Takako Shimizu

Microbiological outcome of complicated urinary tract infections treated with levofloxacin: a pharmacokinetic/pharmacodynamic analysis.

The pharmacodynamic targets representing 90% probability thresholds for bacterial eradication were determined in patients with complicated urinary tract infections (UTIs) treated with 500mg of levofloxacin every 24h for 7-14 days. Of 241 pre-treatment strains from 156 patients, 21 strains persisted after treatment. In each patient, plasma concentrations of levofloxacin were simulated based on population pharmacokinetic parameters and patient-specific data. Minimum inhibitory concentrations (MICs) of levofloxacin for the pre-treatment strains determined in our previous study were used. The pharmacodynamic targets representing 90% probability thresholds for bacterial eradication were determined by logistic regression analyses. For all the isolates, Gram-negative bacilli, Gram-positive cocci, Escherichia coli and Enterococcus faecalis, the target values of the area under the concentration-time curve (AUC)/MIC were 14.65, 31.46, 4.85, 43.00 and 3.06, respectively, and the targets of the maximum plasma concentration (C(max))/MIC were 1.22, 2.74, 0.39, 3.61 and 0.25, respectively. Such thresholds of AUC/MIC and C(max)/MIC in complicated UTIs would be lower than those in infections of other sites. In particular, the C(max)/MIC thresholds for Gram-positive cocci and E. faecalis were <1. These findings suggested that, in addition to its plasma concentration, the high concentration of levofloxacin in the urine might play a role in eradicating bacteria.

Pharmacokinetics and Safety of a Single Oral Dose of Mirogabalin in Japanese Subjects With Varying Degrees of Renal Impairment

Mirogabalin (DS‐5565) is a novel preferentially selective α2δ‐1 ligand being developed for the treatment of diabetic peripheral neuropathic pain and postherpetic neuralgia. The current multicenter open‐label study determined the effect of varying degrees of renal impairment on the pharmacokinetics and safety of a single dose of mirogabalin 5 mg in Japanese subjects. A total of 30 subjects (6 subjects per renal function category [normal, mild, moderate, or severe impairment; and end‐stage renal disease (ESRD)]) were enrolled and completed the study. The AUClast increased with severity of renal impairment; the geometric least‐squares mean ratios of AUClast compared with subjects with normal renal function were 1.3, 1.9, 3.6, and 5.3 for patients with mild, moderate, and severe impairment and ESRD, respectively. In accordance with this AUClast increase, apparent total body clearance (CL/F), renal clearance (CLr), and the cumulative percentage of mirogabalin dose excreted into urine all decreased with severity of renal impairment. There were no deaths and no severe treatment‐related adverse events (TEAEs), serious TEAEs, or TEAEs resulting in study discontinuation. Mirogabalin was well tolerated in Japanese subjects with normal renal function and those with mild to severe renal impairment. It was also tolerated in subjects with ESRD but with a higher incidence of TEAEs. The most frequently reported TEAEs were dizziness (ESRD, n = 3), somnolence (ESRD, n = 2), and vomiting (ESRD, n = 2). Based on these data, a mirogabalin dose adjustment will be considered in Japanese subjects with moderate to severe renal impairment and those with ESRD.

Population Pharmacokinetics of Edoxaban in Japanese Atrial Fibrillation Patients With Severe Renal Impairment

This is a population pharmacokinetic (PopPK) analysis to predict PK of edoxaban, a direct‐acting oral anticoagulant, in nonvalvular atrial fibrillation (NVAF) patients with severe renal impairment (SRI; creatinine clearance [CLcr] <30 mL/min). Data from a phase 3 study recently conducted in Japanese NVAF patients (n = 90), including patients with SRI, were used to update the ENGAGE PopPK model that had been developed based on pooled data from the phase 3 ENGAGE AF‐TIMI 48 study and 13 phase 1 PK studies, which included few patients with SRI. The final model indicated that the ENGAGE PopPK model was applicable to Japanese patients in that the model‐simulated and study‐observed concentration‐time profiles were in agreement. Estimated model parameters after the addition of Japanese SRI data were consistent with those derived from the original ENGAGE PopPK data set. The model‐predicted exposure in NVAF patients with SRI who received edoxaban at a 15‐mg, once‐daily dose was similar to that in patients with normal renal function or with mild renal impairment receiving a 30‐mg dose. This suggests that efficacy and safety data from the ENGAGE AF study can be used to support dose setting for NVAF patients with SRI.

Clinical safety, tolerability, pharmacokinetics and pharmacodynamics of the novel factor Xa inhibitor DY-807f in healthy volunteers.

INTRODUCTION Since Vitamin K antagonists are associated with various limitations such as narrow therapeutic window, slow onset and offset of effect, and numerous interactions with food and drugs, new oral anticoagulants targeted to inhibit thrombin or factor Xa (FXa) have been developed. DY-807f is a highly selective, reversible and orally bioavailable FXa inhibitor. OBJECTIVES This article describes a first-in-human study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single ascending oral doses of the novel direct FXa inhibitor DY-807f in healthy males. METHODS a placebo-controlled, single-blinded, randomized, single ascending dose study with 84 subjects (10, 30, 60, 120, 240, and 360 mg). Effects of food and formulation (tablet vs solution) on bioavailability of 60 mg were also assessed as a crossover design. RESULTS DY-807f doses were safe and well-tolerated with no dose-dependent increase in adverse events up to 360 mg. Pharmacokinetics profiles were consistent across doses with rapid absorption, biphasic elimination, and terminal elimination half-life of 10.5 to 12.4 hours. Coagulation parameters (Activated Partial Thromboplastin Time (aPTT) and Prothrombin Time (PT)) were linearly correlated with plasma DY-807 (free base of DY-807f) concentrations (correlation coefficient: 0.786 for aPTT, 0.945 for PT). CONCLUSIONS Single doses of DY-807f are safe and well-tolerated up to 360 mg with predictable pharmacokinetic and pharmacodynamic profiles.

Single‐ and multiple‐dose escalation study to assess pharmacokinetics, pharmacodynamics and safety of oral esaxerenone in healthy Japanese subjects

To characterize the pharmacokinetics, pharmacodynamics and safety of esaxerenone, a mineralocorticoid receptor antagonist, in healthy adult Japanese men.

Ischemic changes and blood coagulation abnormalities as complications of pneumococcal meningitis

One explanation for cerebral infarctions that occur as a complication of pneumococcal meningitis is blood coagulation abnormalities. We investigated the clinical features, laboratory test results, magnetic resonance imaging (MRI) findings, and pathological features of 10 patients with pneumococcal meningitis between 2006 and 2013 to examine the abnormal findings that may be associated with prognosis. Five patients (50%) that had Glasgow Outcome Scale scores between 1 and 4 were classified as the poor outcome group. In this group, the MRI revealed a high signal intensity on the diffusion-weighted image (DWI), and there was an abnormal signal along the cerebral cortex and Virchow-Robin spaces, which were characterized pathologically by ischemic changes. The plasma thrombin-antithrombin complex (TAT) levels showed greater differences between the poor and good prognosis groups than platlet and D-dimer levels; this suggested that high plasma TAT levels indicate a poor prognosis.