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Purpose Sepsis-associated immunosuppression increases hospital-acquired infection and viral reactivation risk. A key underlying mechanism is programmed cell death protein-1 (PD-1)-mediated T-cell function impairment. This is one of the first clinical safety and pharmacokinetics (PK) assessments of the anti-PD-1 antibody nivolumab and its effect on immune biomarkers in sepsis. Methods Randomized, double-blind, parallel-group, Phase 1b study in 31 adults at 10 US hospital ICUs with sepsis diagnosed ≥ 24 h before study treatment, ≥ 1 organ dysfunction, and absolute lymphocyte count ≤ 1.1 × 10 3 cells/μL. Participants received one nivolumab dose [480 mg ( n  = 15) or 960 mg ( n  = 16)]; follow-up was 90 days. Primary endpoints were safety and PK parameters. Results Twelve deaths occurred [ n  = 6 per study arm; 40% (480 mg) and 37.5% (960 mg)]. Serious AEs occurred in eight participants [ n  = 1, 6.7% (480 mg); n  = 7, 43.8% (960 mg)]. AEs considered by the investigator to be possibly drug-related and immune-mediated occurred in five participants [ n  = 2, 13.3% (480 mg); n  = 3, 18.8% (960 mg)]. Mean ± SD terminal half-life was 14.7 ± 5.3 (480 mg) and 15.8 ± 7.9 (960 mg) days. All participants maintained > 90% receptor occupancy (RO) 28 days post-infusion. Median (Q1, Q3) mHLA-DR levels increased to 11,531 (6528, 19,495) and 11,449 (6225, 16,698) mAbs/cell in the 480- and 960-mg arms by day 14, respectively. Pro-inflammatory cytokine levels did not increase. Conclusions In this sepsis population, nivolumab administration did not result in unexpected safety findings or indicate any ‘cytokine storm’. The PK profile maintained RO > 90% for ≥ 28 days. Further efficacy and safety studies are warranted. Trial registration number (clinicaltrials.gov) NCT02960854.

In this study, once-daily treatment with oral daclatasvir plus sofosbuvir was associated with high rates of sustained virologic response among patients with genotype 1, 2, or 3 HCV infection, including those in whom previous therapy with telaprevir or boceprevir had failed. Chronic infection with hepatitis C virus (HCV) affects approximately 170 million people worldwide and is a major cause of cirrhosis and hepatocellular carcinoma. 1 , 2 HCV-related morbidity and mortality are increasing; since 2007, HCV-related deaths in the United States have exceeded those from human immunodeficiency virus (HIV) infection. 3 , 4 HCV is classified into six major genotypes. 5 , 6 Genotypes 1, 2, and 3 are found worldwide, with subtype 1a predominating in the United States and subtype 1b predominating in Europe, Japan, and China. 5 , 7 , 8 Peginterferon alfa–ribavirin treatment for chronic HCV infection is associated with a sustained virologic response (undetectable HCV RNA . . .

Background. Reversing immune exhaustion with an anti-PD-L1 antibody may improve human immunodeficiency virus type 1 (HIV-1)–specific immunity and increase clearance of HIV-1–expressing cells. Methods. We conducted a phase I, randomized, double-blind, placebo-controlled, dose-escalating study of BMS-936559, including HIV-1–infected adults aged ≥18 to ≤70 years on suppressive antiretroviral therapy with CD4+ counts ≥350 cells/μL and detectable plasma HIV-1 RNA by single-copy assay. Data on single infusions of BMS-936559 (0.3 mg/kg) versus placebo are described. The primary outcomes were safety defined as any grade 3 or greater or immune-related adverse event (AE) and the change in HIV-1 Gag-specific CD8+ T cell responses from baseline to day 28 after infusion. Results. Eight men enrolled: 6 received 0.3 mg/kg of BMS-936559, and 2 received placebo infusions. There were no BMS-936559-related grade 3 or greater AEs. In 1 participant, asymptomatic hypophysitis (a protocol-defined immune-related AE) was identified 266 days after BMS-936559 infusion; it resolved over time. The mean percentage of HIV-1 Gag-specific CD8+ T cells expressing interferon γ increased from baseline (0.09%) through day 28 (0.20%; P = .14), driven by substantial increases in 2 participants who received BMS-936559. Conclusions. In this first evaluation of an immunologic checkpoint inhibitor in healthy HIV-1–infected persons, single low-dose BMS-936559 infusions appeared to enhance HIV-1–specific immunity in a subset of participants. Clinical Trials Registration. NCT02028403.

