevant to a few dozen of you, so unless you have lung or pancreatic cancer, you have better things to do than read any further.
 
 
Erlotinib is a chemotherapy drug used in the treatment of advanced non-small cell lung cancer (NSCLC) and advanced pancreatic cancer. It is sold in the United States under the brand name Tarceva ®.        It works by inhibiting the epidermal growth factor receptor tyrosine kinase (HER1/EGFR).  It was approved for use in treating lung cancer in 2005.  While not brand new, it’s still new enough that we are still learning how best to work with patients using this drug to maximize the benefit the drug provides in fighting cancer.
 
It comes as no surprise that because this drug inhibit epidermal growth factor, it adversely skin related tissue that depend on this growth factor and commonly causes skin rashes and diarrhea as side effects.  Adverse liver reactions have also been reported and patients with compromised liver function should use this drug with caution.
It is interesting to note that there is a correlation between the severity of erlotinib caused skin rash and efficacy of the drug in treating non-small cell lung cancer.  A large clinical trial concluded: “Physicians and patients should view rash development as a positive event indicative of greater likelihood of clinical benefit.”  In other words, it’s a good sign when cancer patients get skin rashes from this drug, it means it is working against the cancer.  The severity of the rash is not directly correlated with blood concentrations of the drug. [1]
 
There are two main considerations at this point that need to be kept in mind for patients taking erlotinib.  Both absorption and breakdown of the drug are easily changed, and this will change the potential impact the drug has on the tumor.  The solubility of erlotinib changes significantly with pH.  As pH increases, the drug becomes less soluble and more difficult to absorb.  Thus with this drug,  acidity in the stomach greatly affects absorption.  The more acidic the stomach, the better the drug is absorbed.  Only about 60% of the drug is absorbed if taken while fasting when the stomach is not generating acid.  When taken with food almost 100% of the drug is absorbed.  Taking erlotinib with the commonly used antacids known as proton pump inhibitors (PPIs) such as omeprazole or Nexium, cuts absorption by about half. [2]    Most doctors or at least pharmacists will know about this interaction and advise the patient to be aware of this and usually suggest that they stop taking
 the
antacids.
 
As naturopathic oncologists we are aware of how complex regulating stomach pH can be.  Simply not taking a PPI does not guarantee that the stomach will generate acid.        We are aware that many patients who have been prescribed PPIs for gastro-esophageal reflux disease (GERD) were initially hypochlohydric, that is they produce inadequate stomach acid, and that this initial condition may have caused their reflux symptoms.  Giving a patient who is taking erlotinib a supplement such as betaine hydrochloride to increase the acidity of the stomach, or even herbs that stimulate acid production has the potential of significantly increasing drug absorption.        Anything that neutralizes stomach acidity will lower drug absorption.  We are not talking by small increments but halving or doubling absorption.
 
The other consideration that we should pay attention to is the breakdown of erlotinib in the body.  Erlotinib is metabolized and broken down by the CYP 450 enzyme pathway, in particular the CYP3A4 enzyme.  The breakdown products are excreted from the liver in the bile.
 
We are aware of a number of things that affect the production of CYP3A4 enzymes in the body and these in turn can change levels of erlotinib significantly.  One example is cigarette smoking.        Smoking increases production of CYP3A4 so the drug is metabolized and eliminated faster.  As smoking is a risk factor for both pancreatic cancer and certainly for lung cancer, it should not be a surprise to discover that many patients who have these cancers have been or are currently smokers. In nonsmokers that half life of the drug is between 9-12 hours, while in smokers it is only 4-5 hours. In smokers, the amount of drug that the tumor is exposed to is one half to one third that of non-smokers who take the same dose. 
 
From a naturopathic oncology perspective this is one more reason to make certain that our patients are not smoking.  If they have only recently stopped, we should realize that the drugs impact will possibly increase over time as their levels of CYP3A4 decrease.[3]
 
A number of drugs are known to have significant impacts on CYP3A4 production.  For example Ketoconazole is a potent CYP3A4 inhibitor and giving it to a patient taking erlotinib will increase the drug’s impact by 70%.  While the opposite effect is triggered by the antibiotic rifampicin used to treat lung conditions such as tuberculosis and which increases production of CYP3A4.  Taking this drug for a week before taking erlotinib will decrease erlotinib’s impact by as much as 80%.
 
This gets more complicated.  Erlotinib itself inactivates CYP3A4.  It does so in a time and concentration dependent manner.  Thus the longer one takes the drug and the higher doses one takes it in, the slower it is eliminated and the more impact it will have.  This effect may outweigh other considerations but at this point we don’t know whether we should advise decreasing doses over time as drug impact increases.  It does not appear that medical oncologists are making any changes in their dosing strategies in response to these pharmacokinetic changes that occur in patients over time.  These changes might explain a gradual increase in side effects. [4]
 
My eminent colleague, Dr Tim Birdsall, recently brought up several concerns to me about giving certain nutritional supplements to patients who are taking erlotinib.        He pointed out that green tea extracts could interfere with CYP3A4 action.  It seems that green tea extracts, can inhibit CYP3A4 and that, depending on the brand of green tea extract tested, this inhibitory effect can be as low 6% but as high as 90%.[6,7]     Thus depending on the brand, green tea may significantly increase the impact of erlotinib, at least initially.  Overtime, the erlotinib itself may inhibit the enzyme.
 
