Steady-State Pharmacokinetics of Intravenous Hydromorphone in Japanese Patients With Renal Impairment and Cancer Pain.

Background: The opioid analgesic hydromorphone has a low renal excretion ratio; however, exposure after oral administration is several times higher in those with moderate or severe renal impairment. Objectives: We evaluated the impact of renal impairment on the steady-state pharmacokinetics of intravenously administered hydromorphone in patients with cancer being treated for pain. Design: This was an open-label, prospective, parallel-comparison, interventional clinical pharmacology study. Setting/Subjects: This study was conducted at one hospital in Japan. Using creatinine clearance (CLcr) values, patients were grouped according to kidney function: CLcr ≥90 mL/min (normal), 60-<90 mL/min (mild impairment), 30-<60 mL/min (moderate impairment), or <30 mL/min (severe impairment). Measurements: Hydromorphone was administered by constant infusion to patients at the same constant dose rate as at the time of enrollment. Hydromorphone and its glucuronide metabolite concentrations in plasma and urine were measured by liquid chromatography-mass spectrometry. Pharmacokinetic parameters at steady state were assessed using noncompartmental analysis. Results: Thirty-two patients were enrolled (normal, n = 3; mild, n = 10; moderate, n = 15; and severe, n = 4). Adjusted geometric mean ratios for hydromorphone steady-state clearance (CLss) for patients with impaired versus normal renal function were 0.69 (90% confidence interval [CI], 0.41-1.14), 0.52 (90% CI, 0.31-0.84), and 0.55 (90% CI, 0.30-1.02) for mild, moderate, or severe impairment, respectively. Exposures to the metabolite hydromorphone-3-glucuronide generally increased with renal impairment. No adverse event was reported. Conclusion: Hydromorphone CLss in patients with impaired renal function (moderate and severe) was decreased ∼50% of that of normal renal function.

Efficacy and Safety of Esaxerenone in Hypertensive Patients with Diabetic Kidney Disease: A Multicenter, Open-Label, Prospective Study.

INTRODUCTION: Clinical data of esaxerenone in hypertensive patients with diabetic kidney disease (DKD) are lacking. We evaluated the efficacy and safety of esaxerenone in patients with DKD and an inadequate response to blood pressure (BP)-lowering treatment. METHODS: In this multicenter, open-label, prospective study, patients were divided into urinary albumin-to-creatinine ratio subcohorts (UACR < 30, 30 to < 300, and 300 to < 1000 mg/gCr). Esaxerenone was initiated at 1.25 mg/day and followed by incremental dose escalation based on BP and serum potassium level monitoring. The treatment period was 12 weeks. The primary endpoint was change in morning home systolic BP/diastolic BP (SBP/DBP) from baseline to end of treatment (EOT). Secondary endpoints included achievement rate of target BP, change in UACR from baseline, and safety. RESULTS: In total, 113 patients were enrolled. Morning home SBP/DBP significantly decreased from baseline to EOT in the total population (- 11.6/- 5.2 mmHg, both p < 0.001) and in all UACR subcohorts (all p < 0.001). The target BP achievement rate was 38.5%. Significant reductions in bedtime home and office BPs were also shown in the total population and all UACR subcohorts. UACR significantly improved from baseline to EOT in the total (- 50.9%, p < 0.001) and all UACR subcohorts (all p < 0.001). Incidence of serum potassium elevation as drug-related treatment emergent adverse events was 2.7%. The change from baseline in estimated glomerular filtration rate (eGFR) was - 4.8 mL/min/1.73 m2. CONCLUSION: Esaxerenone demonstrated a BP-lowering effect and improved albuminuria. The effects were consistent regardless of the severity of albuminuria without clinically relevant serum potassium elevation and eGFR reduction. CLINICAL TRIAL REGISTRATION: jRCTs06119002.

Rationale and Design of the Efficacy and Safety of Esaxerenone in Hypertensive Patients With Left Ventricular Hypertrophy (ESES-LVH) Study　- Protocol for a Multicenter, Open-Label, Exploratory Interventional Study.