In 21 patients with hepatitis C virus genotype 1 infection who had had no response to prior treatment, sustained virologic responses were achieved in 4 of 11 who were treated with two antiviral agents alone and in 9 of 10 who were treated with the antiviral agents plus peginterferon and ribavirin. Approximately 180 million people worldwide are infected with hepatitis C virus (HCV), including 4.1 million in the United States. 1 , 2 HCV infection is the most common cause of chronic liver disease in the United States and a leading cause of cirrhosis and hepatocellular carcinoma globally. 3 , 4 HCV is classified into six major genotypes; genotype 1 is predominant in the United States and is the most difficult to treat. 5 , 6 Treatment of HCV genotype 1 infection with peginterferon alfa and ribavirin for 48 weeks results in 24-week sustained virologic response (undetectable HCV RNA 24 weeks after the end of therapy) in . . .

New drugs for hepatitis C The development of direct-acting antiviral agents to treat chronic hepatitis C virus (HCV) infection, much needed clinically, has focused largely on inhibitors of two viral enzymes, the protease NS3 and NS5B, an RNA-dependent RNA polymerase essential for HCV replication. BMS-790052, identified using chemical genetics as a powerful specific HCV inhibitor, is a small-molecule inhibitor of a third viral molecule that has no known enzyme activity, the non-structural protein 5A (NS5A). A research team from Bristol-Myers Squibb this week reports on the discovery and virological profile of BMS-790052 and discloses clinical trial observations with this compound in normal healthy volunteers and HCV-infected subjects. These results establish proof-of-concept for HCV NS5A inhibition as a clinically relevant mechanism. In vitro data point to synergistic interactions with known HCV inhibitors, suggesting that cocktails of antiviral agents may be a viable therapeutic approach. Almost 200 million people worldwide are chronically infected with hepatitis C virus. Current treatments are poorly tolerated and not wholly effective, so new drugs are needed. Here, a potent new inhibitor of hepatitis C virus is described. This inhibitor targets the viral protein NS5A, and shows potential as part of a therapeutic regimen based on a combination of viral inhibitors. The worldwide prevalence of chronic hepatitis C virus (HCV) infection is estimated to be approaching 200 million people 1 . Current therapy relies upon a combination of pegylated interferon-α and ribavirin, a poorly tolerated regimen typically associated with less than 50% sustained virological response rate in those infected with genotype 1 virus 2 , 3 . The development of direct-acting antiviral agents to treat HCV has focused predominantly on inhibitors of the viral enzymes NS3 protease and the RNA-dependent RNA polymerase NS5B 4 . Here we describe the profile of BMS-790052, a small molecule inhibitor of the HCV NS5A protein that exhibits picomolar half-maximum effective concentrations (EC 50 ) towards replicons expressing a broad range of HCV genotypes and the JFH-1 genotype 2a infectious virus in cell culture. In a phase I clinical trial in patients chronically infected with HCV, administration of a single 100-mg dose of BMS-790052 was associated with a 3.3 log 10 reduction in mean viral load measured 24 h post-dose that was sustained for an additional 120 h in two patients infected with genotype 1b virus. Genotypic analysis of samples taken at baseline, 24 and 144 h post-dose revealed that the major HCV variants observed had substitutions at amino-acid positions identified using the in vitro replicon system. These results provide the first clinical validation of an inhibitor of HCV NS5A, a protein with no known enzymatic function, as an approach to the suppression of virus replication that offers potential as part of a therapeutic regimen based on combinations of HCV inhibitors.

