Cobicistat (GS-9350): A Potent and Selective Inhibitor of Human CYP3A as a Novel Pharmacoenhancer

Xu, Lianhong; Liu, Hongtao; Murray, Bernard P.; Callebaut, Christian; Lee, Melody S.; Hong, Allen Y.; Strickley, Robert G.; Tsai, Luke Y.; Stray, Kirsten M.; Wang, Yujin; Rhodes, Gerry; Desai, Manoj C.

doi:10.1021/ml1000257

Cited by 172 publications

(185 citation statements)

References 26 publications

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“…After extensive structure activity relationship studies with desoxy-ritonavir, cobicistat (Fig. 14C) was identified as a potent, selective, and orally bioavailable inhibitor of CYP3A (Xu et al, 2010).…”

Section: Investigations Of Human Cytochrome P450 Enzymes Withmentioning

confidence: 99%

“…Cobicistat is also more selective for CYP3A than ritonavir, with much reduced inhibitory activity toward CYP2D6, CYP2C8, and CYP2C9. In addition, in vitro studies suggest that cobicistat may have a lower potential to cause undesired drug-drug interactions and lipid disorders than ritonavir (Xu et al, 2010).…”

Section: Investigations Of Human Cytochrome P450 Enzymes Withmentioning

confidence: 99%

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Correlating Structure and Function of Drug-Metabolizing Enzymes: Progress and Ongoing Challenges

et al. 2013

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This report summarizes a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics at Experimental Biology held April 20-24 in Boston, MA. Presentations discussed the status of cytochrome P450 (P450) knowledge, emphasizing advances and challenges in relating structure with function and in applying this information to drug design. First, at least one structure of most major human drugmetabolizing P450 enzymes is known. However, the flexibility of these active sites can limit the predictive value of one structure for other ligands. A second limitation is our coarse-grain understanding of P450 interactions with membranes, other P450 enzymes, NADPH-cytochrome P450 reductase, and cytochrome b 5 . Recent work has examined differential P450 interactions with reductase in mixed P450 systems and P450:P450 complexes in reconstituted systems and cells, suggesting another level of functional control. In addition, protein nuclear magnetic resonance is a new approach to probe these protein/protein interactions, identifying interacting b 5 and P450 surfaces, showing that b 5 and reductase binding are mutually exclusive, and demonstrating ligand modulation of CYP17A1/b 5 interactions. One desired outcome is the application of such information to control drug metabolism and/or design selective P450 inhibitors. A final presentation highlighted development of a CYP3A4 inhibitor that slows clearance of human immunodeficiency virus drugs otherwise rapidly metabolized by CYP3A4. Although understanding P450 structure/function relationships is an ongoing challenge, translational advances will benefit from continued integration of existing and new biophysical approaches.

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Section: Investigations Of Human Cytochrome P450 Enzymes Withmentioning

confidence: 99%

Section: Investigations Of Human Cytochrome P450 Enzymes Withmentioning

confidence: 99%

Correlating Structure and Function of Drug-Metabolizing Enzymes: Progress and Ongoing Challenges

et al. 2013

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“…RTV and COBI both serve as mechanism-based inhibitors of CYP3A4 in vivo (43,44); however, RTV is also known to induce the expression of various metabolic enzymes, including CYP3A4, in primary human hepatocytes in vitro (30). Very few studies aimed at investigating the relative effects of COBI as an inducer of metabolic enzyme expression have thus far been conducted, although it has been suggested that the induction potential of COBI is less than that of RTV (45) and that COBI is not expected to induce CYP3A4 expression (46). It was recently suggested that the hepatic uptake of RTV occurs chiefly by passive diffusion (47).…”

Section: Discussionmentioning

confidence: 99%

Interaction of Rifampin and Darunavir-Ritonavir or Darunavir-Cobicistat In Vitro

Roberts

Khoo

Owen

et al. 2017

Antimicrob Agents Chemother

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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...

