Effects of strong and moderate CYP3A4 inducers on the pharmacokinetics of fedratinib in healthy adult participants

• Published in: Cancer chemotherapy and pharmacology Vol. 88; no. 3; pp. 369 - 377
• Main Authors: Ogasawara, Ken, Kam, Jeanelle, Thomas, Mark, Liu, Liangang, Liu, Mary, Xue, Yongjun, Surapaneni, Sekhar, Carayannopoulos, Leonidas N., Zhou, Simon, Palmisano, Maria, Krishna, Gopal
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.09.2021; Springer Nature B.V
• Subjects: Adult; Alkynes - pharmacology; Antiretroviral drugs; Area Under Curve; Benzoxazines - pharmacology; Cancer Research; Chromatography, Liquid; Confidence intervals; Cyclopropanes - pharmacology; Cytochrome; Cytochrome P-450 CYP3A Inducers - pharmacology; Cytochromes; Dosage; Drug Interactions; Efavirenz; Enzyme inhibitors; Female; Humans; Janus kinase; Janus kinase 2; Janus Kinase 2 - antagonists & inhibitors; Kinases; Liquid chromatography; Male; Mass spectrometry; Mass spectroscopy; Medicine; Medicine & Public Health; Men; Middle Aged; Myelofibrosis; NCT; NCT03983239; Oncology; Original Article; Pharmacokinetics; Pharmacology; Pharmacology/Toxicology; Protein Kinase Inhibitors - adverse effects; Protein Kinase Inhibitors - pharmacokinetics; Pyrrolidines - adverse effects; Pyrrolidines - pharmacokinetics; Rifampin; Rifampin - pharmacology; Sulfonamides - adverse effects; Sulfonamides - pharmacokinetics; Tandem Mass Spectrometry; Young Adult; Inducer; Fedratinib; CYP3A4; Rifampin; Efavirenz; Drug–drug interaction
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-021-04292-4

Purpose Fedratinib is an oral and selective Janus kinase 2 inhibitor that is indicated for treatment of adults with intermediate-2 or high-risk primary or secondary myelofibrosis. Fedratinib is metabolized by cytochrome P450s (CYPs), primarily CYP3A4. The objective of this study was to determine the effects of the strong CYP3A4 inducer rifampin and moderate CYP3A4 inducer efavirenz on the pharmacokinetics of single doses of fedratinib. Methods This Phase 1, open-label, two-part study (Part 1 for rifampin and Part 2 for efavirenz) was conducted in healthy adult men and women. A single dose of fedratinib (500 mg) was administered on Day 1. Participants received rifampin 600 mg daily or efavirenz 600 mg daily on Days 9–18. On Day 17, a single dose of fedratinib (500 mg) was coadministered with rifampin or efavirenz. Plasma fedratinib concentrations were measured using validated liquid chromatography–tandem mass spectrometry. Results Maximum observed plasma fedratinib concentrations were lowered by approximately 70% and 30% during coadministration with rifampin or efavirenz, respectively, compared with fedratinib alone. Geometric means of fedratinib area under the plasma concentration–time curve from 0 to infinity were decreased by 81% (90% confidence interval [CI], 77–83%) and 47% (90% CI, 40–53%) during coadministration with rifampin or efavirenz, respectively. Fedratinib was generally well tolerated when administered alone or in combination with rifampin or efavirenz. Conclusion Significant reductions in fedratinib exposure were observed in the presence of strong or moderate CYP3A4 inducers. These results suggest that agents that are strong or moderate inducers of CYP3A4 should be avoided when coadministered with fedratinib. Trial Registration Number NCT03983239 (Registration date: June 12, 2019).