title: Interaction of Rifampin and Darunavir-Ritonavir or Darunavir-CobicistatIn Vitro.
abstract: Treatment of HIV-infected patients coinfected withMycobacterium tuberculosisis challenging due to drug-drug interactions (DDIs) between antiretrovirals (ARVs) and antituberculosis (anti-TB) drugs. The aim of this study was to quantify the effect of cobicistat (COBI) or ritonavir (RTV) in modulating DDIs between darunavir (DRV) and rifampin (RIF) in a human hepatocyte-basedin vitromodel. Human primary hepatocyte cultures were incubated with RIF alone or in combination with either COBI or RTV for 3 days, followed by coincubation with DRV for 1 h. The resultant DRV concentrations were quantified by high-performance liquid chromatography with UV detection, and the apparent intrinsic clearance (CLint.app.) of DRV was calculated. Both RTV and COBI lowered the RIF-induced increases in CLint.app.in a concentration-dependent manner. Linear regression analysis showed that log10RTV and log10COBI concentrations were associated with the percent inhibition of RIF-induced elevations in DRV CLint.app., where β was equal to -234 (95% confidence interval [CI] = -275 to -193;P< 0.0001) and -73 (95% CI = -89 to -57;P< 0.0001), respectively. RTV was more effective in lowering 10 μM RIF-induced elevations in DRV CLint.app.(half-maximal [50%] inhibitory concentration [IC50] = 0.025 μM) than COBI (IC50= 0.223 μM). Incubation of either RTV or COBI in combination with RIF was sufficient to overcome RIF-induced elevations in DRV CLint.app., with RTV being more potent than COBI. These data provide the firstin vitroexperimental insight into DDIs between RIF and COBI-boosted or RTV-boosted DRV and will be useful to inform physiologically based pharmacokinetic (PBPK) models to aid in optimizing dosing regimens for the treatment of patients coinfected with HIV andM. tuberculosis.
authors.affiliation: Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Owain
authors.initials: O
authors.lastname: Roberts
authors.affiliation: Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Saye
authors.initials: S
authors.lastname: Khoo
authors.affiliation: Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Owen
authors.affiliation: Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom siccardi@liverpool.ac.uk.
authors.forename: Marco
authors.initials: M
authors.lastname: Siccardi
mesh_terms: D018501:Antirheumatic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000995:Antitubercular Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002478:Cells, Cultured; D000069547:Cobicistat / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000069454:Darunavir / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D008657:Metabolic Clearance Rate / Q000187:drug effects; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D012293:Rifampin / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019438:Ritonavir / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D018501:Antirheumatic Agents; D000995:Antitubercular Agents; D000069547:Cobicistat; D019438:Ritonavir; D012293:Rifampin; D000069454:Darunavir
keywords: antiretroviral agents; cobicistat; darunavir; drug-drug interaction; human immunodeficiency virus; in vitro; rifampin; ritonavir