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Evaluation of Potential Drug‐Drug Interaction Risk of Pexidartinib With Substrates of Cytochrome P450 and P‐Glycoprotein

Pexidartinib is approved for treatment of adults with symptomatic tenosynovial giant cell tumor. In vitro data showed pexidartinib's potential to inhibit and induce cytochrome P450 (CYP) 3A, inhibit CYP2C9, CYP2C19 and P‐glycoprotein (P‐gp). Herein, 2 open‐label, single‐sequence, crossover stud...

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Detalles Bibliográficos
Autores principales: Zahir, Hamim, Kobayashi, Fumiaki, Zamora, Cynthia, Gajee, Roohi, Gordon, Michael S., Babiker, Hani M., Wang, Qiang, Greenberg, Jonathan, Wagner, Andrew J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891582/
https://www.ncbi.nlm.nih.gov/pubmed/32918831
http://dx.doi.org/10.1002/jcph.1734
Descripción
Sumario:Pexidartinib is approved for treatment of adults with symptomatic tenosynovial giant cell tumor. In vitro data showed pexidartinib's potential to inhibit and induce cytochrome P450 (CYP) 3A, inhibit CYP2C9, CYP2C19 and P‐glycoprotein (P‐gp). Herein, 2 open‐label, single‐sequence, crossover studies evaluated the drug‐drug interaction potential of pexidartinib on CYP enzymes (CYP2C9, CYP2C19, and CYP3A) and P‐gp. Thirty‐two subjects received single oral doses of midazolam (CYP3A substrate) and tolbutamide (CYP2C9 substrate) alone and after single and multiple oral doses of pexidartinib. Twenty subjects received single oral doses of omeprazole (CYP2C19 substrate) and digoxin (P‐gp substrate) alone or with pexidartinib. Analysis of variance was conducted to determine the effect of pexidartinib on various substrates’ pharmacokinetics. No drug‐drug interaction was concluded if the 90% confidence interval of the ratio of test to reference was within the range 80% to 125%. Coadministration of single and multiple doses of pexidartinib resulted in 21% and 52% decreases, respectively, in the area under the plasma concentration–time curve from time zero to the last measurable time point (AUC(last)) of midazolam, whereas AUC(last) values of tolbutamide increased 15% and 36%, respectively. Omeprazole exposure decreased on concurrent administration with pexidartinib, the metabolite‐to‐parent ratio was similar following omeprazole administration alone vs coadministration with pexidartinib; pexidartinib did not affect CYP2C19‐mediated metabolism. Maximum plasma concentrations of digoxin slightly increased (32%) with pexidartinib coadministration; no significant effect on digoxin AUC(last). These results indicate that pexidartinib is a moderate inducer of CYP3A and a weak inhibitor of CYP2C9 and does not significantly affect CYP2C19‐mediated metabolism or P‐gp transport.