Abstract Certain fluoroquinolones and macrolide antibiotics have been associated with prolongation of the corrected QT (QTc) interval or QT dispersion, leading to cardiac arrhythmias. Garenoxacin is a des-F(6)-quinolone with broad-spectrum antimicrobial activity and a favorable pharmacokinetic/pharmacodynamic profile. Its effects on electrocardiographic (ECG) parameters in healthy volunteers have not been reported. The cardiac safety profile of garenoxacin was further examined using data from healthy volunteers enrolled in 5 dose-ranging and comparative Phase I clinical studies. This was a retrospective analysis of 5 randomized, double-blind, placebo-controlled studies in which 224 healthy volunteers received oral or intravenous garenoxacin (50–1200 mg/d) for 1 to 28 days' dosing duration (≤14 days' therapeutic duration). The effects of garenoxacin on the QT interval corrected using Bazett's formula (QTcB) and Fridericia's formula (QTcF) and the PR interval were assessed by counts of outliers, linear regressions, and exposure-response plots. Absence of a concentration-dependent effect of garenoxacin on changes from baseline ECG parameters was concluded if the 95% CI for the linear regression slopes of derived QTc- or PR-interval parameters relative to C max and C avg0–12 (average garenoxacin plasma concentration from 0–12 hours after dosing) values for garenoxacin contained zero. No clinically relevant changes in the QTc or PR intervals were observed over a range of garenoxacin plasma concentrations (C max: 0.5–38.6 μg/mL, oral dose range; 3.36–21.4 μg/mL, intravenous dose range). No volunteer had a prolongation from baseline that exceeded established thresholds for the QTcB or QTcF interval (>450 milliseconds for men, >470 milliseconds for women) or the PR interval (>250 milliseconds). One subject had a change in QTcB of 67 milliseconds 4 hours after administration of garenoxacin 400 mg PO on day 7, but the actual value was 418 milliseconds (baseline, 351 milliseconds); the corresponding change in QTcF was 49 milliseconds (actual, 408 milliseconds; baseline, 359 milliseconds). The means for other derived ECG parameters were generally similar between garenoxacin-treated volunteers and placebo controls. In this retrospective analysis of data from healthy volunteers, garenoxacin had no clinically relevant dose-, route-of-administration-, or concentration-dependent effects on the QTc or PR interval across a dose range from 50 to 1200 mg/d.

Background and Objectives The combination of direct-acting antiviral agents in patients with chronic hepatitis C virus (HCV) infection has demonstrated clinical benefit; however, evaluation of potential drug–drug interactions is required prior to therapy. Methods An open-label study assessed the pharmacokinetics and tolerability of the HCV NS5A replication complex inhibitor daclatasvir and the HCV NS3 protease inhibitor asunaprevir when co-administered in healthy subjects. Daclatasvir 60 mg once daily and asunaprevir 600 mg twice daily were dosed for 7 days alone followed by combination dosing for 14 days at 30 mg once daily and 200 mg twice daily, respectively. Further assessments were provided comparing exposures from the current study with those from studies in HCV-infected patients receiving either the same or higher doses of daclatasvir or asunaprevir administered alone or together. Results Dose-normalized daclatasvir and asunaprevir morning exposures were comparable with control in healthy subjects, with geometric mean area under the concentration–time curve ratios of 1.202 (90 % CI 1.113–1.298) and 0.868 (90 % CI 0.726–1.038), respectively. In HCV patients daclatasvir and asunaprevir exposures were largely comparable, when administered together or alone. Conclusions Additional data support the conclusion that there is no clinically meaningful interaction between daclatasvir and asunaprevir in either healthy subjects or HCV-infected patients, including those also receiving peginterferon-α/ribavirin, and that the combination of daclatasvir 60 mg once daily and asunaprevir 200 mg twice daily is generally well-tolerated.

