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Acid-reducing medications should be used cautiously when combined with erlotinib
Asif Siddiqui
Erlotinib, an epidermal growth factor receptor inhibitor, is subject to multiple drug-drug interactions.
Erlotinib (Tarceva; Genentech, Astellas) is approved for treatment of advanced or metastatic non–small cell lung cancer, as well as combined with gemcitabine for locally advanced, unresectable or metastatic pancreatic cancer.
Due to metabolism of erlotinib via the cytochrome P450 (CYP) isoenzyme 3A4, and to a lesser extent 1A2, 3A4 inhibitors and inducers are primarily responsible for alterations in drug exposure. Erlotinib absorption also can alter drug exposure.
Medications that increase the pH of the upper gastrointestinal (GI) tract can reduce erlotinib solubility, thereby reducing the bioavailability of erlotinib. Medications that can increase upper GI tract pH include proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs).
The product monograph for erlotinib warns that the co-administration of erlotinib with omeprazole (Prilosec, AstraZeneca), a PPI, may decrease erlotinib exposure — based on area under the curve (AUC) — by 46%. There is limited published literature to aid in managing this drug-drug interaction.
The only published literature is limited to pharmacokinetic data. Some of that literature — along with a brief review of pharmacokinetic data for PPIs, H2RAs and erlotinib — will be presented below to aid clinical decision making regarding these drug-drug interactions.
Erlotinib pharmacokinetics
There are two primary factors that affect solubility and absorption of erlotinib.
Erlotinib bioavailability is roughly 60% when taken on an empty stomach. Bioavailability increases and reaches nearly 100% when taken with food. The solubility of erlotinib is inversely proportional to gastric pH. A pH of less than 5 is ideal for erlotinib solubility; as pH increases, erlotinib solubility decreases.
Medications that raise gastric pH thereby can decrease erlotinib solubility and reduce AUC and maximum plasma concentrations (Cmax). In the case of omeprazole, erlotinib AUC decreased by 46% and Cmax decreased by 61%. The clinical significance of a reduction in AUC and/or Cmax is currently unknown, as most available literature describes pharmacokinetics of this drug-drug interaction and not clinical efficacy.
Proton pump inhibitors
Omeprazole, the only PPI mentioned in the erlotinib product monograph, is indicated for the treatment of duodenal and gastric ulcers, as well as the treatment for gastroesophageal reflux disease (GERD).
The mechanism of action for omeprazole is based on gastric acid suppression by inhibition of H+/K+ ATPase enzyme system in gastric parietal cells. Onset of action of antisecretory activity of omeprazole is 1 to 2 hours. Despite having a fairly short plasma half-life of less than 1 hour, duration of inhibition can last up to 72 hours.
Intragastric acidity over 24 hours decreases by nearly 100% with multiple daily doses of either 20 mg or 40 mg omeprazole. Upon discontinuation, normal secretory activity returns within 3 to 5 days. The long duration of action is similar in other PPIs. Esomeprazole (Nexium, AstraZeneca), for example, maintains intragastric pH >4 for 12 to 17 hours.
As mentioned, there are limited published data on the effects of acid-suppressing medication on erlotinib exposure.
In one case, published in 2010 in the British Journal of Clinical Pharmacology, Rob ter Heine, PhD, PharmD, of the department of pharmacy at Meander Medical Center in the Netherlands, and colleagues monitored erlotinib trough concentrations 2 days before the IV administration of pantoprazole, for 2 days while receiving treatment with continuous IV pantoprazole at 8 mg/hour, and for 2 days after initiation of oral pantoprazole dosed at 40 mg twice daily.
The minimal required trough concentration for effective EGFR inhibition with erlotinib is 0.5 mg/L. For the 2 days before the initiation of continuous IV pantoprazole, erlotinib trough concentrations were therapeutic at 0.96 mg/L and 0.97 mg/L. Erlotinib concentrations decreased substantially during the 2 days concentrations were monitored while the patient was treated with continuous IV pantoprazole. Erlotinib trough concentrations were measured as low as 0.52 mg/L and as subtherapeutic as 0.41 mg/L.
When treatment was changed to oral pantoprazole, plasma trough concentrations returned to therapeutic levels at 0.87 mg/L and 0.96 mg/L. Researchers said the low and subtherapeutic erlotinib plasma concentrations were explained by the fact that acid secretion was completely inhibited with high-dose continuous IV pantoprazole; however, there was still some degree of acid secretion with oral pantoprazole resulting in therapeutic plasma concentrations.
