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Introduction: Erlotinib’s gastrointestinal solubility and absorption are decreased by proton pump inhibitors (PPIs). Since erlotinib is a lipophilic drug, we hypothesized that concomitant intake with the fatty beverage milk may be a feasible way to increase erlotinib uptake. We performed a two-period, randomized, crossover study to investigate the influence of cow’s milk with 3.9% fat on the exposure of erlotinib with and without the PPI esomeprazole in patients with non-small cell lung cancer (NSCLC). The effect of esomeprazole was studied in an additional intrapatient comparison. Method: Pharmacokinetic sampling was performed on days 7 and 14 during 24 consecutive hours. During the 7 days prior to pharmacokinetic sampling, erlotinib was taken daily with 250 mL of either water or milk. In the PPI arm, esomeprazole (40 mg once daily 3 h prior to erlotinib) was taken for 3 days. Results: Erlotinib area under the curve from time zero to 24 h (AUC24) did not significantly change when administered with milk, compared with water, in both non-PPI users (n = 14; − 3%; 95% confidence interval [CI] − 12 to 8%; p = 0.57) and patients who used esomeprazole (n = 15; 0%; 95% CI − 15 to 17%; p = 0.95). Esomeprazole decreased erlotinib AUC24 by 47% (n = 9; 95% CI − 57 to − 34%; p < 0.001) and Cmax by 56% (95% CI − 64 to − 46%; p < 0.001). No differences in toxicities were observed between milk and water. Conclusion: Milk with 3.9% fat has no effect on the exposure to erlotinib in NSCLC patients, independent of PPI use. The combination with milk is safe and well tolerated. Concomitant esomeprazole treatment strongly decreased both erlotinib AUC24 and Cmax and should be avoided if possible.

Background Erlotinib is an oral EGFR tyrosine kinase inhibitor used in NSCLC. Drug absorption depends largely on its solubility in the stomach and gastrointestinal tract. Potentially, erlotinib -as lipophilic drug- is ought to dissolve better in a fatty drink such as full cow’s milk compared to water. Gastric acid reducing agents like proton pump inhibitors (PPIs) decrease the solubility and thus the uptake of erlotinib. Hence, we hypothesized that administration of cow’s milk may be a feasible way to increase erlotinib uptake (both with or without PPI co-administration). We performed a two-period randomized cross-over study to investigate the influence of full cow’s milk compared to water on the exposure of erlotinib with and without the PPI esomeprazole in NSCLC patients. Methods During 24 hours, pharmacokinetic sampling (PK) was performed at days 7 and 14. In the 7 days prior to PK, erlotinib was taken daily with either 250 mL water or full cow’s milk. Patients were assigned whether to receive erlotinib with (arm A) or without esomeprazole (40mg qd; arm B) 3 hours prior to erlotinib intake starting 3 days prior to PK. Primary endpoint was change in geometric mean for the area under the curve (AUC0-24h). A linear mixed model was used to analyze AUCs and maximal concentration (Cmax). Results Twelve of the 20 patients used erlotinib without a PPI. Erlotinib AUC0-24h decreased non-significantly with 5% (95%CI: -14 to + 5%; P = 0.3) when administered with milk compared to water in the non-PPI patients. Also in the 8 patients who did use esomeprazole, erlotinib AUC0-24h did not differ between intake with water or milk (95%CI: -29 to + 40%; P = 1.0). Cmax did not differ in non-PPI users (P = 0.6) and in PPI users (P = 0.9). However, esomeprazole decreased erlotinib AUC0-24h with 48% (95%CI: -61 to -31%; P Conclusions Exposure to erlotinib did not change by erlotinib intake with milk compared to water in both the PPI and non-PPI patients. Therefore, the combination with milk instead of water is safe and well tolerated. Esomeprazole strongly decreased both erlotinib AUC0-24h and Cmax, and should be avoided if possible. Clinical trial identification NTR 6148. Legal entity responsible for the study Ron H.J. Mathijssen. Funding Roche. Disclosure R.H. Mathijssen: Research grant / Funding (institution): Roche; Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas; Research grant / Funding (institution): Boehringer; Research grant / Funding (institution): Cristal Therapeutics; Honoraria (self), Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pamgene; Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Research grant / Funding (institution): Sanofi; Honoraria (self): Servier; Research grant / Funding (institution): Bayer. All other authors have declared no conflicts of interest.

Purpose: Pharmacokinetics of docetaxel can be measured in vivo using positron emission tomography (PET) and a microdose of radiolabeled docetaxel ([11C]docetaxel). The objective of this study was to investigate whether a [11C]docetaxel PET microdosing study could predict tumor uptake of therapeutic doses of docetaxel. Experimental Design: Docetaxel-naïve lung cancer patients underwent 2 [11C]docetaxel PET scans; one after bolus injection of [11C]docetaxel and another during combined infusion of [11C]docetaxel and a therapeutic dose of docetaxel (75 mg·m−2). Compartmental and spectral analyses were used to quantify [11C]docetaxel tumor kinetics. [11C]docetaxel PET measurements were used to estimate the area under the curve (AUC) of docetaxel in tumors. Tumor response was evaluated using computed tomography scans. Results: Net rates of influx (Ki) of [11C]docetaxel in tumors were comparable during microdosing and therapeutic scans. [11C]docetaxel AUCTumor during the therapeutic scan could be predicted reliably using an impulse response function derived from the microdosing scan together with the plasma curve of [11C]docetaxel during the therapeutic scan. At 90 minutes, the accumulated amount of docetaxel in tumors was less than 1% of the total infused dose of docetaxel. [11C]docetaxel Ki derived from the microdosing scan correlated with AUCTumor of docetaxel (Spearman ρ = 0.715; P = 0.004) during the therapeutic scan and with tumor response to docetaxel therapy (Spearman ρ = −0.800; P = 0.010). Conclusions: Microdosing data of [11C]docetaxel PET can be used to predict tumor uptake of docetaxel during chemotherapy. The present study provides a framework for investigating the PET microdosing concept for radiolabeled anticancer drugs in patients. Clin Cancer Res; 19(15); 4163–73. ©2013 AACR.