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Randomized Controlled Trial
. 2022 Nov:155:113695.
doi: 10.1016/j.biopha.2022.113695. Epub 2022 Sep 19.

Influence of esomeprazole on the bioavailability of afatinib: A pharmacokinetic cross-over study in patients with non-small cell lung cancer

G D Marijn Veerman  1 , Daan P Hurkmans  2 , Marthe S Paats  3 , Esther Oomen-de Hoop  2 , Cor H van der Leest  4 , Eric R E van Thiel  5 , Joachim G J V Aerts  3 , Roelof W van Leeuwen  6 , Anne-Marie C Dingemans  3 , Ron H J Mathijssen  2
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Free article
Randomized Controlled Trial

Influence of esomeprazole on the bioavailability of afatinib: A pharmacokinetic cross-over study in patients with non-small cell lung cancer

G D Marijn Veerman et al. Biomed Pharmacother. 2022 Nov.
Free article

Abstract

Afatinib is an oral small-molecule kinase inhibitor (SMKI) approved for treatment of metastatic non-small cell lung cancer (NSCLC) with an epidermal growth factor receptor (EGFR) driver mutation. Although oral administration is convenient, most SMKIs experience pH-dependent solubility. A drug-drug interaction between afatinib and proton-pump inhibitors (PPIs) has, however, never been studied in humans. Hence, we performed a randomized, three-period cross-over study. Afatinib (30 mg or 40 mg) was administered without PPI (period A), concomitantly with esomeprazole (period B) and three hours after esomeprazole intake (period C). Primary objective was the area under the curve (AUC0-24 h) comparing period A to period B and period A to period C. Secondary objectives were other pharmacokinetic parameters and toxicity. Linear mixed effect modelling was performed for differences in AUC0-24 h and Cmax between periods A and B and periods A and C. In 18 evaluable NSCLC patients, concomitant use of 40 mg esomeprazole decreased the steady-state afatinib AUC0-24 h with 10.2% (95% CI -29.2 to +14.0%; p = 0.564) compared to afatinib administration without PPI. Esomeprazole intake three hours prior to afatinib did not significantly influence afatinib AUC0-24 h (-0.6%; 95% CI -14.9 to +16.1%; p = 1.0). No differences in toxicity were observed. To conclude, esomeprazole did not change the exposure to afatinib in patients with NSCLC. Since there is no clinically relevant drug-drug interaction, esomeprazole can safely be co-administered with afatinib. This is important for clinical practice, because other EGFR-SMKIs (e.g. erlotinib and gefitinib) do experience clinically relevant drug-drug interactions with acid-suppressive agents.

Keywords: Afatinib; Drug-interaction; Esomeprazole; Non-small cell lung cancer; Pharmacokinetics; Proton-pump inhibitor.

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Conflict of interest statement

Conflict of interest statement G.D. Marijn Veerman reports grants from Eli Lilly, outside the submitted work, Roelof W.F. van Leeuwen reports grants from Bayer, Astellas, Pfizer, BMS and Roche, outside the submitted work (paid to institution), Ron H.J. Mathijssen reports an unrestricted grant from Boehringer-Ingelheim (paid to institution). Furthermore, Ron H.J. Mathijssen reports grants from Servier, Sanofi, Bayer, Astellas, Pamgene, Cristal Therapeutics, Pfizer, and Novartis, outside the submitted work (paid to institution), Joachim G.J.V Aerts reports grants from Boehringer-Ingelheim, outside the submitted work (paid to institution), Anne-Marie C. Dingemans reports grants from Boehringer-Ingelheim, outside the submitted work (paid to institution), All other authors declare no to have competing interests.

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