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“…In particular, Cobi is a potent inhibitor of CYP3A enzymes, the main metabolizing pathway of this class of antiretrovirals. 11 Like RTV, Cobi inactivates CYP3A in a concentration-and time-dependent fashion, exhibiting a CYP3A inactivation rate of 0.44 min -1 and an inhibition constant of 939 nmol/L in vitro (corresponding values for RTV were 0.23 min -1 and 256 nmol/L). Potent inhibition of CYP3A activity has also been demonstrated with Cobi in a Phase I study in healthy volunteers (n#60).…”

Section: Overview Of Pharmacologymentioning

confidence: 99%

“…However, due to its more selective inhibition of CYP3A, Cobi has a lower potential for off-target drug interactions than the standard boosting agent RTV, and lower likelihood for enzymatic induction. Cobi, unlike RTV, is devoid of anti-HIV activity in vitro, displaying a mean IC 50 of .30 mmol/L in a HIV-1 protease enzymatic assay (vs 0.0006 mmol/L with RTV), a mean half maximal effective concentration (EC 50 ) of .30 mmol/L in a cell-based HIV infection assay (vs 0.0133 mmol/L with RTV), 11 and no activity against primary HIV isolates. 13 Absorption of Cobi is rapid after oral administration, with the maximum plasma concentration (C max ) of the drug being reached within 4 hours (Table 1). 14 As may be expected for a drug that is both a mechanism-based inhibitor of CYP3A and a CYP3A substrate, exposure to Cobi was nonlinear across oral dosages of 50-300 mg/day in healthy volunteers, with exposure increasing more than proportionally with increasing dose (up to 47-fold).…”

Section: Overview Of Pharmacologymentioning

confidence: 99%

Impact and differential clinical utility of cobicistat-boosted darunavir in HIV/AIDS

Cossu¹,

Astuti²,

Capetti³

et al. 2015

VAAT

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Cobicistat (Cobi) is a pharmacoenhancer, without anti-HIV activity, that optimizes systemic exposures of protease inhibitors (PIs) such as atazanavir (ATV) and darunavir (DRV). In particular, Cobi is a potent inhibitor of cytochrome P450 (CYP) 3A enzymes, the main metabolizing pathway of this class of antiretrovirals. Due to its more selective inhibition of CYP3A, Cobi has a lower potential for off-target drug interactions than the standard boosting agent ritonavir (RTV), and lower likelihood for enzymatic induction. In pharmacokinetic studies of healthy volunteers, DRV boosted with Cobi attains plasma concentrations that are comparable to those achieved with 100 mg RTV as booster. In Phase III clinical trials, conducted in naïve subjects, the coformulation yielded high rates of suppression of viral replication, on average 82%-83% of treated patients reaching undetectable viremia after 48 weeks of therapy. The selection of resistance associated with mutations was a rare event and no phenotypic resistance to DRV emerged in viral failures. Generally, Cobi was well tolerated; however, it has been shown to decrease estimated creatinine clearance (ClCr) due to inhibition of tubular secretion of creatinine. Cobi, therefore, should not be initiated in patients with ClCr less than 70 mL/min, if any coadministered agent (eg, emtricitabine, lamivudine, tenofovir disoproxil fumarate, or adefovir) requires dose adjustment based on ClCr.DRV/Cobi fixed-dose combination is part of an important evolution of antiretroviral therapy toward simpler yet potent formulations. In this setting, it is important to combine potency, simplicity, safety, and high genetic barrier, as in this case.

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Cobicistat (GS-9350): A Potent and Selective Inhibitor of Human CYP3A as a Novel Pharmacoenhancer

Cited by 172 publications

References 26 publications

Correlating Structure and Function of Drug-Metabolizing Enzymes: Progress and Ongoing Challenges

Correlating Structure and Function of Drug-Metabolizing Enzymes: Progress and Ongoing Challenges

Interaction of Rifampin and Darunavir-Ritonavir or Darunavir-Cobicistat In Vitro

Impact and differential clinical utility of cobicistat-boosted darunavir in HIV/AIDS

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