Abemaciclib Inhibits Renal Tubular Secretion Without Changing Glomerular Filtration Rate.

Autor: Chappell JC; Eli Lilly and Company, Indianapolis, Indiana, USA., Turner PK; Eli Lilly and Company, Indianapolis, Indiana, USA., Pak YA; Eli Lilly and Company, Indianapolis, Indiana, USA., Bacon J; Eli Lilly and Company, Indianapolis, Indiana, USA., Chiang AY; Eli Lilly and Company, Indianapolis, Indiana, USA., Royalty J; Covance Early Clinical Development, Madison, Wisconsin, USA., Hall SD; Eli Lilly and Company, Indianapolis, Indiana, USA., Kulanthaivel P; Eli Lilly and Company, Indianapolis, Indiana, USA., Bonventre JV; Brigham and Women's Hospital, Boston, Massachusetts, USA.
Jazyk: angličtina
Zdroj: Clinical pharmacology and therapeutics [Clin Pharmacol Ther] 2019 May; Vol. 105 (5), pp. 1187-1195. Date of Electronic Publication: 2018 Dec 30.
DOI: 10.1002/cpt.1296
Abstrakt: 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.
(© 2018 Eli Lilly and Company. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)
Databáze: MEDLINE
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