Drug Design, Development and Therapy (Mar 2022)

Co-Administration with Voriconazole Doubles the Exposure of Ruxolitinib in Patients with Hematological Malignancies

  • Zhao Y,
  • Chen P,
  • Dou L,
  • Li F,
  • Li M,
  • Xu L,
  • Chen J,
  • Jia M,
  • Huang S,
  • Wang N,
  • Luan S,
  • Yang J,
  • Bai N,
  • Liu D

Journal volume & issue
Vol. Volume 16
pp. 817 – 825

Abstract

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Yingxin Zhao,1,* Peng Chen,2,* Liping Dou,1– 3,* Fei Li,2 Meng Li,2 Lingmin Xu,2 Jing Chen,2 Mingyu Jia,2 Sai Huang,2 Nan Wang,1,2 Songhua Luan,2 Jinling Yang,2 Nan Bai,4 Daihong Liu1,2 1Medical School of Chinese PLA, Beijing, People’s Republic of China; 2Department of Hematology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China; 3The Second School of Clinical Medicine, Southern Medical University, Guangzhou, People’s Republic of China; 4Center of Medicine Clinical Research, Department of Pharmacy, Medical Supplies Center of Chinese PLA General Hospital, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Daihong Liu, Medical School of Chinese PLA, No. 28 Fuxing Road, Haidian District, Beijing, 100853, People’s Republic of China, Email [email protected] Nan Bai, Center of Medicine Clinical Research, Department of Pharmacy, Medical Supplies Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Haidian District, Beijing, 100853, People’s Republic of China, Email [email protected]: Ruxolitinib is newly approved for glucocorticoid-refractory acute graft-versus-host disease (GVHD) in patients undergoing allo-geneic hematopoietic stem-cell transplantation (allo-HSCT), and voriconazole is commonly used in allo-HSCT recipients for the prophylaxis or treatment of invasive fungal infections (IFIs). Drug–drug interaction (DDI) may occur between them because their metabolic pathways overlap and can be inhibited by voriconazole, including cytochrome P450 (CYP) isozymes 3A4 and 2C9.Objective: In the present study, we aimed to investigate the DDI between ruxolitinib and voriconazole in patients with hematological malignancies.Methods: A total of 12 patients with hematologic malignancies were enrolled in this single-arm, single-center, Phase I/II, fixed sequence self-control study. All subjects received 5 mg ruxolitinib alone, followed by the co-administration of ruxolitinib and voriconazole. The plasma concentrations of the two drugs were determined by two well-validated high-performance liquid chromatography-tandem mass spectrometry methods. Phoenix WinNonlin software was used to compare the differences in maximum plasma concentration (Cmax), time to Cmax (Tmax), terminal elimination half-life (T1/2), and apparent plasma clearance (CL/F), as well as area under the curve from time zero to last (AUClast) and AUC from time zero to infinity (AUCinf) between the two periods.Results: After pre-treatment with voriconazole, no significant change existed in Tmax, while Cmax, T1/2, AUClast, and AUCinf of ruxolitinib were significantly increased by 50.4%, 81.3%, 110.1%, and 118.3%, respectively, and CL/F was significantly decreased to 43.6% compared with patients receiving ruxolitinib alone.Conclusion: Our findings confirmed a moderate inhibitory DDI between ruxolitinib and voriconazole as voriconazole decreased the elimination and increased the exposure of ruxolitinib in patients with hematologic malignancies. We recommended a dose reduction regimen when voriconazole and ruxolitinib were coadministered. Drug monitoring might help determine the ruxolitinib treatment concentration for aGVHD patients, improve efficacy, and reduce toxicity.Keywords: pharmacokinetics, ruxolitinib, voriconazole, drug–drug interaction, graft-versus-host disease

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