Histamine-2 receptor antagonists
H2RAs, such as ranitidine, inhibit binding of histamine-2 receptors of gastric parietal cells, reducing gastric acid secretion. Ranitidine also reduces gastric acid secretion in response to stimuli such as food, caffeine or insulin. Ranitidine has a half-life of 2 to 3 hours and a duration of action of roughly 8 to 12 hours.
According to the erlotinib product monograph, administration of erlotinib 2 hours after an oral ranitidine dose of 300 mg resulted in a 33% reduction in erlotinib exposure and a 54% decrease in Cmax. When erlotinib was administered with ranitidine at 150 mg orally twice daily — 10 hours after the previous evening dose and 2 hours before morning dose — erlotinib AUC decreased by 15% and Cmax by 17%.
Cimetidine (Tagamet, Prestige), another H2RA, has a shorter duration of action than ranitidine and results in an 80% reduction in gastric acid secretion for 4 to 5 hours after a 300-mg oral dose. The use of cimetidine with erlotinib has its limitations, as cimetidine can be a potent CYP3A4 inhibitor, the primary pathway for erlotinib metabolism.
Discussion
Acid-reducing medications are among some of the most commonly used medications by patients, including those with cancer. Guidance is needed to help clinicians make decisions when they begin erlotinib treatment for patients who also are being treated with acid-suppressing medications.
A patient’s medication list should be reviewed to identify potential drug-drug interactions.
PPIs are commonly prescribed to treat GERD, as well as for treatment of Helicobacter pylori-related peptic ulcers. Treatment with PPIs, such as omeprazole, leads to extended periods of elevated pH with repeated daily doses. Levels typically exceed the pH of 5 necessary for optimal solubility for EGFR inhibition.
Due to this extended antisecretory period, separation of PPIs and erlotinib may not eliminate this drug-drug interaction. One class of acid-reducing medications that may be an option is that of H2RAs, which include ranitidine, cimetidine, famotidine and nizatidine. Some H2RAs — such as CYP3A4 inhibitors — have potential drug-drug interactions, which limit their use with erlotinib.
One benefit of H2RAs is their shorter duration of action. Ranitidine can be considered an option if used in a staggered manner with erlotinib. When administered 10 hours after or 2 hours before erlotinib, treatment with ranitidine led to only a minor reduction in erlotinib AUC and Cmax.
Antacids — such as those that contain calcium carbonate, sodium bicarbonate, magnesium or aluminum salts — typically do not raise gastric pH above 5 for prolonged periods and can be considered for treatment of occasional gastric reflux.
Smoking cigarettes while on treatment with erlotinib can have a similar reduction in erlotinib exposure, reducing AUC by 35.9% and Cmax by 65.2%. The erlotinib product monograph recommends a cautious dose increase, not to exceed 300 mg daily, as a method to overcome reduced drug exposure.
There are limited data to support safety and efficacy of increased erlotinib doses beyond 14 days. Increasing the dose above 150 mg daily may be one pathway for overcoming the drug interaction with acid-reducing medications; however, more research is needed to elucidate safety and efficacy.
Conclusion
When considering which treatment pathway to follow, patients should be evaluated for the appropriateness of acid-reducing medications.
If treatment with acid-reducing medications is warranted, consideration should be given to avoiding PPIs, as the risk of reduced erlotinib exposure may not outweigh its benefit.
H2RAs may be an option, as they have a shorter duration of action and can be successfully separated from erlotinib; however, some members of this class run the risk of having other drug-drug interactions with erlotinib and should be used cautiously.
References:
Duong S. J Oncol Pharm Pract. 2011;17:448-452.
Tarceva [package insert]. South San Francisco, CA: Genentech USA Inc.; 2012. Available at: www.gene.com/gene/products/information/pdf/tarceva-prescribing.pdf. Accessed on Nov. 27, 2012.
ter Heine R. Br J Clin Pharmacol. 2010;70:908-911.
For more information:
Asif Siddiqui, PharmD, BCOP, is a clinical pharmacy specialist in thoracic/head and neck medical oncology at The University of Texas MD Anderson Cancer Center. He can be reached at The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Box 377, Houston, TX 77030; email: asiddiqui@mdanderson.org.
Disclosure: Siddiqui reports no relevant financial disclosures.