Pharmacokinetics, Efficacy, and Safety of Darunavir/Ritonavir 800/100 mg Once-Daily in Treatment-Naïve and -Experienced Patients

dWe report that GRL-0519, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing tris-tetrahydrofuranylurethane (tris-THF) and a sulfonamide isostere, is highly potent against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC 50 ], 0.0005 to 0.0007 M) with minimal cytotoxicity (50% cytotoxic concentration [CC 50 ], 44.6 M). GRL-0519 blocked the infectivity and replication of HIV-1 NL4-3 variants selected by up to a 5 M concentration of ritonavir, lopinavir, or atazanavir (EC 50 , 0.0028 to 0.0033 M). GRL-0519 was also potent against multi-PIresistant clinical HIV-1 variants isolated from patients who no longer responded to existing antiviral regimens after long-term antiretroviral therapy, highly darunavir (DRV)-resistant variants, and HIV-2 ROD . The development of resistance against GRL-0519 was substantially delayed compared to other PIs, including amprenavir (APV) and DRV. The effects of nonspecific binding of human serum proteins on GRL-0519's antiviral activity were insignificant. Our analysis of the crystal structures of GRL-0519 (3OK9) and DRV (2IEN) with protease suggested that the tris-THF moiety, compared to the bis-THF moiety present in DRV, has greater water-mediated polar interactions with key active-site residues of protease and that the tris-THF moiety and paramethoxy group effectively fill the S2 and S2= binding pockets, respectively, of the protease. The present data demonstrate that GRL-0519 has highly favorable features as a potential therapeutic agent for treating patients infected with wild-type and/or multi-PIresistant variants and that the tris-THF moiety is critical for strong binding of GRL-0519 to the HIV protease substrate binding site and appears to be responsible for its favorable antiretroviral characteristics.

Section: Discussionmentioning

confidence: 99%

GRL-0519, a Novel Oxatricyclic Ligand-Containing Nonpeptidic HIV-1 Protease Inhibitor (PI), Potently Suppresses Replication of a Wide Spectrum of Multi-PI-Resistant HIV-1 Variants In Vitro

Amano

Tojo

Salcedo-Gómez

et al. 2013

“…and DRV/c (800/150 mg q.d.) in HIV-infected patients are broadly similar (53,54). However, in a study conducted in healthy volunteers, it has been reported that the minimum concentration (C min ) of DRV is 30% lower in individuals treated with DRV/c than individuals treated with DRV/r (55).…”

Section: Discussionmentioning

confidence: 92%

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

Roberts

Khoo

Owen

et al. 2017

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...

“…In subjects taking DRV QD, 52 of 60 (87%) C trough values were above 550 ng/ml, the 50% effective concentration (EC 50 ) (adjusted for protein binding) for resistant virus (7)(8)(9). The lowest measured DRV exposure for the one subject who failed to maintain viral load suppression was 618 ng/ml at week 4.…”

Section: Resultsmentioning

confidence: 99%

Pharmacokinetic Evaluation of Darunavir Administered Once or Twice Daily in Combination with Ritonavir or the Three-Direct-Acting Antiviral Regimen of Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir in Adults Coinfected with Hepatitis C and Human Immunodeficiency Viruses

King

Khatri

Trinh

et al. 2017

The three-direct-acting antiviral (3D) regimen containing ombitasvir, paritaprevir, ritonavir, and dasabuvir with or without ribavirin (RBV) is approved for treatment of hepatitis C virus (HCV) genotype 1 (GT1)/human immunodeficiency virus type 1 (HIV-1) coinfection. Results of a pharmacokinetic substudy of 3D and darunavir are presented. HCV/HIV-1-coinfected subjects were randomized to maintain an antiretroviral regimen with darunavir at 800 mg once daily (QD) or switched to a regimen with darunavir at 600 mg twice daily (BID). On study day 1, subjects received 3D and RBV plus darunavir for 12 weeks. Pharmacokinetic parameters were compared for darunavir and ritonavir with and without 3D (week 4 and day Ϫ1). Pharmacokinetic parameters of 3D were compared to historical data. Ten subjects received darunavir QD, and 12 subjects received darunavir BID. The central value ratios (90% confidence interval [CI]) for maximum concentrations (C max ), area under the plasma concentration-time curve between 0 and 24 h postdose (AUC 24 ), and trough plasma concentration at 24 h postdose (C 24 ) of darunavir administered QD with 3D versus administration of darunavir alone were 0.92 (0.72, 1.18), 0.83 (0.71, 0.98), and 0.64 (0.44, 0.93), respectively. The ratios (90% CI) for darunavir C max , AUC 12 , and C 12 administered BID with 3D were 0.92 (0.76, 1.12), 0.88 (0.73, 1.05), and 0.73 (0.58, 0.92), respectively. Exposures of 3D were similar to or slightly lower than those in historical data. All darunavir trough concentrations (C trough ) associated with an HIV-1 RNA level of Ͼ40 copies/ml were above the darunavir 50% effective concentration (EC 50 ) of 550 ng/ml for resistant virus. In conclusion, the 3D regimen with darunavir QD or BID did not affect darunavir C max and AUC, whereas the darunavir C trough decreased. Changes in pharmacokinetic parameters of 3D were not considered clinically significant. Episodes of intermittent HIV-1 viremia were infrequent and were not associated with darunavir C trough values below 550 ng/ml. (This study has been registered at ClinicalTrials.gov under identifier NCT01939197.) KEYWORDS DAA, darunavir, HCV, HIV, paritaprevir, dasabuvir, ombitasvir