Dr Birdsall also brought up the possibility that curcumin might also inhibit the enzyme’s action and increase erlotinib’s impact.  But in this case the situation is far from clear. An experiment in which curcumin was given to rats along with docetaxel (another, but quite different, type of chemotherapy) found that co-administration significantly increased impact of the docetaxel and one possible explanation put forward is that it did this by inhibiting CYP3A4. [8]    A different paper looked specifically for interactions between curcumin and CYP3A4 and found no effect at all on the enzyme’s activity at any concentration of curcumin given.  [9]
 
Green tea’s ability to inhibit CYP3A4 and thus slow erlotinib’s breakdown may be why my good colleague Michael Uzick writes me that green tea and, “…genistein have been shown to enhance the effectiveness of tarceva.”  Dr. Uzick also suggests to his patients a combination of soy isolate genistein, vitamin D and hot sauna treatments, all for the sake of increasing impact of erlotinib treatment. [10]
 
From a naturopathic oncology perspective, our focus is to increase the tumor killing effect of this drug prescribed by medical oncologists.  Patients who are taking this drug are in dire circumstances and are likely to die.  Thus it behooves us to increase the drug’s effectiveness.  At this point there is no evidence that these supplements increase side effects experienced by patient but there is reason to hope that the drug will be more effective at stopping the cancer’s growth. 
 
Another colleague, Dan Rubin, tells me that he always gives an extract of Sea Buckthorn to patients taking erlotinib.  Sea Buckthorn is often of benefit to conditions that impact the skin and mucosal lining of the intestines and according to Dr. Rubin it counters some of the skin and intestinal symptoms brought on by taking erlotinib.  At this point no published evidence supports this specific use. 
 
Dr. Rubin also suggests that these patients take the hormone melatonin in large doses.        Melatonin also inhibits EGFR, the same growth factor that erlotinib blocks but melatonin does this through a different chemical mechanism. [11]   Dr. Rubin believes that the two together will have synergistic effect against the cancer.
 
No doubt with time there will be a growing body of evidence on which to base our recommendations to patients.  Keep in mind that this drug has been in use for about only seven years and only in a limited number of patients with advanced cancer that have typically not responded to first line treatments.
 
References:
 
1. Wacker B, Nagrani T, Weinberg J, Witt K, Clark G, Cagnoni PJ. Correlation between development of rash and efficacy in patients treated with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in two large phase III studies. Clin Cancer Res. 2007 Jul 1;13(13):3913-21.
Free full text
http://clincancerres.aacrjournals.org/content/13/13/3913.long
 
2. OSI Pharmaceuticals, and Genentech. Tarceva prescribing information 2009
 
3. Hamilton M, Wolf JL, Rusk J, Beard SE, Clark GM, Witt K, Cagnoni PJ.Effects of smoking on the pharmacokinetics of erlotinib. Clin Cancer Res. 2006 Apr 1;12(7 Pt 1):2166-71
Free full text http://clincancerres.aacrjournals.org/content/12/7/2166.long
 
4. Duckett DR, Cameron MD. Metabolism considerations for kinase inhibitors in cancer treatment. Expert Opin Drug Metab Toxicol. 2010 Oct;6(10):1175-93.  Free text:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2940961
 
5. Tim Birdsall, private communication via email 24 March 2012
 
6. Nishikawa M, Ariyoshi N, Kotani A, Ishii I, Nakamura H, Nakasa H, Ida M, Nakamura H, Kimura N, Kimura M, Hasegawa A, Kusu F, Ohmori S, Nakazawa K, Kitada M. Effects of continuous ingestion of green tea or grape seed extracts on the pharmacokinetics of midazolam. Drug Metab Pharmacokinet. 2004 Aug;19(4):280-9.
PMID: 15499196
 
6. Wanwimolruk S, Wong K, Wanwimolruk P. Variable inhibitory effect of different brands of commercial herbal supplements on human cytochrome P-450 CYP3A4. Drug Metabol Drug Interact. 2009;24(1):17-35. PMID: 19353999
7. Yan YD, Marasini N, Choi YK, Kim JO, Woo JS, Yong CS, Choi HG. Effect of dose and dosage interval on the oral bioavailability of docetaxel in combination with a curcumin self-emulsifying drug delivery system (SEDDS). Eur J Drug Metab Pharmacokinet. 2011 Dec 27. [Epub ahead of print] PMID: 22201019
 
8. Mach CM, Chen JH, Mosley SA, Kurzrock R, Smith JA. Evaluation of liposomal curcumin cytochrome p450 metabolism. Anticancer Res. 2010 Mar;30(3):811-4. PMID: 20393001
 
9. Michael Uzick. Oncanp Chat posting.
 
10. Blask DE, Sauer LA, Dauchy RT. Melatonin as a chronobiotic/anticancer agent: cellular, biochemical, and molecular mechanisms of action and their implications for circadian-based cancer therapy.  Curr Top Med Chem. 2002 Feb;2(2):113-32. PMID: 11899096
 
 
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