Cefiderocol, a new injectable siderophore cephalosporin antibiotic, has promising in vitro and in vivo activity against Gram‐negative bacteria including multidrug‐resistant Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae. Cefiderocol is mainly renally eliminated. The pharmacokinetics and safety of cefiderocol in subjects with renal impairment were assessed following a single 1000‐mg intravenous 1‐hour infusion of cefiderocol. Subjects with mild, moderate, or severe renal impairment and end‐stage renal disease (ESRD) requiring hemodialysis were compared with demographically (age, body mass index, and sex) matched healthy subjects with normal renal function. The effect of hemodialysis on the clearance of cefiderocol was also assessed. Total drug clearance from plasma (CL) and terminal half‐life (t1/2) correlated with renal function. Ratios (90% confidence intervals) of area under the plasma concentration‐time curve from 0 to infinity (AUC) in mild, moderate, severe, and ESRD groups compared to those with normal renal function were 1.0 (0.8‐1.3), 1.5 (1.2‐1.9), 2.5 (2.0‐3.3), and 4.1 (3.3‐5.2), respectively. Maximum plasma concentration (Cmax) was similar between renal‐impairment groups and the normal‐renal‐function group. Approximately 60% of cefiderocol was removed by hemodialysis for 3 to 4 hours. The plasma‐protein‐unbound fraction was similar between various renal function groups. The incidence of adverse events did not appear to have any correlation with the degree of renal impairment. Single 1000‐mg intravenous doses of cefiderocol were generally well tolerated in subjects with impaired renal function except for 1 subject who discontinued due to urticaria. In conclusion, renal impairment impacted AUC, CL, and t1/2 without affecting Cmax. Cefiderocol was significantly removed by intermittent hemodialysis.

Introduction and Aims: JTZ-951 is a potent inhibitor of hypoxia inducible factor prolyl hydroxylase (HIF-PHD) with in vitro human IC 50 of 0.106 µmol/L. Phase 1 studies in healthy subjects showed dose-related increases in JTZ-951 plasma levels following single and once daily (QD) administration. The current study was conducted to characterize the pharmacokinetics (PK), pharmacodynamics (PD), and safety of JTZ-951 in patients with end-stage renal disease (ESRD) with anemia receiving hemodialysis (HD). The purpose was to define a dose/exposure range to enable dose-ranging trials in the target population. Methods: This was a single-blind, placebo-controlled, ascending dose study at 2, 5, 10, and 15 mg JTZ-951 QD (n=6 active, 2 placebo/dose) for 15 days. Key inclusion criteria were males and females (18-75 years) with ESRD on HD thrice weekly, hemoglobin (Hgb) ≥8.5 to ≤11.0 g/dL on Day -1 [baseline (BL)], ESA-naïve, or a 7-day washout of Epoetin-α; exclusion criteria were transferrin saturation (TSAT) ≤20% or ferritin ≤200 ng/mL, hyporesponsiveness to ESAs, AST, ALT, or ALP>2x upper limit of normal (ULN), total bilirubin >1.5x ULN. IV iron was discontinued 30 days before JTZ-951 dosing. At appropriate intervals, laboratory safety tests, vitals, and 12-lead ECGs were assessed; blood samples were obtained for hematology (e.g., reticulocytes, Hgb), iron-related parameters, erythropoietin (EPO), and vascular endothelial growth factor (VEGF). Plasma and urine were quantified for JTZ-951 PK with validated methods. Results: JTZ-951 was rapidly absorbed with peak levels (C max ) at 0.5-1.5 hrs. Mean effective half-life (t 1/2eff ) was ∼11 hrs and was dose-independent demonstrating linear kinetics. JTZ-951 C max and area under the curve (AUC) increased roughly dose proportionally, with minimal accumulation (∼20%) on Day 15 (consistent with t 1/2eff ), low inter-subject variability in AUC (∼30%), demonstrating reproducible kinetics in HD patients. EPO changes at 2 mg were similar to placebo; from 5 to 15 mg there were marginal, transient, dose dependent EPO increases that were similar on Days 1 and 15. Reticulocyte counts increased with dose (5 to 15 mg) from Day 5 onwards. Mean Hgb levels at 2 mg declined over the 2-week period (similar to placebo); at 5 mg Hgb declined initially, then stabilized by Day 10, albeit without positive changes from BL on Day 16. At 10 mg, Hgb increased on Day 16, with mean 0.74 ± 1.1 g/dL (range: -0.7 to 2.3 g/dL; n=5) change from BL. At 15 mg, 3 subjects discontinued treatment prior to Day 15 based on predefined Hgb increase criteria and one discontinued on Day 12 due to stenosis of fistula (not related to JTZ-951); in the remaining two subjects, Day 16 Hgb increases were 1.4 and 1.6 g/dL. Dose-dependent increases in Hgb were observed. Dose-dependent changes in ferritin, hepcidin, TIBC, and UIBC, with stable serum iron levels, indicated iron mobilization. There were no dose-related changes in VEGF, laboratory safety parameters, vital signs and ECGs. Daily JTZ-951 administration for 15 days was s...

