Work

Inflammation Investigated as a Source of Pharmacokinetic Variability of Atazanavir in AIDS Clinical Trials Group Protocol A5224s

Year: 2017

Type: article

Abstract: BACKGROUND: Inflammation is associated with the downregulation of drug metabolizing enzymes and transporters. Thus, we investigated the chronic inflammatory state associated with HIV infection as a source of pharmacokinetic variability of atazanavir. We also explored the association of total bilirubin concentrations with markers of inflammation and endothelial activation. METHODS: Apparent oral clearance (CL/F) of atazanavir was estimated from plasma samples collected from participants in AIDS Clinical Trials Group Study A5202. Several inflammatory and endothelial activation biomarkers were measured at baseline and weeks 24 and 96 as part of metabolic substudy A5224s: high-sensitivity C-reactive protein (hsCRP), interleukin-6, tumour necrosis factor-α and its soluble receptors, soluble vascular cellular and intracellular adhesion molecules and total bilirubin. Statistical analysis was performed by a matrix of correlation coefficients between atazanavir CL/F and biomarker concentrations measured at week 24. The correlation between atazanavir clearance and percentage change in bilirubin from baseline to weeks 24 and 96, and between biomarkers and bilirubin concentrations at each week were also evaluated. RESULTS: Among 107 participants, there were no significant correlations observed between atazanavir CL/F and inflammatory and endothelial activation biomarkers measured at week 24 (P≥0.24). As expected, bilirubin increased with increasing exposure to atazanavir (rho=-0.25, P=0.01). Bilirubin concentrations were inversely correlated (P<0.01) with each of the biomarkers except hsCRP. CONCLUSIONS: Atazanavir CL/F did not correlate with the inflammatory biomarkers changes. Inflammatory-mediated inhibition of cytochrome P450 3A may have been attenuated due to atazanavir-associated increases of bilirubin, which has known anti-inflammatory properties.

Source: Antiviral Therapy

DOI: 10.3851/imp3209

Authors: Charles S Venuto, Jihoon Lim, Susan Messing, Peter W Hunt, Grace A McComsey, Gene D Morse

Institutions: AIDS Clinical Trials Group, University of Rochester Medicine, University of Rochester, University at Buffalo, State University of New York, University of California, San Francisco, University Hospitals Cleveland Medical Center, Case Western Reserve University

Language: English

Topic: HIV/AIDS drug development and treatment

Subfield: Infectious Diseases

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: green

Funders: National Institutes of Health, National Institute of Allergy and Infectious Diseases, Fogarty International Center, National Center for Research Resources, National Center for Advancing Translational Sciences

Awards: G1050281965, Units for HIV/AIDS Clinical Trials Networks, G1068660208, G1118287939, G1158968046, G1169301292, G119332616, G1214792496, G1225594167, Stanford AIDS Clinical Trials Unit, G1593133010, WASHINGTON UNIVERSITY AIDS CLINICAL TRIALS UNIT, G16708505, G1678638035, G1691243131, G183157880, G185513119, Vanderbilt HIV Clinical Trials Unit, G1865158448, G1939689254, G1978423557, G2093356446, G2115505793, G2127051194, G2135258891, G2241242742, G2268686290, G232810045, G2370685347, G2394140265, G2501702145, UAB Center for Clinical and Translational Science (CCTS) UL1, G2539633428, G2737559749, G2833553957, ADULT AIDS CLINICAL TRIALS UNIT, Cornell Clinical Trials Unit, G3142995538, G3179975197, Johns Hopkins AIDS Clinical Trials Unit, General Clinical Research Center, G3483687112, GBV-C effects on CD4 activation and expansion, G3672534956, G374818150, UW Clinical HIV Integrated Research Program, AIDS International Training and Research Program, G3873853564, G390975780, G3922356, ADULT THERAPEUTIC CLINICAL TRIALS PROGRAM FOR AIDS, Philadelphia IMPAACT Clinical Trials Unit, G4099673573, G4303839426, G4553935269, G4649361189, G488872913, Case Clinical Trials Unit, U of Colorado Center for AIDS Research, University of Pittsburgh Clinical Trials Unit, G5031627105, G5046654427, ADULT THERAPEUTIC CLINICAL TRIALS PROGRAM IN AIDS, Integrated University of Puerto Rico Clinical Trials Unit, G5268332287, G5382207646, The University of Rochester Clinical and Translational Science Institute, G5431849782, ADULT ACTG CENTRAL GROUP, G5469398932, G5588634031, G5647179126, UCSD Department of Medicine HIV/AIDS Clinical Trials Unit, Case AIDS Clinical Trials Unit, Philadelphia IMPAACT Clinical Trials Unit, G6186512954, G6270489734, G650174051, UNC Clinical and Translational Science Award, G6615853387, G6643580741, University of Cincinnati AIDS Clinical Trials Unit- UC ACTU, G6687940712, G6812155733, UCSF HIV Clinical Trials Unit, Partners Healthcare Systems/Harvard Medical School/Boston Medical Center AIDS CTU, G7401883790, G7807354757, G8487837538, HIV/AIDS Clinical Trials Unit, G857487509, Institute of Human Virology Clinical Trials Unit, G878552033, Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections, AIDS Clinical Trial Group Laboratory Center, Center for AIDS Research at Emory University, Statistical and Data Management Center (SDMC), Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections (ACTG), The University of North Carolina Center for AIDS Research, Columbia Collaborative HIV/AIDS Clinical Trials Unit, University of North Carolina Global HIV Prevention and Treatment Clinical Trials Unit, G926868656, G936311976, G961682679

OpenAlex ID: W2769766941

FWCI: 0.193

Cites: 52

Cited by: 7

Related to: 10