Treatment of HIV-infected patients coinfected with Mycobacterium tuberculosis 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 in vitro 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 int.app. ) of DRV was calculated. Both RTV and COBI lowered the RIF-induced increases in CL int.app. in a concentrationdependent manner. Linear regression analysis showed that log 10 RTV and log 10 COBI concentrations were associated with the percent inhibition of RIF-induced elevations in DRV CL int.app. , where  was equal to Ϫ234 (95% confidence interval [CI] ϭ Ϫ275 to Ϫ193; P Ͻ 0.0001) and Ϫ73 (95% CI ϭ Ϫ89 to Ϫ57; P Ͻ 0.0001), respectively. RTV was more effective in lowering 10 M RIF-induced elevations in DRV CL int.app. (half-maximal [50%] inhibitory concentration [IC 50 ] ϭ 0.025 M) than COBI (IC 50 ϭ 0.223 M). Incubation of either RTV or COBI in combination with RIF was sufficient to overcome RIF-induced elevations in DRV CL int.app. , with RTV being more potent than COBI. These data provide the first in vitro 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 M. tuberculosis.
KEYWORDS antiretroviral agents, cobicistat, darunavir, drug-drug interaction, human immunodeficiency virus, in vitro, rifampin, ritonavirA pproximately 25% of human immunodeficiency virus (HIV) type 1 (HIV-1)-infected patients worldwide are coinfected with Mycobacterium tuberculosis (1, 2) (referred to here as HIV-tuberculosis [TB] patients), with such coinfections accounting for 390,000 deaths in 2014 (3). The clinical management of HIV-TB patients presents significant challenges, especially in resource-limited settings (2, 4), where virological failure or intolerance to first-line antiretroviral therapy requires the use of HIV protease inhibitors (PIs) (5). PIs largely undergo phase I metabolism by cytochrome P450 3A4 (CYP3A4) and are also substrates of P-glycoprotein (P-GP; ABCB1) (6). Consequently, PIs are commonly administered in combination with pharmacokinetic (PK) boosters, such as ritonavir (RTV) or cobicistat (COBI), which act by inhibiting CYP3A4-mediated PI metabolism and P-GP-mediated PI efflux, thereby improving the PK profile of PIs by prolonging PI half-life and increasing PI bioavailability (7-9).Rifampin (RIF) is an essential component of short-course anti-TB treatment regimens (2, 10); however, RIF is also a potent...