An evaluation of the possible interaction of gastric acid suppressing medication and the EGFR tyrosine kinase inhibitor erlotinib☆
Introduction
Erlotinib is a reversible tyrosine kinase inhibitor (TKI) of the epidermal growth factor receptor (EGFR) with efficacy in non-small cell lung cancer (NSCLC) and pancreatic cancer [1], [2]. The NCIC Clinical Trials Group (CTG) BR.21 clinical trial demonstrated erlotinib improved the overall survival (OS) and quality of life of participants with advanced NSCLC, after standard chemotherapy had failed, compared with placebo (HR = 0.70, p < 0.001) [1]. Plasma concentrations of erlotinib may be an important factor in determining the degree of clinical benefit from the treatment. CYP1A isoforms, the enzymes responsible for the metabolism of erlotinib, are induced by cigarette smoke [1]. For example, active smokers in BR.21 had approximately half the median trough concentrations of erlotinib at steady state compared to those who were not actively smoking while on trial. In addition, non-active smokers had a higher incidence of adverse events, particularly rash and diarrhea, than active smokers, likely secondary to greater erlotinib exposure [3]. Further, erlotinib is primarily metabolized by CYP3A4; therefore, compounds which increase CYP3A4 activity potentially can reduce erlotinib plasma levels and its therapeutic activity [4]. This suggests that factors that can reduce plasma concentrations of the drug may result in reduced clinical benefit for patients [1].
Erlotinib requires an acidic environment for maximal absorption and its solubility in aqueous solution is dependent on the protonation of the secondary amine group within the molecule. The amine group has a pKa of 5.42 and maximal absorption occurs at a pH of 2.0 [4]. As a result, gastric acid suppressing medications (AS), which increase gastric pH, have the potential to affect the bioavailability of erlotinib. In healthy volunteers studies, the concurrent administration of the proton pump inhibitor (PPI) omeprazole or the histamine 2 receptor antagonist (H2RA) ranitidine with erlotinib reduced both the AUC and Cmax of erlotinib compared with erlotinib administered alone (AUC decrease: omeprazole 46% and ranitidine 33%; Cmax decrease: omeprazole 61% and ranitidine 54% reduction) [4]. As a result of these drug interaction studies, the erlotinib product monograph recommends that PPIs should not be taken concurrently with erlotinib since they provide continuous gastric acid suppression [4]. The product monograph further recommends that if AS medications are required, H2RAs should be considered instead due to their reversible effect and that they should be administered in a staggered fashion 10 h before and 2 h after the erlotinib dose to allow for erlotinib absorption [4]. In contrast, a single patient report by Ter Heine and colleagues found that erlotinib levels were only significantly decreased during high dose intravenous administration of pantoprazole and returned to within the normal range when switching to high dose oral administration [5].
Currently, there are no data reported in the literature documenting the impact of the erlotinib – PPIs/H2RAs drug interaction on the outcome of participants with advanced NSCLC who are treated with erlotinib. The NCIC CTG BR.21 trial was conducted prior to the recommendation regarding the potential interaction with PPIs and H2Ras and did not restrict the use of these drugs. We evaluated the impact of the concurrent use of PPIs/H2RA with erlotinib on pharmacokinetics, adverse events, progression free survival (PFS) and OS in participants with advanced NSCLC.
Section snippets
Participants
BR.21 was an international, double-blind, randomized phase III clinical trial of erlotinib vs. placebo in participants with advanced or metastatic NSCLC after standard chemotherapy had failed [1]. A total of 731 participants were randomized in a 2:1 ratio to either erlotinib (150 mg daily) or placebo. Data on reported concomitant medication use was collected at baseline and during treatment, including start and stop dates. As per trial protocol, plasma was collected for PK analysis at baseline,
Patient population
Fig. 1 summarizes the number of participants treated with erlotinib or placebo by AS usage; 190 of 485 participants (39%) on the erlotinib arm and 75 of 242 (31%) participants on placebo were recorded as utilizing AS medications at one point during the trial. Baseline patient characteristics for the AS users and AS non-users cohorts were similar (Table 1). Eighty-one participants on erlotinib and 38 participants on placebo were taking AS medications at the time of randomization; of these, only
Discussion
The usage of PPIs and H2RAs is common; for example, it is estimated that in 2007–2008, 21.1% of Canadians were prescribed PPIs and 8.8% H2RAs [7]. Based on our analysis, it can be estimated that a similar proportion of participants with advanced NSCLC take PPIs/H2RAs. This possibly may lower the efficacy of erlotinib as AS suppressive medications have the potential to reduce the absorption of the medication. This potential interaction is not restricted to erlotinib. For example, dasatinib [AUC]
Conflict of interest
The authors would like to report no relevant conflicts of interest for this manuscript.
Acknowledgements
J.F. Hilton is a NCIC CTG drug development fellow, supported by grants from the Terry Fox Foundation Training Program in Transdisciplinary Cancer Research in partnership with CIHR and AstraZeneca Canada. He is also a recipient of the University of Ottawa Postgraduate Training Fellowship.
The NCIC Clinical Trials Group is funded by a grant from the Canadian Cancer Society Research Institute.
P. Bradbury is a recipient of a Cancer Care Ontario Research Chair in Experimental Therapeutics.
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Sites of presentation: Poster Discussion Session (Abstract #7523), Metastatic NSCLC Session, ASCO Annual Meeting, 2011.