Detecting Selpercatinib in Human Plasma with High Performance Liquid Chromatography–Ultraviolet (HPLC–UV)

A recent joint study between Meiji Pharmaceutical University (Tokyo, Japan) and The Japanese Foundation for Cancer Research (Tokyo, Japan) has developed a high performance liquid chromatography–ultraviolet (HPLC–UV) method for measuring selpercatinib blood levels in hopes of simplifying therapeutic drug monitoring in clinical practice, reducing adverse events and optimizing efficacy. An article based on this study was published in Drug Discovery Therapy (1).

An adenosine triphosphate-competitive and highly selective oral small-molecule inhibitor of the rearranged during transfection (RET) kinase, selpercatinib shows efficacy and safety in the treatment of RET fusion-positive lung and thyroid cancers and RET mutant medullary thyroid cancer (2–4). In a phase-3 trial conducted with patients with advanced RET-mutant medullary thyroid cancer, the most common undesirable effects during selpercatinib treatment were hypertension (42.5%), dry mouth (31.6%), diarrhea, and elevated alanine aminotransferase levels. This led to a reduced dose in 38.9% and dose interruptions in 56.0% of patients receiving selpercatinib (4). In addition, chylous effusions, a newly identified treatment-related issue, have been reported to occur in a dose-dependent manner in patients with RET-mutant thyroid cancer receiving selpercatinib (5).

Previously, only liquid chromatography–tandem mass spectrometry (LC–MS/MS) methods have been reported for selpercatinib quantitation in human plasma (6). While LC–MS/MS enables rapid, accurate, and sensitive drug quantitation across various biological matrices, its high cost and maintenance requirements limit its accessibility in hospitals. The researchers performing the study believed that HPLC was more affordable than LC–MS/MS and therefore more suited to routine clinical use, which inspired them to develop this method (1).

The chromatography system developed by the researchers consisted of an HPLC instrument equipped with a pump, a UV detector, and an autosampler. Chromatographic separation was achieved on a reversed-phase column with a guard column at ambient temperature. The mobile phase, a mixture of 0.5% KH₂PO₄ (pH 4.5) and acetonitrile (70:30, v/v), was delivered at a flow rate of 1.0 mL/min over a 15 min run. UV detection was performed at 240 nm.

The authors of the paper are aware of certain limitations within their research. RET fusions are present in a variety of malignancies, including 1–2% of lung cancers, 10–20% of papillary thyroid cancers, and rarely in other solid tumors (7). The method was therefore not used to evaluate selpercatinib levels in patient samples. Furthermore, the researchers did not assess the selectivity of this method with respect to concomitant medications or their metabolites in patients on selpercatinib. Future studies should confirm selectivity in clinical samples from patients treated with selpercatinib (1).

Plasma: © kpn1968 - stock.adobe.com

References

Suzuki, W.; Gando, Y.; Yasu, T. Development of a Simple High-Performance Liquid Chromatography-Ultraviolet Detection Method for Selpercatinib Determination in Human Plasma. Drug Discov. Ther. 2024. DOI: 10.5582/ddt.2024.01076

1. Drilon, A.; Oxnard, G. R.; Tan, D. S. W.; et al. Efficacy of Selpercatinib in RET Fusion-Positive Non-Small-Cell Lung Cancer. N. Engl. J Med. 2020, 383, 813–824. DOI: 10.1056/NEJMoa2005653
2. Wirth, L. J.; Sherman, E.; Robinson, B.; et al. Efficacy of Selpercatinib in RET-Altered Thyroid Cancers. N. Engl. J. Med. 2020, 383 (9), 825–835. DOI: 10.1056/NEJMoa2005651
3. Hadoux, J.; Elisei, R.; Brose, M. S.; et al. Phase 3 Trial of Selpercatinib in Advanced RET-Mutant Medullary Thyroid Cancer. N. Engl. J. Med. 2023, 389 (20), 1851–1861. DOI: 10.1056/NEJMoa2309719
4. Prete, A.; Gambale, C.; Cappagli, V.; et al. Chylous Effusions in Advanced Medullary Thyroid Cancer Patients Treated with Selpercatinib. Eur. J. Endocrinol. 2022, 187 (6), 905–915. DOI: 10.1530/EJE-22-0643
5. Gulikers, J. L.; van Veelen, A. J.; Sinkiewicz, E. M. J.; et al. Development and Validation of an HPLC-MS/MS Method to Simultaneously Quantify Brigatinib, Lorlatinib, Pralsetinib and Selpercatinib in Human K2-EDTA Plasma. Biomed. Chromatogr. 2023, 37 (6), e5628. DOI: 10.1002/bmc.5628
6. Stransky, N.; Cerami, E.; Schalm, S.; Kim, J. L. Lengauer C. The Landscape of Kinase Fusions in Cancer. Nat. Commun. 2014, 5, 4846. DOI: 10.1038/ncomms5846