Impact of fedratinib on the pharmacokinetics of transporter probe substrates using a cocktail approach.

Autor: Ogasawara, Ken, Wood-Horrall, Rebecca N., Thomas, Mark, Thomas, Michael, Liu, Liangang, Liu, Mary, Xue, Yongjun, Surapaneni, Sekhar, Carayannopoulos, Leonidas N., Zhou, Simon, Palmisano, Maria, Krishna, Gopal
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Zdroj: Cancer Chemotherapy & Pharmacology; Dec2021, Vol. 88 Issue 6, p941-952, 12p
Abstrakt: Introduction: Fedratinib, an oral, selective Janus kinase 2 inhibitor, has been shown to inhibit P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 2, and multidrug and toxin extrusion (MATE) 1 and MATE2-K in vitro. The objective of this study was to evaluate the influence of fedratinib on the pharmacokinetics (PK) of digoxin (P-gp substrate), rosuvastatin (OATP1B1/1B3 and BCRP substrate), and metformin (OCT2 and MATE1/2-K substrate).Methods: In this nonrandomized, fixed-sequence, open-label study, 24 healthy adult participants received single oral doses of digoxin 0.25 mg, rosuvastatin 10 mg, and metformin 1000 mg administered as a drug cocktail (day 1, period 1). After a 6-day washout, participants received oral fedratinib 600 mg 1 h before the cocktail on day 7 (period 2). An oral glucose tolerance test (OGTT) was performed to determine possible influences of fedratinib on the antihyperglycemic effect of metformin.Results: Plasma exposure to the three probe drugs was generally comparable in the presence or absence of fedratinib. Reduced metformin renal clearance by 36% and slightly higher plasma glucose levels after OGTT were observed in the presence of fedratinib. Single oral doses of the cocktail ± fedratinib were generally well tolerated.Conclusions: These results suggest that fedratinib has minimal impact on the exposure of P-gp, BCRP, OATP1B1/1B3, OCT2, and MATE1/2-K substrates. Since renal clearance of metformin was decreased in the presence of fedratinib, caution should be exercised in using coadministered drugs that are renally excreted via OCT2 and MATEs.Trial Registration: Clinicaltrials.gov NCT04231435 on January 18, 2020. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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