Pharmacokinetics of Ruxolitinib in HIV Suppressed Individuals on Antiretroviral Agent Therapy from the ACTG A5336 Study
| Autor: | Amy Kantor, Charles Flexner, Christina Gavegnano, Michael M. Lederman, Selwyn J. Hurwitz, Sijia Tao, Edgar T. Overton, Vincent C. Marconi, Raymond F. Schinazi, Randall Tressler, James J. Kohler, Carlos del Rio, Carlee Moser, Athe M. N. Tsibris, Yong Jiang, Jeffrey L. Lennox |
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| Rok vydání: | 2021 |
| Předmět: |
Adult
Cyclopropanes Male Drug Ruxolitinib Efavirenz Metabolic Clearance Rate media_common.quotation_subject Population Integrase inhibitor HIV Infections Pharmacology Article chemistry.chemical_compound Pharmacokinetics Nitriles Humans Distribution (pharmacology) Medicine Drug Interactions Pharmacology (medical) education Janus Kinases media_common education.field_of_study business.industry Body Weight Cytochrome P-450 CYP3A Inducers Middle Aged Benzoxazines Regimen Pyrimidines Anti-Retroviral Agents chemistry Alkynes Pyrazoles Female business medicine.drug |
| Zdroj: | J Clin Pharmacol |
| ISSN: | 1552-4604 0091-2700 |
| Popis: | Ruxolitinib is an FDA-approved orally administered Janus kinase (JAK 1/2) inhibitor that reduces cytokine-induced inflammation. As part of a randomized, Phase 2, open label trial, ruxolitinib (10 mg, bid) was administered to HIV(+), virologically suppressed individuals (33 men, 7 women) on antiretroviral therapy (ART), for 5 weeks. Study objectives were to assess safety, tolerability, pharmacokinetics (PK), and modulation of ongoing inflammation that persists even with viral suppression. 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 (wk1, N = 39 participants) and week 4 or 5 (wk4/5, 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 CL for participants administered efavirenz (a known CYP3A4 inducer). Participants administered an ART regimen with efavirenz had an elevated typical CL/F versus the integrase inhibitor regimen (INSTI) group (22.5 versus 12.9 L/hr; N = 14 versus 25). Post hoc predicted CL/F were likewise, more variable and higher (p < 0.0001) in those administered efavirenz. There was ~ 25% variation in ruxolitinib plasma exposures between wk1 and wk4/5. ART plasma concentrations resembled those from PK studies without ruxolitinib. Therefore, INSTI based ART regimens may be preferred over efavirenz based regimens when ruxolitinib is administered to HIV(+) individuals. |
| Databáze: | OpenAIRE |
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