Pharmacokinetics

The pharmacokinetic parameters of teli-thromycin were reported in a three-period, randomized, crossover study to determine the proportionality of telithromycin phar­ macokinetics after single and multiple dosing in healthy subjects. In each treatment period, subjects received a single oral dose of 400, 800, or 1,600 mg of telithromycin followed four days later by the same dose once daily for seven days. Telithromycin achieved steady state within two to three days of once-daily dosing. A slight accumulation of telithromycin was observed after seven days of therapy, with values of the area under the concentration-time curve (AUC) from 0 to 24 hours approximately 1.5 times higher than those achieved with the single dose.

At a dose of 800 mg daily, telithromycin attained mean maximal and trough plasma concentrations of 2.27 and 0.070 mg per liter, respectively. Elimination was bipha-sic: initial and terminal half-lives were 2.87 and 9.81 hours for the 800-mg dose. Study medication was generally well-tolerated, although adverse events tended to be more frequent at the 1,600-mg dose. A once-daily 800-mg dose of telithromycin, therefore, should maintain an effective concentration in plasma for the treatment of RTI involving the key respiratory pathogens.

Distribution

Of particular importance, pharma-cokinetic studies have shown that telithromycin given once daily as an oral 800-mg dose successfully penetrates bronchopulmonary tissues and fluids, achieving high and sustained concentrations. Telithromycin concentrations in the epithelial lining fluid (peak of 14.8 mcg/ml) and the bronchial mucosa (peak of 3.88 mcg/ml) exceeded the minimum inhibiting concentrations (MICs) of key respiratory pathogens for 12 to 24 hours after dosing. High concentrations were also reached in the alveolar macrophages, indicating potential activity against intracellu-lar pathogens.

In a related study, telithro-mycin offered clinical activity against bacterial infections in patients undergoing surgical procedures for otorhinolaryngologi-cal problems such as chronic otitis media, chronic paranasal sinusitis, chronic tonsillitis, palliative tonsil hyperplasia, and tonsillar infection. Good penetration of telithromycin was shown in the middle ear tissues, the tissues of the paranasal sinuses, and the tonsils. Tissue concentrations three to six hours after a single 600-mg dose of telithromycin were higher than the in vitro MICs of telithromycin for strains of S. pneumoniae and M. catarrhalis.
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Metabolism

Telithromycin is primarily metabolized in the liver. RU76363, an alcohol resulting from loss of aryl rings, is the major hepatic metabolite and is present in concentrations of approximately 13% of telithromycin. After oral administration, two-thirds of the telithromycin dose is eliminated renally as metabolites and one-third is eliminated unchanged. In a seven-day treatment period, approximately 96% is eliminated in the urine within 24 hours of the final dose.