| Autor: |
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. |
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| Zdroj: |
Clinical Pharmacokinetics; Jul2024, Vol. 63 Issue 7, p1037-1044, 8p |
| Abstrakt: |
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). [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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