ABSTRACT Objective: This open-label, parallel-group study determined the pharmacokinetics of garenoxacin in subjects with severe renal impairment, including subjects maintained on dialysis. Research design and methods: Subjects were assigned to one of four groups according to their underlying renal function: creatinine clearance (CLcr) > 80 mL/min, CLcr < 30 mL/min, hemodialysis (HD), and continuous ambulatory peritoneal dialysis (CAPD). Subjects received a single oral 600‑mg dose of garenoxacin. Administration of garenoxacin to subjects receiving hemodialysis was completed in two phases separated by 14 days: 3 h before HD (phase 1) and immediately after HD (phase 2). Main outcome measures: Plasma and urine or dialysate samples were analyzed for garenoxacin, and single-dose pharmacokinetic parameters were estimated. Safety was assessed. Results: Twenty-five subjects received garenoxacin. Compared with healthy controls, garenoxacin area under the concentration–time curve (AUC) and maximum plasma concentration were increased by 51% and lowered by 20%, respectively, in subjects with severe renal impairment. The terminal half-life was prolonged in subjects with severe renal impairment compared with healthy controls (26.5 ± 7 h vs 14.4 ± 3 h, respectively). In subjects receiving HD or CAPD, removal of garenoxacin from systemic circulation was relatively inefficient (HD, 1.5–11.5%; CAPD, 3%), suggesting no need for a supplemental dose of garenoxacin after dialysis. Garenoxacin was well tolerated. Conclusions: Based on the broad therapeutic index of garenoxacin, the effects of renal impairment on garenoxacin exposure are not considered clinically significant. There was a modest increase in AUC in subjects with severe renal impairment and the magnitude of the changes was not considered clinically relevant.

Gatifloxacin is an advanced-generation, 8-methoxy fluoroquinolone that is active against a broad spectrum of pathogens, including antibiotic-resistant Streptococcus pneumoniae. The drug has high oral bioavailability (96%), and, therefore, oral and intravenous formulations are bioequivalent and interchangeable. Gatifloxacin has a large volume of distribution (∼1.8 L/kg), low protein binding (∼20%), and broad tissue distribution and is primarily excreted unchanged in the urine (>80%). Gatifloxacin can be administered without dose modification in patients with hepatic impairment, in women, and in the elderly. In vitro experiments and clinical studies indicate that gatifloxacin does not interact with drugs metabolized by the cytochrome P450 enzyme family. At therapeutically relevant doses, gatifloxacin's pharmacodynamically linked parameters (the ratio of maximum serum concentration to minimum inhibitory concentration and the ratio of the area under the curve to minimum inhibitory concentration) are similar to or better than those of other fluoroquinolones. Clinical studies show that gatifloxacin has limited potential to prolong the QT interval on the electrocardiogram and lacks the potential to cause photosensitivity reactions, to alter oral glucose tolerance, or to cause crystalluria.

Objective: This open-label, parallel-group study determined the pharmacokinetics of garenoxacin in subjects with severe renal impairment, including subjects maintained on dialysis. Research design and methods: Subjects were assigned to one of four groups according to their underlying renal function: creatinine clearance (CL cr ) > 80 mL/min, CL cr < 30 mL/min, hemodialysis (HD), and continuous ambulatory peritoneal dialysis (CAPD). Subjects received a single oral 600-mg dose of garenoxacin. Administration of garenoxacin to subjects receiving hemodialysis was completed in two phases separated by 14 days: 3 h before HD (phase 1) and immediately after HD (phase 2). Main outcome measures: Plasma and urine or dialysate samples were analyzed for garenoxacin, and single-dose pharmacokinetic parameters were estimated. Safety was assessed. Results: Twenty-five subjects received garenoxacin. Compared with healthy controls, garenoxacin area under the concentration-time curve (AUC) and maximum plasma concentration were increased by 51% and lowered by 20%, respectively, in subjects with severe renal impairment. The terminal half-life was prolonged in subjects with severe renal impairment compared with healthy controls (26.5 ± 7 h vs 14.4 ± 3 h, respectively). In subjects receiving HD or CAPD, removal of garenoxacin from systemic circulation was relatively inefficient (HD, 1.5-11.5%; CAPD, 3%), suggesting no need for a supplemental dose of garenoxacin after dialysis. Garenoxacin was well tolerated. Conclusions: Based on the broad therapeutic index of garenoxacin, the effects of renal impairment on garenoxacin exposure are not considered clinically significant. There was a modest increase in AUC in subjects with severe renal impairment and the magnitude of the changes was not considered clinically relevant.