Abstract
In an attempt to investigate the safety, the effect on intestinal bacterial flora and the pharmacokinetics of telithromycin (TEL), a novel ketolide oral antimicrobial agent, phase I clinical studies were performed using 76 subjects (52 in a single administration study and 24 in a multiple administration study) of Japanese healthy male adult volunteers. In the single oral administration study of TEL at doses of 50, 100, 200, 400, 600, 800 and 1, 200 mg under fasting condition, there were no serious or clinically significant adverse events, indicating that TEL was well tolerated at these doses. TEL was rapidly absorbed after oral administration and the plasma level of TEL reached maximum (Cmax) 1.8 to 2.5 hours after administration. After single oral administration of 600mg, which is presumed to be clinically optimal dose in Japanese, the plasma TEL level reached Cmax 2.5 hours after administration and plasma elimination half-life in β phase (T1/2β) was 9.6 hours. Cmax, area under the plasma concentration-time curve (AUC0-24h) and the concentration 24 hours after administration (C24h) in the above condition were 0.91μg/mL, 4.00μg·h/mL and 0.012μg/mL respectively. The apparent systemic clearance (CL/F) and renal clearance (CLR) up to 24 hours after administration were 163.4 L/h and 11.3 L/h respectively. When TEL was orally administered at doses of 400, 600 and 800 mg once daily for 10 days, no serious or clinically significant adverse events were observed, indicating that TEL was well tolerated at these doses. As for the influence of TEL multiple administration on intestinal bacterial flora, TEL caused a transient reduction in the total counts of aerobes, but little changes in the total counts of anaerobes. And Clostridium difficile was not found and the toxin was not detected. Cmax, AUC0-24h, C24h and CL/F at day 10 after administration of 600 mg were 1.18μg/mL, 7.47μg·h/mL, 0.039μg/mL and 86.1 L/h respectively. Cmax at day 10 was increased up to about 1.4 times and AUC at day 10 up to about 1.5 times compared with those values at day 1. The TEL levels in WBC at day 10 were 53.05 and 53.94μg/mL 2 and 6 hours after administration respectively. Those values were about 73 times and 99 times higher than the plasma levels respectively. After administration of 600 mg of TEL at day 10, the cumulative urinary excretion rate of TEL up to 24 hours after administration (Ac(0-24h)) was 12.8% and CLR was 9.6 L/h. In the phase I clinical studies described above by single administration of TEL (50-1, 200mg) and multiple administration of TEL (400, 600 and 800 mg) once daily for 10 days in healthy adult male volunteers, there were no problems of clinical concern in the safety of TEL, and pharmacokinetic characteristics of TEL were elucidated.
