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- Title
The OCT2/MATE1 Interaction Between Trifluridine, Metformin and Cimetidine: A Crossover Pharmacokinetic Study.
- Authors
Guchelaar, Niels A. D.; Buck, Stefan A. J.; van Doorn, Leni; Hussaarts, Koen G. A. M.; Sandberg, Yorick; van der Padt-Pruijsten, Annemieke; van Alphen, Robbert J.; Poppe-Manenschijn, Laura; Vleut, Isolde; de Bruijn, Peter; van Leeuwen, Roelof W. F.; Mostert, Bianca; Eskens, Ferry A. L. M.; Oomen-de Hoop, Esther; Koolen, Stijn L. W.; Mathijssen, Ron H. J.
- Abstract
Background and Objectives: Trifluridine/tipiracil, registered for the treatment of patients with metastatic gastric and colorectal cancer, is a substrate and inhibitor for the organic cation transporter 2 (OCT2) and the multidrug and toxin extrusion protein 1 (MATE1), which raises the potential for drug–drug interactions with other OCT2/MATE1 modulators. Therefore, we prospectively examined the effect of an OCT2/MATE1 inhibitor (cimetidine) and substrate (metformin) on the pharmacokinetics of trifluridine. Methods: In this three-phase crossover study, patients with metastatic colorectal or gastric cancer were sequentially treated with trifluridine/tipiracil alone (phase A), trifluridine/tipiracil concomitant with metformin (phase B) and trifluridine/tipiracil concomitant with cimetidine (phase C). The primary endpoint was the relative difference in exposure of trifluridine assessed by the area under the curve from timepoint zero to infinity. A > 30% change in exposure was considered clinically relevant. A p-value of < 0.025 was considered significant because of a Bonferroni correction. Results: Eighteen patients were included in the analysis. Metformin did not significantly alter the exposure to trifluridine (− 12.6%; 97.5% confidence interval − 25.0, 1.8; p = 0.045). Cimetidine did alter the exposure to trifluridine significantly (+ 18.0%; 97.5% confidence interval 4.5, 33.3; p = 0.004), but this increase did not meet our threshold for clinical relevance. Metformin trough concentrations were not influenced by trifluridine/tipiracil. Conclusions: Our result suggests that the OCT2/MATE1 modulators cimetidine and metformin can be co-administered with trifluridine/tipiracil without clinically relevant effects on drug exposure. Clinical Trial Registration: NL8067 (registered 04-10-2019).
- Subjects
IRINOTECAN; REGORAFENIB; METFORMIN; ORGANIC cation transporters; CIMETIDINE; PHARMACOKINETICS; BONFERRONI correction; DRUG interactions
- Publication
Clinical Pharmacokinetics, 2024, Vol 63, Issue 7, p1037
- ISSN
0312-5963
- Publication type
Article
- DOI
10.1007/s40262-024-01390-3