First-in-Human Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of E6742, a Dual Antagonist of Toll-like Receptors 7 and 8, in Healthy Volunteers.

The first-in-human phase I study for E6742, a dual toll-like receptor (TLR) 7 and TLR8 antagonist, has been conducted to assess the safety, tolerability, and pharmacokinetics of E6742 in healthy volunteers. In a single ascending dose (SAD) study, 42 subjects received 10-800 mg of E6742 in the fasted state, as well as a 100-mg cohort in the fed state for evaluating the effect of food. In a multiple ascending dose (MAD) study, 18 subjects received 100-400 mg of E6742 twice daily for 7 days. E6742 was rapidly absorbed with a median tmax ranging from 1.50 to 2.50 hours across dose groups under the fasted condition, and eliminated with a median t½ ranging from 2.37 to 14.4 hours. After multiple oral doses, a steady state was reached by day 7. In the SAD study, dose proportionality was observed for Cmax , AUC(0-t) , and AUC(0-inf) values of E6742 up to 800 mg, but these values were slightly less than dose proportional at 10 mg. In the MAD study, the Cmax and AUC(0-12h)ss of E6742 appeared to be almost dose proportionally increased between 100 and 200 mg, while these parameters showed more than a dose proportional increase at 400 mg. In addition to safety and good tolerability, this study demonstrated cytokine concentrations in cultured peripheral blood in response to E6742 were suppressed in a dose-dependent manner. Further clinical studies targeting systemic lupus erythematosus patients are currently underway.

Comparison of pharmacokinetics of individual teicoplanin components in patients.

Teicoplanin is a glycopeptide antibiotic comprising six closely related major components whose activities against specific microbial species differ. In order to clarify the significance of monitoring these components separately for determining the therapeutic effectiveness of teicoplanin, we measured the total and unbound concentrations of the main teicoplanin components in plasma and the unbound fractions in patients. Teicoplanin components in plasma were determined separately by high-performance liquid chromatography following a co-extractive clean-up procedure. The concentrations of unbound teicoplanin components were estimated after plasma ultrafiltration. The plasma concentrations of the main components of teicoplanin were strongly correlated with each other. The apparent elimination rate constants of total bound and unbound teicoplanin calculated by population pharmacokinetic parameters were almost same among the components. Furthermore, the mean population unbound clearance corrected by the unbound fraction was almost the same among the components. These results suggest that monitoring the individual components of teicoplanin has no clinical significance based on the pharmacokinetics of teicoplanin.