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Clinical Trial
. 2024 Jul;63(7):1037-1044.
doi: 10.1007/s40262-024-01390-3. Epub 2024 Jun 28.

The OCT2/MATE1 Interaction Between Trifluridine, Metformin and Cimetidine: A Crossover Pharmacokinetic Study

Niels A D Guchelaar  1 , Stefan A J Buck  2 , Leni van Doorn  2 , Koen G A M Hussaarts  2 , Yorick Sandberg  3 , Annemieke van der Padt-Pruijsten  2   3 , Robbert J van Alphen  4 , Laura Poppe-Manenschijn  5 , Isolde Vleut  6 , Peter de Bruijn  2 , Roelof W F van Leeuwen  6 , Bianca Mostert  2 , Ferry A L M Eskens  2 , Esther Oomen-de Hoop  2 , Stijn L W Koolen  2   6 , Ron H J Mathijssen  2
Affiliations
Clinical Trial

The OCT2/MATE1 Interaction Between Trifluridine, Metformin and Cimetidine: A Crossover Pharmacokinetic Study

Niels A D Guchelaar et al. Clin Pharmacokinet. 2024 Jul.

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).

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Conflict of interest statement

Bianca Mostert received consulting fees from Lilly, Servier, BMS, AstraZeneca and Amgen, and research funding from Sanofi, Pfizer and BMS. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
Schematic overview of the potential drug–drug interaction between tipiracil, metformin and cimetidine. Tipiracil is a substrate and inhibitor for the organic cation transporter 2 (OCT2) and the multidrug and toxin extrusion protein 1 (MATE1). Cimetidine inhibits the OCT2 and MATE1 transporter, whereas metformin is a substrate for the OCT2/MATE1 transporter (8). This figure was created using Biorender.com
Fig. 2
Fig. 2
Study overview. PK pharmacokinetic
Fig. 3
Fig. 3
Concentration–time curves of trifluridine during each study phase. Trifluridine/tipiracil alone (phase A, n = 18), compared to trifluridine/tipiracil with concomitant metformin (phase B, n = 18) and trifluridine/tipiracil with concomitant cimetidine (phase C, n = 18). The estimated parameters of patients were dose corrected to 35 mg/m2 of trifluridine/tipiracil. h hours
See this image and copyright information in PMC

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