Pharmacokinetics of the new ketolide telithromycin (HMR 3647) administeredin ascending single and multiple doses

Telithromycin (HMR 3647) is a novel ketolide antimicrobial with goad activi ty against both common and atypical respiratory pathogens, including many r esistant strains. This randomized, three-period crossover study determined the dose proportionality of telithromycin pharmacokinetics after single and multiple dosing in healthy subjects. In each treatment period, subjects re ceived a single oral dose of 400, 800 or 1,600 mg of telithromycin followed 4 days later by the same dose once daily for 7 days. Blood and urine sampl es were taken throughout the study for determination of pharmacokinetic par ameters for telithromycin and RU 76363, its main metabolite. Telithromycin and RU 76363 achieved steady state within 2 to 3 days of once-daily dosing. A slight accumulation of telithromycin was observed after 7 days of therap y, with values of the area under the concentration-time curve from 0 to 24 h approximately 1.5 times higher than those achieved with the single dose. The pharmacokinetics of telithromycin and RU 76363 deviated moderately from dose proportionality. At a dose of 800 mg/day, telithromycin attained mean maximal and trough plasma concentrations of 2.27 and 0.070 mg/liter respec tively. Elimination was biphasic; initial and terminal half-lives were 2.87 and 9.81 h far the 800-mg dose. Study meditation was well tolerated, altho ugh adverse events tended to be more frequent at the 1,600-mg dose. This st udy showed that telithromycin was generally well tolerated and suggests tha t a once-daily 800-mg oral dose of telithromycin maintains an effective con centration in plasma for the treatment of respiratory tract infections invo lving the key respiratory pathogens.