Single-dose pharmacokinetics and pharmacodynamics of sergliflozin etabonate, a novel inhibitor of glucose reabsorption, in healthy volunteers and patients with type 2 diabetes mellitus.

Sergliflozin, the active entity of sergliflozin etabonate, is a selective inhibitor of sodium-dependent glucose cotransporter 2 (SGLT2). The pharmacokinetics and pharmacodynamics of sergliflozin were evaluated following single oral dose administration of sergliflozin etabonate (5-500 mg) in healthy volunteers (n = 22) and patients with type 2 diabetes mellitus (n = 8). The prodrug was rapidly and extensively converted to sergliflozin; the latter displayed linear kinetics, reached maximum plasma concentrations at approximately 30 to 45 minutes postdose (t(max)), and had a plasma elimination half-life (t(1/2)) of approximately 0.5 to 1 hour. Both prodrug and active entity showed low glomerular filtration and/or extensive renal tubular reabsorption, with <0.5% of the administered dose being recovered in the urine. In both populations, sergliflozin etabonate produced a dose-related glucosuria under fasting conditions and following glucose loading but did not appreciably affect urinary electrolyte excretion or fluid balance. The magnitude and duration of the glucosuric effect closely paralleled plasma sergliflozin concentrations. Sergliflozin did not significantly affect fasting plasma glucose levels but produced transient attenuation of the plasma glucose AUC following glucose challenge. Single doses of sergliflozin etabonate 5 to 500 mg were well tolerated, and there were no clinically significant adverse laboratory findings.

Changes in HLA-DR expression, cytokine production and coagulation following endotoxin infusion in healthy human volunteers.

The infusion of a low dose of endotoxin into healthy subjects triggers a complex inflammatory response but the intricacies of which, despite extensive research, are still being unraveled. Nine healthy male volunteers received a dose of 30 Units endotoxin/kg bodyweight as an intravenous bolus. Following endotoxin infusion the concentration of TNF-alpha in their serum rapidly increased within 30 min, peaked after 1-2 h and returned to baseline by 4 h. This corresponded to a similarly rapid increase in anti-inflammatory soluble TNF receptor (sTNFR) levels, which remained elevated for up to 48 h. Increased levels of other cytokines were measured, including IL-6, IL-8, G-CSF, IL-1ra and IL-10. However, these cytokines lagged behind that of TNF-alpha and remained elevated for up to 8 h. Endotoxin injection resulted in complex changes in HLA-DR expression, a marker of monocyte activation state. Initially, following a lag of 2-4 h, HLA-DR expression decreased with a nadir at 8 h, followed by an increase in expression above baseline at 22 h. HLA-DR levels returned to baseline 48 h post-endotoxin challenge. This was in contrast to endotoxin-induced changes in white blood cell (WBC) numbers, which dropped rapidly (at 2-3 h) while HLA-DR levels were stable and then peaked during the nadir in HLA-DR expression (8 h). Furthermore, endotoxin injection caused activation of both fibrinolytic and coagulation pathways. Thus, endotoxin infusion results in complex changes in HLA-DR expression, production of pro- and anti-inflammatory cytokines and activation of coagulation.

Pharmacokinetics and safety assessments of high-dose and 4-week treatment with S-3304, a novel matrix metalloproteinase inhibitor, in healthy volunteers.

AIMS: To investigate the tolerability, safety and pharmacokinetics of S-3304 in healthy volunteers treated with high doses of S-3304 for 28 days. METHODS: Thirty-two healthy volunteers were recruited. Four male and four female subjects were allocated to one of four doses (800 mg, 1600 mg, 2400 mg and 3200 mg). At each dose six volunteers took active medication and two volunteers took placebo in a double-blind fashion. Volunteers took a single dose on days 1 and 28 for pharmacokinetic purposes, and took twice daily doses from day 3-27. The pharmacokinetics of S-3304 and its hydroxy metabolites were evaluated. Tolerance was based on subjective adverse events, clinical examination, vital signs, ECG and laboratory tests including haematology and biochemistry profiles using CTC grading. RESULTS: Doses up to 2400 mg twice daily were generally well tolerated. At 3200 mg twice daily, five volunteers including one randomized to placebo were withdrawn from treatment mainly due to alanine aminotransferase (ALT) elevation. C(max) of S-3304 on day 1, whose geometric mean and 95% confidence interval were 66.3 microg ml(-1) (48.8, 90.0) for 800 mg, 82.6 microg ml(-1) (69.3, 98.6) for 1600 mg, 89.5 microg ml(-1) (79.5, 100.7) for 2400 mg, and 110.5 microg ml(-1) (88.9, 137.7) for 3200 mg, respectively, was correlated with the log-transformed peak ALT (P < 0.0001 for male and P = 0.048 for female volunteers). CONCLUSIONS: In healthy volunteers the maximum tolerated dose of S-3304 was 2400 mg twice daily. ALT elevation was the most frequent dose-limiting factor and was correlated with C(max) on day 1.