Background: The complication of left ventricular (LV) hypertrophy (LVH) is associated with increased incidence of major cardiovascular events. Hypertension is an independent risk factor among several factors contributing to the development of LVH, and thus appropriate treatment of both hypertension and LVH reduces the risk of developing heart failure. Mineralocorticoid-receptor blockers (MRBs) have been reported to improve the prognosis of LVH, but use of currently available MRBs is limited by adverse events. Esaxerenone is a novel selective nonsteroidal MRB recently approved for treatment of hypertension. Although the renoprotective effect of esaxerenone has been demonstrated in both preclinical and clinical studies, little data is available in terms of its cardioprotective effects. Methods and Results: This multicenter, open-label, exploratory interventional study was designed to evaluate the safety and efficacy of esaxerenone in combination with renin-angiotensin system (RAS) inhibitors or calcium-channel blockers (CCBs). Eligible criteria are hypertensive patients with LVH, and target blood pressure (BP) not reached with an RAS inhibitor or a CCB. The primary endpoints are change from baseline in seated home BP (early morning systolic/diastolic BPs), and change and %change from baseline in the LV mass index at the end of treatment. Conclusions: This study will provide the first clinical evidence of the antihypertensive effect and safety of esaxerenone in hypertensive patients with LVH.

Analysis of fluoroquinolone-resistance using MIC determination and homology modelling of ParC of contemporary Mycoplasma genitalium strains.

INTRODUCTION: The mechanisms of fluoroquinolone-resistance of Mycoplasma genitalium were analysed by a new method. METHODS: M. genitalium strains from urinary sediments of patients with urethritis were isolated and examined antimicrobial susceptibilities and the mutations in ParC, GyrA and 23S rRNA. Docking models between gyrase and topoisomerase IV with sitafloxacin showed that two binding modes in which the amine moiety at the C-7 position rotated could be constructed. RESULTS: Among 18 strains, 13 strains had mutations with amino-acid changes at Serine 83 in ParC. The MICs of moxifloxacin or sitafloxacin for three strains with only S83I in ParC were 2, 1 and 8 mg/L (moxifloxacin) or 0.13, 0.13 and 1 mg/L (sitafloxacin), respectively. In contrast, the MICs of moxifloxacin or sitafloxacin for 3 strain with S83N in ParC were 0.25, 0.13 and 0.25 mg/L (moxifloxacin) or 0.06, 0.03, and 0,03 mg/L (sitafloxacin), respectively, not significantly different from wild-type isolates. The docking model of sitafloxacin and topoisomerase IV showed that the oxygen atom at the gamma position of Serine 83 of ParC interacted with the sitafloxacin carboxylate moiety. When the S83I substitution occurs, the isoleucine side chain is lipophilic and the residue hydropathy changes from hydrophilicity to hydrophobicity and important H-bond interactions between serine and the carboxylate moiety are lost. When the serine 83 to asparagine substitution (S83N) occurred, the asparagine side chain is hydrophilic and the residue hydropathy does not change. CONCLUSION: The docking model suggests that Ser83 replacements causes attenuation or loss of activity of fluoroquinolones such as sitafloxacin.

Effects of concomitant use of prasugrel with edoxaban on bleeding time, pharmacodynamics, and pharmacokinetics of edoxaban in healthy elderly Japanese male subjects: a clinical pharmacology study.

