Tucatinib Inhibits Renal Transporters OCT2 and MATE Without Impacting Renal Function in Healthy Subjects.

Abstract

Tucatinib is a potent tyrosine kinase inhibitor selective for human epidermal growth factor receptor 2 (HER2) approved by the US Food and Drug Administration for the treatment of HER2-positive metastatic breast cancer and in development for other HER2-positive solid tumors. Modest, reversible serum creatinine (SCr) elevations have been observed in tucatinib clinical trials. SCr is conveyed by the renal drug transporters organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1) and 2-K (MATE2-K) and can increase in the presence of inhibitors of these transporters. In vitro, tucatinib inhibited OCT2-, MATE1-, and MATE2-K-mediated transport of metformin, with IC50 values of 14.7, 0.340, and 0.135 µM, respectively. Tucatinib also inhibited OCT2- and MATE1-mediated transport of creatinine, with IC50 values of 0.107 and 0.0855 µM, respectively. A phase 1 study with metformin administered orally in the absence and presence of tucatinib was conducted in 18 healthy subjects. Renal function was assessed by measuring glomerular filtration rate (GFR; based on iohexol plasma clearance) and endogenous markers (SCr, cystatin C-based estimated glomerular filtration rate [eGFR]) with and without tucatinib. Metformin exposure increased (1.4-fold) and renal clearance decreased (29.99-17.64 L/h) with tucatinib, with no effect on metformin maximum concentration. Creatinine clearance transiently decreased 23% with tucatinib. GFR and eGFR, which are unaffected by OCT2 and/or MATE1/2-K transport, were unchanged with tucatinib. These data demonstrate that tucatinib inhibits OCT2- and MATE1/2-K-mediated tubular secretion of creatinine, which may manifest as mild SCr elevations that are not indicative of renal impairment.

• Authors: Ariel R Topletz-Erickson, Anthony J Lee, JoAl G Mayor, Evelyn L Rustia, Layth I Abdulrasool, Amanda L Wise, Ben Dailey, Sharon DeChenne, Luke N Walker, Stephen C Alley, Christopher J Endres
• Journal: Journal of clinical pharmacology (J Clin Pharmacol) Vol. 61 Issue 4 Pg. 461-471 (04 2021) ISSN: 1552-4604 [Electronic] England
• PMID: 32989831 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 Seattle Genetics, Inc. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.

Chemical References

• Antineoplastic Agents
• Organic Cation Transport Proteins
• Organic Cation Transporter 2
• Oxazoles
• Pyridines
• Quinazolines
• SLC47A1 protein, human
• tucatinib
• Metformin
• Creatinine
• ERBB2 protein, human
• Receptor, ErbB-2

Topics

• Adolescent
• Adult
• Aged
• Animals
• Antineoplastic Agents (pharmacology)
• Biological Transport (drug effects)
• Creatinine (blood)
• Cross-Over Studies
• Dogs
• Female
• Glomerular Filtration Rate
• HEK293 Cells
• Healthy Volunteers
• Humans
• Inhibitory Concentration 50
• Madin Darby Canine Kidney Cells
• Male
• Metformin (pharmacokinetics)
• Middle Aged
• Organic Cation Transport Proteins (antagonists & inhibitors)
• Organic Cation Transporter 2 (antagonists & inhibitors)
• Oxazoles (pharmacology)
• Pyridines (pharmacology)
• Quinazolines (pharmacology)
• Receptor, ErbB-2 (antagonists & inhibitors)
• Young Adult