Interaction of Rifampin and Darunavir-Ritonavir or Darunavir-Cobicistat <i>In Vitro</i>


Roberts, Owain, Khoo, Saye ORCID: 0000-0002-2769-0967, Owen, Andrew ORCID: 0000-0002-9819-7651 and Siccardi, Marco ORCID: 0000-0002-3539-7867 (2017) Interaction of Rifampin and Darunavir-Ritonavir or Darunavir-Cobicistat <i>In Vitro</i>. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 61 (5). e01776-e01716.

[img] Text
160816_Interaction of Rifampicin and Ritonavir-Darunavir or Cobicistat-Darunavir In Vitro.pdf - Author Accepted Manuscript
Download (558kB)

Abstract

Treatment of HIV-infected patients coinfected with <i>Mycobacterium tuberculosis</i> is 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-based <i>in vitro</i> model. 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 (CL<sub>int.app.</sub>) of DRV was calculated. Both RTV and COBI lowered the RIF-induced increases in CL<sub>int.app.</sub> in a concentration-dependent manner. Linear regression analysis showed that log<sub>10</sub> RTV and log<sub>10</sub> COBI concentrations were associated with the percent inhibition of RIF-induced elevations in DRV CL<sub>int.app.</sub>, where β was equal to -234 (95% confidence interval [CI] = -275 to -193; <i>P</i> < 0.0001) and -73 (95% CI = -89 to -57; <i>P</i> < 0.0001), respectively. RTV was more effective in lowering 10 μM RIF-induced elevations in DRV CL<sub>int.app.</sub> (half-maximal [50%] inhibitory concentration [IC<sub>50</sub>] = 0.025 μM) than COBI (IC<sub>50</sub> = 0.223 μM). Incubation of either RTV or COBI in combination with RIF was sufficient to overcome RIF-induced elevations in DRV CL<sub>int.app.</sub>, with RTV being more potent than COBI. These data provide the first <i>in vitro</i> experimental 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 and <i>M. tuberculosis</i>.

Item Type: Article
Uncontrolled Keywords: antiretroviral agents, cobicistat, darunavir, drug-drug interaction, human immunodeficiency virus, in vitro, rifampin, ritonavir
Depositing User: Symplectic Admin
Date Deposited: 06 Apr 2017 12:13
Last Modified: 13 Feb 2024 14:57
DOI: 10.1128/AAC.01776-16
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3006814
Dimensions
Altmetric
CORE (COnnecting REpositories)