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

Abstract

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 (AUC 24) 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 AUC 24 by 47% (n = 9; 95% CI − 57 to − 34%; p < 0.001) and C max 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 AUC 24 and C max and should be avoided if possible.

Plasma Predictive Features in Treating EGFR-Mutated Non-Small Cell Lung Cancer

“…All samples were analyzed with validated liquid chromatography-tandem mass spectrometric assays [41,42]. Additionally, samples from patients included in this study who also participated in a previous pharmacokinetic study with erlotinib were integrated [43]. Time between last intake and blood withdrawal was calculated with the patient reporting time of last intake.…”

Feasibility of Extrapolating Randomly Taken Plasma Samples to Trough Levels for Therapeutic Drug Monitoring Purposes of Small Molecule Kinase Inhibitors

“…In total 2105 blood samples with corresponding trough samples were analyzed. Samples were taken from patients participating in nine different prospective pharmacokinetic studies (Table 1) [17][18][19][20][21][22][23][24][25]. Table 2 presents per drug pharmacokinetic parameters used, analyzed cohorts, relative differences and 90% confidence interval (90%CI) of the relative difference.…”

“…A long-term prospective population pharmacokinetic study on imatinib plasma concentrations in GIST patients [19] Environmental and genetic factors affecting transport of imatinib by OATP1A2 [18] Predictive Value of CYP3A and ABCB1 Phenotyping Probes for the Pharmacokinetics of Sunitinib: the ClearSun Study [22] Relationship Between Sunitinib Pharmacokinetics and Administration Time: Preclinical and Clinical Evidence [21] Influence of the Acidic Beverage Cola on the Absorption of Erlotinib in Patients With Non-Small-Cell Lung Cancer [23] Influence of Cow's Milk and Esomeprazole on the Absorption of Erlotinib: A Randomized, Crossover Pharmacokinetic Study in Lung Cancer Patients [24] Influence of Probenecid on the Pharmacokinetics and Pharmacodynamics of Sorafenib [20] Influence of the Proton Pump Inhibitor Esomeprazole on the Bioavailability of Regorafenib: A Randomized Crossover Pharmacokinetic Study [17] The effects of esomeprazole on the bioavailability of afatinib in patients with non-small-cell lung cancer [25]…”

“…For erlotinib 455 samples from 59 patients were available for analysis [23,24]. The samples were sorted according to time after once daily intake of the erlotinib and available PK samples obtained during the prospective PK study.…”

Proton pump inhibitors may reduce the efficacy of ribociclib and palbociclib in metastatic breast cancer patients

“…Studies to date have reported other instances of DDIs between PPIs and TKIs (i.e. pazopanib, sunitinib, ge tinib, and erlotinib) [7,[28][29][30][31][32][33]. A meta-analysis of 16 retrospective studies involving various solid tumors with a total of 372418 patients demonstrated that PPI therapy had a signi cant impact on survival outcomes in patients receiving oral anticancer drugs [34].…”