No abstract

Background: Trans Sodium Crocetinate (TSC) is a bipolar synthetic carotenoid under development as a drug to enhance oxygenation to hypoxic tissue in addition to standard of care. TSC acts via a novel mechanism of action, improving the diffusivity of oxygen in blood plasma. Thus, it is based on physical-chemical principles, unlike most drugs which are based on biochemistry-based mechanisms. We explored the use of escalating doses and multiple daily dosing of TSC as a potential therapeutic for patients suffering from hypoxemia due to SARS-CoV-2 infection. Methods: Individuals ≥18 years who were hospitalized with confirmed SARS-CoV-2 infection and hypoxemia, defined as SpO2 < 94% on room air or requiring supplemental oxygen, WHO ordinal scale 3 through 7 (exclusive of Extra Corporeal Membrane Oxygenation [ECMO]) were enrolled in cohorts of six subjects, each of whom received the same dose (0.25, 0.5, 1.0, or 1.5 mg/kg) of TSC via intravenous bolus every 6 hours in addition to standard of care (SOC). This report describes the safety and efficacy results from the lead-in phase of the study and the population pharmacokinetics (PK) analyses. Safety was assessed as the number of serious adverse events and dose-limiting toxicities (DLTs) observed with each dose. Several efficacy parameters were examined in the lead-in phase and descriptive statistics of efficacy parameters are provided. No formal statistical analyses were performed. The population PK analyses were based on previous analyses and examination of the concentration profiles, and two-compartment linear pharmacokinetic models were evaluated and validated. Covariates, including body size, age, sex, organ function, and dose level, were evaluated for inclusion into the model. Results: TSC was well tolerated. There were no treatment emergent adverse events (TEAEs) reported. There were 2 serious adverse events (SAEs) reported during the study, neither were considered treatment-related. A total of 24 (96%) subjects survived. One subject (4.0%) died during the study as a result of an SAE (respiratory failure), and that event was determined to be due to COVID-19 complications and not related to study drug. There was an observed reduction in the time to improvement in WHO Ordinal Scale with increasing dose. The median time to 1-point reduction in subjects receiving 0.25 mg/kg was 11.5 days versus 7.5 days in the 1.5 mg/kg treatment cohort. The overall range across all doses was 1 day to 28 days. A total of 36.0% of subjects had a 1-point improvement in WHO Ordinal Scale to Day 7. The 1.5 mg/kg dose resulted in observed superior outcomes for multiple secondary clinical outcomes: time to 1-point WHO Ordinal Score improvement through Day 29/discharge, 1-point improvement by Day 7, days to return to room air, and hospital length of stay. The PK results showed that the two-compartment model fit the data well. Clearance decreased with increasing dose level and there was no evidence that clearance was affected by covariates other than dose level. Conclusions: These findings suggest that TSC administration every 6 hours at doses up to 1.5 mg/kg for up to 15 days is safe and well tolerated with predictable pharmacokinetics and demonstrated an observed clinical benefit in the treatment of COVID-19-related hypoxemia.

JNJ-56914845 (GSK2336805) is a hepatitis C virus nonstructural protein 5A inhibitor under development for the treatment of chronic hepatitis C (CHC) infection. This open-label, parallel-group, 2-part study evaluated the pharmacokinetics and safety of a single oral 60 mg dose of JNJ-56914845 in 4 cohorts: healthy, mild, moderate, and severe hepatic impairment (n = 8/cohort). Severity of hepatic impairment was categorized using Child-Pugh score, and the healthy subjects were matched for age, sex, body mass index, and smoking status to the moderate hepatic impairment cohort. JNJ-56914845 plasma AUC0-∞ was 26%, 52%, and 45% lower in subjects with mild, moderate, and severe hepatic impairment, respectively, relative to healthy subjects with no difference in half-life among the groups. The apparent oral clearance and volume of distribution were higher in subjects with hepatic impairment. The lower plasma concentrations were largely explained by decreased plasma protein binding in hepatically impaired subjects. One subject with severe hepatic impairment had 2 non-drug-related serious adverse events: an esophageal bleed requiring hospitalization, encephalopathy. Although hepatically impaired subjects have lower exposures than healthy matched controls, they had similar or slightly higher exposures than those observed in past studies of noncirrhotic, CHC patients, suggesting that no dose adjustments for hepatic impairment will be needed.