BACKGROUND: Dual therapy with a direct oral anticoagulant (DOAC) plus a P2Y12 receptor inhibitor is recommended in patients with nonvalvular atrial fibrillation who undergo percutaneous coronary intervention. Thus, we evaluated the effects of DOAC edoxaban plus P2Y12 receptor inhibitor prasugrel on bleeding time (BT), and pharmacodynamics (PD) and pharmacokinetics (PK) of edoxaban in healthy elderly Japanese male subjects. METHODS: A single-center, clinical pharmacology study with randomized, open-label, repeated dosing enrolled 24 participants in two groups of 12 receiving 30 mg edoxaban once daily for 3 days; then 30 mg edoxaban plus 2.5 mg prasugrel (Group 1) or 30 mg edoxaban plus 3.75 mg prasugrel (Group 2) once daily for 5 days. Primary endpoint was BT by the Ivy method. Secondary endpoints were the PD parameters of prothrombin time (PT), activated partial thromboplastin time (aPTT), prothrombin fragment F1 + 2 (F1 + 2), and P2Y12 reaction units (PRU), and PK profiles of edoxaban alone and in combination with prasugrel. RESULTS: Geometric least squares mean of BT ratios (vs. baseline) for 3-day edoxaban treatment were 1.097 (90% confidence interval (CI) 0.911-1.321) in Group 1 and 1.327 (90% CI 1.035-1.703) in Group 2; for 5-day edoxaban plus 2.5 mg and 3.75 mg prasugrel, they were 1.581 (90% CI 1.197-2.087) and 1.996 (90% CI 1.482-2.690), respectively. Contributions of prasugrel to the effects (edoxaban + prasugrel/edoxaban) were 1.442 (90% CI 1.096-1.897) in Group 1 and 1.504 (90% CI 1.172-1.930) in Group 2. Edoxaban prolonged PT and aPTT and decreased F1 + 2. Adding on prasugrel did not appreciably change PT, aPTT, or F1 + 2. Prasugrel reduced PRU, whereas edoxaban had no effect on PRU. We recorded 26 adverse events; 23 were treatment-emergent (positive fecal occult blood test). All participants with adverse events recovered during follow-up. CONCLUSIONS: Coadministration of 2.5 mg and 3.75 mg prasugrel with 30 mg edoxaban prolonged BT in healthy elderly Japanese male subjects. The effect was dependent on the dose of prasugrel. Prasugrel did not affect PD or PK profiles of edoxaban. Edoxaban had no effect on PD of prasugrel. TRIAL REGISTRATION: Japan Registry of Clinical Trials No. jRCTs071190006; registration date, 26-April-2019.

Sensory evaluation of edoxaban orally disintegrating tablets: an open-label interventional study (secondary publication).

BACKGROUND: This study involved a sensory evaluation of edoxaban orally disintegrating (OD) tablets in patients with nonvalvular atrial fibrillation who had been receiving the existing edoxaban film-coated tablets before the study. METHODS: Edoxaban OD tablets 30 or 60 mg were prescribed for patients who had been receiving the existing 30- or 60-mg edoxaban film-coated tablets before the study. Each dose group was randomized into groups taking the tablets with or without water. After ingestion of the edoxaban OD tablet, each patient was asked to complete a sensory evaluation questionnaire (12 items). RESULTS: In the evaluation of satisfaction with edoxaban OD tablets, 52.8% of the patients perceived "no difference" from the existing edoxaban film-coated tablets and 34.9% indicated that they were more satisfied with the OD tablets, thus demonstrating a relatively high degree of satisfaction. When asked about convenience and reliability in using edoxaban OD tablets, about half of the patients perceived "no difference" from the existing edoxaban film-coated tablets and the remaining half indicated preference for the OD tablets. Responses about taste, flavor, ease of ingestion, and motivation to continue taking edoxaban indicated the overall acceptance of the OD tablets. Recognition of edoxaban OD tablets was rated as "easy" by about half of the patients and "difficult" by the remaining half. Among all patients, 49.5% preferred a change to edoxaban OD tablets. The degree of satisfaction with taste, flavor, and ease of ingestion, as well as overall satisfaction, tended to be greater when the OD tablets were taken with rather than without water, and the percentage of patients who preferred a change was higher in the group taking the OD tablets with water. CONCLUSIONS: This study indicated that the degree of satisfaction with taste, flavor, ease of ingestion, and convenience, as well as overall satisfaction, in addition to motivation to continue drug intake and sense of confidence were greater for OD tablets than for the existing edoxaban film-coated tablets. Edoxaban OD tablet is a promising formulation for inducing greater patient adherence to medication and therefore ensures better treatment response. TRIAL REGISTRATION: UMIN-CTR UMIN000028788, registered 23-Aug-2017.

In vitro and in vivo antibacterial activities of DK-507k, a novel fluoroquinolone.

