Pharmacokinetics of Ruxolitinib in HIV Suppressed Individuals on Antiretroviral Agent Therapy from the ACTG A5336 Study

• Type of Material: Article
• Authors: Selwyn Hurwitz, Emory University; Sijia Tao, Emory University; Christina Gavegnano, Emory University; RL Tressler, NIAID; Yong Jiang, Emory University; Athe Tsibris, Harvard Medical School; Carlos del Rio, Emory University; Carlos Del Rio, Emory University; Edgar T Overton, University of Alabama Birmingham; Michael M Lederman, Case Western Reserve University; Amy Kantor, Harvard T.H. Chan School of Public Health; Carlee Moser, Harvard T.H. Chan School of Public Health; James Kohler, Emory University; Jeffrey Lennox, Emory University; Vincent Marconi, Emory University; Charles W Flexner, Johns Hopkins University; Raymond Schinazi, Emory University
• Language: English
• Date: 2021-07-23
• Publisher: WILEY
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2021, The American College of Clinical Pharmacology
• Final Published Version (URL): http://dx.doi.org/10.1002/jcph.1930
• Title of Journal or Parent Work: JOURNAL OF CLINICAL PHARMACOLOGY
• Volume: 61
• Issue: 12
• Start Page: 1555
• End Page: 1566
• Grant/Funding Information: VCM has received investigator-initiated research grants (to the institution) and consultation fees (both unrelated to the current work) from Lilly, Bayer, Gilead Sciences and ViiV. CF received consultation fees unrelated to the current work from Merck, Mylan Pharmaceuticals, and ViiV. MML has consulted for Lilly and he has received competitive grant funding from Gilead (to his institution). JLL has consulted for Gilead and has received grant funding from ViiV (to his institution). All other authors report no potential conflicts. Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number UM1-AI-068634, UM1-AI-068636 and UM1-AI-106701. RFS is a shareholder of Incyte Corp. VCM and RFS received support from the Emory CFAR (P30-AI-050409). RFS provided funding support for the study drug and was also funded in part by R01-MH-116695.; This work was supported in part by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number UM1-AI-068634, UM1-AI-068636 and UM1-AI-106701. VCM and RFS received support from the Emory CFAR (P30-AI-050409). RFS provided funding support for the study drug and was also funded in part by R01-MH-116695. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This study was presented in part at the Conference on Retroviruses and Opportunistic infections (CROI) in 2019 in Seattle, WA, USA (Marconi, et al., Abstract #37) and 2020, Boston, MA, USA (Hurwitz, S.J., et al, Abstract # 00452). We are grateful to the patients and clinical staff at the participating sites for their generous contributions to this work and especially the ACTG, SDMC, participating CRSs, and Specialty Laboratories including the Brigham and Women’s Hospital, Harvard Medical School, Case Western Reserve University, and Emory University School of Medicine.
• Keywords: Pharmacology & Pharmacy; population PK; Life Sciences & Biomedicine; POPULATION PHARMACOKINETICS; CYP3A INDUCTION; NONMEM analysis; Science & Technology; EFAVIRENZ; INHIBITION; MODEL; HIV; ruxolitinib; drug-drug interactions; INCB018424 PHOSPHATE; PLASMA; antiretroviral agents

Abstract

Ruxolitinib is a US Food and Drug Administration–approved orally administered Janus kinase (1/2) inhibitor that reduces cytokine-induced inflammation. As part of a randomized, phase 2, open-label trial, ruxolitinib (10 mg twice daily) was administered to HIV-positive, virologically suppressed individuals (33 men, 7 women) on antiretroviral therapy (ART) for 5 weeks. Herein, we report the population PK subsequently determined from this study. Plasma concentrations of ruxolitinib (294 samples) and antiretroviral agents were measured at week 1 (N = 39 participants) and week 4 or 5 (N = 37). Ruxolitinib PK was adequately described with a 2-compartment model with first-order absorption and elimination with distribution volumes normalized to mean body weight (91.5 kg) and a separate typical clearance for participants administered efavirenz (a known cytochrome P450 3A4 inducer). Participants administered an ART regimen with efavirenz had an elevated typical apparent oral clearance versus the integrase inhibitor regimen group (22.5 vs 12.9 L/hr; N = 14 vs 25). Post hoc predicted apparent oral clearance was likewise more variable and higher (P <.0001) in those administered efavirenz. There was an ≈25% variation in ruxolitinib plasma exposures between week 1 and week 4/5. ART plasma concentrations resembled those from PK studies without ruxolitinib. Therefore, integrase inhibitor–based ART regimens may be preferred over efavirenz-based regimens when ruxolitinib is administered to HIV-positive individuals.