1. The OCT2/MATE1 Interaction Between Trifluridine, Metformin and Cimetidine: A Crossover Pharmacokinetic Study.
- Author
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Guchelaar NAD, Buck SAJ, van Doorn L, Hussaarts KGAM, Sandberg Y, van der Padt-Pruijsten A, van Alphen RJ, Poppe-Manenschijn L, Vleut I, de Bruijn P, van Leeuwen RWF, Mostert B, Eskens FALM, Oomen-de Hoop E, Koolen SLW, and Mathijssen RHJ
- Subjects
- Adult, Aged, Female, Humans, Male, Middle Aged, Colorectal Neoplasms drug therapy, Colorectal Neoplasms metabolism, Drug Combinations, Organic Cation Transporter 2 metabolism, Prospective Studies, Pyrrolidines pharmacokinetics, Pyrrolidines administration & dosage, Stomach Neoplasms drug therapy, Stomach Neoplasms metabolism, Thymine, Cimetidine pharmacokinetics, Cimetidine pharmacology, Cimetidine administration & dosage, Cross-Over Studies, Drug Interactions, Metformin pharmacokinetics, Metformin administration & dosage, Metformin pharmacology, Organic Cation Transport Proteins metabolism, Organic Cation Transport Proteins antagonists & inhibitors, Trifluridine pharmacokinetics, Trifluridine administration & dosage
- 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)., (© 2024. The Author(s).)
- Published
- 2024
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