The influence of green tea extract on nintedanib's bioavailability in patients with pulmonary fibrosis

Abstract

Nintedanib is an oral small-molecule kinase inhibitor and first-line treatment for idiopathic pulmonary fibrosis. Nintedanib is a substrate of the drug efflux transporter ABCB1. Green tea flavonoids –especially epigallocatechin gallate (EGCG)– are potent ABCB1 modulators. We investigated if concomitant administration of green tea extract (GTE) could result in a clinically relevant herb-drug interaction. Patients were randomized between A-B and B-A, with A being nintedanib alone and B nintedanib with GTE. Both periods lasted 7 days, in which nintedanib was administered twice daily directly after a meal. In period B, patients additionally received capsules with GTE (500 mg BID, >60% EGCG). Pharmacokinetic sampling for 12 h was performed at day 7 of each period. Primary endpoint was change in geometric mean for the area under the curve (AUC0–12 h). A linear mixed model was used to analyse AUCs and maximal concentration (Cmax). In 26 included patients, the nintedanib AUC0–12 h was 21% lower (95% CI −29% to −12%; P < 0.001) in period B (with GTE) compared to period A. Cmax did not differ significantly between periods; − 14% (95% CI −29% to +4%; P = 0.12). The detrimental effect was predominant in patients with the ABCB1 3435 C>T wild type variant. No differences in toxicities were observed. Exposure to nintedanib decreased with 21% when administered 60 min after GTC for only 7 days. This is a statistically significant interaction which could potentially impair treatment efficacy. Before patients and physicians should definitely be warned to avoid this combination, prospective clinical validation of an exposure-response relationship is necessary.