Influence of Cow’s Milk and Esomeprazole on the Absorption of Erlotinib: A Randomized, Crossover Pharmacokinetic Study in Lung Cancer Patients

Erlotinib is a tyrosine kinase inhibitor (TKI) registered for the treatment of epidermal growth factor receptor (EGFR)-mutated metastatic non-small cell lung cancer (NSCLC) [1, 2]. It is indicated in combination with gemcitabine as first-line therapy for unresectable or metastatic pancreatic cancer [1]. Erlotinib is orally administered on a daily basis at a dose of 150 and 100 mg once daily for NSCLC and pancreatic cancer, respectively. Intra- and interpatient variability differs significantly due to interactions with food [3], concomitant medication [4], and lifestyle factors (i.e. smoking) [5, 6].

The bioavailability of erlotinib largely depends on its solubility in the stomach and passive diffusion and probable active cellular transport in the gastrointestinal tract [7]. Optimal drug absorption is reached at a physiologically low intragastric pH (i.e. pH value of 1), since erlotinib is then protonized and is thus better soluble [8]. However, various acid-reducing drugs, including histamine-2 receptor antagonists (e.g. ranitidine) and proton pump inhibitors (PPIs; e.g. omeprazole) may lead to a 40–50% decrease in erlotinib absorption due to an increase in intragastric pH [9]. It has been previously demonstrated that this impaired systemic exposure to erlotinib can be corrected when administered in combination with the acidic beverage cola [10]. However, daily intake of acidic and highly caloric beverages such as cola or orange juice has disadvantages, such as dental problems, disrupted bone mineral composition, and weight gain [11]. We hypothesized that a healthier way to enhance erlotinib bioavailability could be by making use of the effects of other food components. The exposure of erlotinib is increased 33–66% when administered concomitantly with a high-fat meal [3]. We explored this potentially positive food effect as a proof-of-principle by optimizing erlotinib absorption in the presence of a beverage containing fat. In the past, milk-based drug formulations have shown to be equally effective compared with standard formulations in terms of solubility and dispersion [12]. Milk is consumed worldwide by billions of people. It is a healthy beverage that contains essential proteins, vitamins and minerals (e.g. calcium and phosphorus). Cow’s milk accounts for more than 80% of the global milk production [13].

This is the first study that investigates the effects of erlotinib administered concomitantly with high-fat whole cow’s milk compared with water. In addition, a direct intrapatient comparison to study the effects of esomeprazole on the systemic exposure of erlotinib has never been made. Therefore, we also explored the potential drug–drug interaction of esomeprazole use on the absorption of erlotinib.

This study reports the absence of a pharmacokinetic effect of cow’s milk with 3.9% fat on exposure to erlotinib in NSCLC patients, independent of PPI use. Additionally, this study showed a decrease in erlotinib AUC₂₄ of almost 50% and a decrease in C_max of more than 50% when erlotinib was administered 3 h after esomeprazole intake.

A possible explanation for the lack of effect of milk on erlotinib exposure is that the 3.9% fat content of cow’s milk is not high enough to affect absorption. In absolute values, patients were administered 9.75 g (250 mL × 3.9%) of fat from milk. This is relatively low in comparison with a high-fat meal, which consists of 500–600 kilocalories of pure fat [3] (c.q. 56–67 g). The effect of a high-fat meal on erlotinib disposition ranges from a 33% AUC increase when taken 2 h after erlotinib administration [22], to a 66% increase in AUC of erlotinib when food and drug are taken concomitantly [23]. In theory, the negative effect of esomeprazole of almost 50% decrease in AUC₂₄ could be overcome by coadministration of a high-fat meal.

An additional reported effect of increasing the bioavailability of erlotinib with coadministration of a high-fat meal was a decrease in interpatient variability [3]. The benefits of less interpatient variability are a more predictable effectivity and toxicity on a large scale, since more patients will be administered within the therapeutic window. Our data show that milk also reduced interpatient variability, especially in the PPI arm (Table 2). Although, on average, bioavailability did not change, the lower interpatient variability would be an argument in favor of erlotinib administration with milk instead of water.

Another reason why erlotinib absorption was not affected by milk could be that the strong pH buffering capacity of milk [12] prevents the intragastric pH from decreasing. Hence, the beneficial effect of the milk’s fat is counteracted by switching erlotinib to its less soluble, non-ionized form, which is not an optimal condition for transluminal transportation across gastrointestinal cells. Furthermore, there is no evidence of milk interacting with drug transporters or hepatic cytochrome P450 isoenzymes.

Average milk consists of 3–4% fat [13]. Since we used cow’s milk with the highest fat content (3.9%) commercially available, it is unlikely that lighter variants of cow’s milk would have a higher effect on the bioavailability of erlotinib. Nevertheless, cow’s milk may be of interest for increasing systemic exposure of TKIs with vaster food effects, i.e. lapatinib (up to 325% and 200% AUC increase with a high- and low-fat meal, respectively) [3]. In line with milk, yoghurt (0.4% fat [24]) is not expected to interact with erlotinib absorption and could also be considered safe. Coadministration with yoghurt was previously studied and was considered safe for the TKI nilotinib [3, 25].

Moreover, for the first time, we conducted an intrapatient comparison on the effects of esomeprazole on the AUC₂₄ and C_max of erlotinib, which is in line with previous research with erlotinib and omeprazole [9]. We hence warn patients and prescribers of this possible harmful interaction, which could lead to therapy ineffectiveness. Potential solutions for patients who are dependent on PPI use may be a delayed PPI intake until erlotinib is fully absorbed or by taking erlotinib concomitantly with cola [10]. Albeit practical, the most feasible solution is a critical reconsideration of the need to prescribe a PPI and discontinuation of the PPI where possible.

Another way to increase the aqueous solubility, and therewith bioavailability, of erlotinib could be to improve its formulation [26]. A phospholipid formulation showed an improved pharmacokinetic profile in rats [27]. Before this new formulation could be considered to be implemented in clinical practice, further research should first be conducted to determine its possible benefits and deficits.

Furthermore, the absence of a milk effect on erlotinib exposure is probably also the reason why this study found no differences in patient-reported toxicity. This is not surprising as, for erlotinib, the plasma concentration is correlated with the occurrence of the most prevalent adverse effects of skin rash and diarrhea [28]. Erlotinib intake with milk is just as safe as intake with water, and could thus be advised to patients as an alternative for administration with water, for example to mitigate mild gastrointestinal reflux complaints or as the patient’s preference.

Interestingly, although esomeprazole reduced erlotinib exposure by half, patients did not report less toxicity; however, the 3-day period during which patients had to take esomeprazole was most likely too short to have a noticeable effect on toxicity. When esomeprazole is taken for a longer period of time, the chronic decrease in erlotinib exposure could have a more distinctive effect of less toxicity.

Whole cow’s milk with 3.9% fat has no clinically relevant effects on the exposure of erlotinib in NSCLC patients, independent of PPI use. The combination with milk instead of water is safe and well tolerated, and may be a good alternative for some patients. Meanwhile, the use of esomeprazole 3 h prior to erlotinib intake strongly decreased both erlotinib AUC₂₄ and C_max, and should be avoided if possible.