Can an Acidic Beverage Reduce Interactions Between Proton Pump Inhibitors and Erlotinib?

The past decade has been marked by the identification of multiple driver mutations that define new molecular subsets of non–small-cell lung cancer (NSCLC). This triggered the development of small-molecule tyrosine kinase inhibitors (TKIs), with a shift from intravenous to orally administered therapy, which is more flexible and convenient. Because TKIs are administered orally and generally have a narrow therapeutic window, the bioavailability and pharmacokinetics of these drugs are subject to interact with food or other drugs that may cause suboptimal dose levels. Most TKIs are weak bases, and the first step in making these agents bioavailable is dissolution, a frequent rate-limiting step of absorption. Dissolution begins in the stomach and depends on the fluid volume, gastric motility, and gastric pH. When the stomach pH is elevated (eg, after using an acid-reducing agent), there is a delay in the dissolution of epidermal growth factor receptor (EGFR)TKIs with a basic pKa (acid dissociation constant). Erlotinib has a reported basic pKa of 5.4 and achieves maximal solubility (0.4 mg/mL) in solutions with an acid pH of 2. The most common class of acid-reducing agents, proton pump inhibitors (PPIs), yield a median gastric pH . 5, which would be predicted to significantly reduce erlotinib dissolution and absorption (a 46% decrease in the median erlotinib area under the curve [AUC] with PPIs and a 33% decrease with H2 antagonists in healthy volunteers). 4-6 In North America and Western Europe, patients with cancer (20% to 55%) routinely use acid-reducing agents. Can the timing of the administration of the acid-reducing agent be amply separated from that of the antitumor therapy to avoid drug-drug interactions? This is a rational proposal for H2 antagonists. However, because of the prolonged duration of acid suppression with PPIs, sequence or scheduling changes of these agents may not effectively allow recovery of an acidic environment sufficient to promote erlotinib absorption. Thus, if patients must continue PPI treatment, a possible option could be temporary gastric reacidification with erlotinib administration, which may facilitate the dissolution, solubilization, and absorption of the treatment within the critical absorption window. The first proof of concept was demonstrated with the acidic beverage Coca-Cola (CC; The Coca-Cola Company, Atlanta, GA), which enhanced ketoconazole absorption (to approximately 65% of the mean) in the presence of omeprazole. These results inspired the article by van Leeuwen et althat accompanies this editorial. The authors hypothesized that an interaction between concurrent treatment with erlotinib and a PPI (esomeprazole 40 mg) could be reversed by taking erlotinib with the CC acidic beverage. Twenty-eight evaluable patients were analyzed. The mean erlotinib exposure in patients who used esomeprazole was significantly increased by the concomitant use of CC (mean AUC [0 to 12 h] increase, 39%; P 5 .004), whereas erlotinib exposure in patients who consumed CC instead of water without a PPI proved to be clinically irrelevant (mean AUC [0 to 12 h] increase, 9%; P 5 .03). This trial reinforces the well-known point of the key role of pH-dependent solubility in the absorption of erlotinib, but the results should be interpreted with caution given the interindividual variability in drug absorption that was observed. In fact, wide interval ranges (212% up to1136%) and (24% up to1199%) in the mean AUC and maximum serum concentration, respectively, were observed in patients exposed to erlotinib and esomeprazole after CC compared with water intake. This suggests that other factors, such as gastric emptying rates, optimal volume of beverage, and potential esomeprazole-induced inhibition of drug transporters, may also be instrumental in influencing drug absorption. Some patients may suffer from the absence or low production of hydrochloric stomach acid or Zollinger-Ellison syndrome, which can also explain interpatient heterogeneity. As the study by van Leeuween et al suggests, we cannot eliminate patient noncompliance, but this is unlikely because patients were closely followed. The caffeine component of such a beverage might potentially interact with erlotinib pharmacokinetics through interactions at the cytochrome (CYP) 1A2 enzyme level, but this study states that this is unlikely. However, intragastric pH was not measured in this population to underpin one of the hypotheses that could provide us additional data on the real effect of CC intake. The use of this strategy to enhance erlotinib absorption will have to be closely monitored for therapeutic effectiveness because it may not work adequately for every patient. Similarly, gefitinib exhibits diminished solubility, and therefore, a benefit close to that obtained with erlotinib might be predicted, but we cannot recommend it because there are no data on gefitinib in this study. Furthermore, this strategy might not be relevant for afatinib because this TKI is highly soluble throughout the physiologic pH range of 1 to 7.5; therefore, interactions with acid-reducing agents are not expected. Another scenario would be to increase the dose of erlotinib and thus improve drug exposure. This option was not tested in the