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Abemaciclib Inhibits Renal Tubular Secretion Without Changing Glomerular Filtration Rate
Author(s) -
Chappell Jill C.,
Turner P. Kellie,
Pak Y. Anne,
Bacon James,
Chiang Alan Y.,
Royalty Jane,
Hall Stephen D.,
Kulanthaivel Palaniappan,
Bonventre Joseph V.
Publication year - 2019
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.1296
Subject(s) - renal function , medicine , metformin , cystatin c , pharmacology , creatinine , endocrinology , urinary system , lipocalin , acute kidney injury , chemistry , diabetes mellitus
Abemaciclib, an inhibitor of cyclin dependent kinases 4 and 6, is indicated for metastatic breast cancer treatment. Reversible increases in serum creatinine levels of ~15–40% over baseline have been observed following abemaciclib dosing. This study assessed the in vitro and clinical inhibition of renal transporters by abemaciclib and its metabolites using metformin (a clinically relevant transporter substrate), in a clinical study that quantified glomerular filtration and iohexol clearance. In vitro , abemaciclib inhibited metformin uptake by organic cation transporter 2, multidrug and toxin extrusion (MATE)1, and MATE2‐K transporters with a half‐maximal inhibitory concentration of 0.4–3.8 μM. Clinically, abemaciclib significantly increased metformin exposure but did not significantly affect measured glomerular filtration rate, serum neutrophil gelatinase‐associated lipocalin (NGAL), serum cystatin‐C, or the urinary markers of kidney tubular injury, NGAL and kidney injury molecule‐1.