Abstract
Background and Objective
The objectives of this study were to evaluate the effect of sotorasib on metformin pharmacokinetics and pharmacodynamics and the effect of metformin on sotorasib pharmacokinetics in healthy subjects. Sotorasib is an oral, small molecule inhibitor of the Kirsten rat sarcoma oncogene homolog (KRAS) G12C mutant protein (KRASG12C) protein approved by the U.S. Food and Drug Administration in 2021 for the treatment of KRASG12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC) in adults who have received at least one prior systemic therapy
Methods
This was a phase I, single-center, open-label, three-period, fixed-sequence study. Subjects received single oral doses of metformin 850 mg, sotorasib 960 mg, and metformin 850 mg with sotorasib 960 mg. Urine and plasma were collected and assayed for metformin and sotorasib pharmacokinetics. Blood glucose was also measured for metformin pharmacodynamics. In addition, an in vitro study was conducted to determine whether sotorasib was an inhibitor of MATE1/2K or OCT2 transport.
Results
Geometric least-squares mean ratio of sotorasib area under the concentration–time curve from time 0 to infinity and peak plasma concentration were 0.910 and 0.812, respectively, when sotorasib was coadministered with metformin compared with administration of sotorasib alone. Geometric least-squares mean ratio of metformin area under the concentration–time curve from time 0 to infinity and peak plasma concentration were 0.99 and 1.00, respectively, when comparing metformin coadministered with sotorasib to metformin alone. Geometric mean estimates of serum glucose area under the concentration–time curve from time 0 to 2 h following metformin alone, sotorasib alone, and metformin with sotorasib were 179, 222, and 194, respectively.
Conclusions
These results demonstrated that coadministration of metformin with sotorasib does not impact sotorasib exposure to a clinically significant extent. Coadministration of sotorasib with metformin does not affect metformin exposure or its antihyperglycemic effect, in contrast to the inhibitory effect observed in vitro. Doses of sotorasib 960 mg and metformin 850 mg were safe and well tolerated when coadministered to healthy subjects.
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Acknowledgments
We thank Chris James and Philip Wong for their oversight of the bioanalytical methods, and Mary Ann Simiens for her support in the preparation of this manuscript and contributions to the pharmacokinetic analysis and clinical study report during the conduct of the study. We thank Na Li and Mark Warren for their assistance in the design and performance of the in vitro transporter studies.
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The studies included in this article and the analyses reported were funded by Amgen Inc., Thousand Oaks, CA, USA.
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All authors are employees and stockholders of Amgen Inc.
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The study followed the ethical principles of the Declaration of Helsinki, the International Conference on Harmonization Guideline for Good Clinical Practice, and local regulations (US Code of Federal Regulations Title 21). The protocol, informed consent, and amendments were approved by the Institutional Review Board (Salus Institutional Review Board, Austin, TX, USA).
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All authors contributed to the study conception and design. The first draft of the manuscript was written by IV and JW and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
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Vuu, I., Wahlstrom, J. & Houk, B.E. Impact of Sotorasib on the Pharmacokinetics and Pharmacodynamics of Metformin, a MATE1/2K Substrate, in Healthy Subjects. Clin Pharmacokinet 62, 267–275 (2023). https://doi.org/10.1007/s40262-022-01192-5
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DOI: https://doi.org/10.1007/s40262-022-01192-5