The antibacterial activities of DK-507k, a novel quinolone, were compared with those of other quinolones: ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, sitafloxacin, and garenoxacin (BMS284756). DK-507k was as active as sitafloxacin and was as active as or up to eightfold more active than gatifloxacin, moxifloxacin, and garenoxacin against Streptococcus pneumoniae, methicillin-susceptible and methicillin-resistant Staphylococcus aureus, and coagulase-negative staphylococci. DK-507k was as active as or 4-fold more active than garenoxacin and 2- to 16-fold more active than gatifloxacin and moxifloxacin against ciprofloxacin-resistant strains of S. pneumoniae, including clinical isolates and in vitro-selected mutants with known mutations. DK-507k inhibited all ciprofloxacin-resistant strains of S. pneumoniae at 1 microg/ml. A time-kill assay with S. pneumoniae showed that DK-507k was more bactericidal than gatifloxacin and moxifloxacin. The activities of DK-507k against most members of the family Enterobacteriaceae were comparable to those of ciprofloxacin and equal to or up to 32-fold higher than those of gatifloxacin, levofloxacin, moxifloxacin, and garenoxacin. DK-507k was fourfold less active than sitafloxacin and ciprofloxacin against Pseudomonas aeruginosa, while it was two to four times more potent than levofloxacin, gatifloxacin, moxifloxacin, and garenoxacin against P. aeruginosa. In vivo, intravenous treatment with DK-507k was more effective than that with gatifloxacin and moxifloxacin against systemic infections caused by S. aureus, S. pneumoniae, and P. aeruginosa in mice. In a mouse model of pneumonia due to penicillin-resistant S. pneumoniae, DK-507k administered subcutaneously showed dose-dependent efficacy and eliminated the bacteria from the lungs, whereas gatifloxacin and moxifloxacin had no significant efficacy. Oral treatment with DK-507k was slightly more effective than that with ciprofloxacin in a rat model of foreign body-associated urinary tract infection caused by a P. aeruginosa isolate for which the MIC of DK-507k was fourfold higher than that of ciprofloxacin. Oral administration of DK-507k to rats achieved higher peak concentrations in serum and higher concentrations in cumulative urine than those achieved with ciprofloxacin. These data indicate the potential advantages of DK-507k over other quinolones for the treatment of a wide range of community-acquired infections.

In vitro antibacterial activities of DQ-113, a potent quinolone, against clinical isolates.

The antibacterial activity of DQ-113, formerly D61-1113, was compared with those of antibacterial agents currently available. MICs at which 90% of the isolates tested are inhibited (MIC90s) of DQ-113 against clinical isolates of methicillin-susceptible and -resistant Staphylococcus aureus and methicillin-susceptible and -resistant coagulase-negative staphylococci were 0.03, 0.008, 0.03, and 0.06 microg/ml, respectively. Moreover, DQ-113 showed the most potent activity against ofloxacin-resistant and methicillin-resistant S. aureus, with a MIC90 of 0.25microg/ml. DQ-113 inhibited the growth of all strains of Streptococcus pneumoniae, including penicillin-resistant strains, and Streptococcus pyogenes at 0.06 microg/ml, and DQ-113 was more active than the other quinolones tested against Enterococcus faecalis and Enterococcus faecium with MIC90s of 0.25 and 2 microg/ml, respectively. Against vancomycin-resistant enterococci, DQ-113 showed the highest activity among the reference compounds, with a MIC range from 0.25 to 2 microg/ml. DQ-113 also showed a potent activity against Haemophilus influenzae, including ampicillin-resistant strains (MIC90, 0.015 microg/ml), and Moraxella catarrhalis (MIC90, 0.03 microg/ml). The activity of DQ-113 was roughly comparable to that of levofloxacin against all species of ENTEROBACTERIACEAE: The MICs of DQ-113 against ofloxacin-susceptible Pseudomonas aeruginosa ranged from 0.25 to 2 microg/ml, which were four times higher than those of ciprofloxacin. From these results, DQ-113 showed the most potent activity against gram-positive pathogens among antibacterial agents tested.