Telithromycin (HMR 3647) is a novel ketolide antimicrobial with good activity against both common and atypical respiratory pathogens, including many resistant 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 received 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 samples were taken throughout the study for determination of pharmacokinetic parameters 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 therapy, 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 respectively. Elimination was biphasic; initial and terminal half-lives were 2.87 and 9.81 h for the 800-mg dose. Study medication was well tolerated, although adverse events tended to be more frequent at the 1,600-mg dose. This study showed that telithromycin was generally well tolerated and suggests that a once-daily 800-mg oral dose of telithromycin maintains an effective concentration in plasma for the treatment of respiratory tract infections involving the key respiratory pathogens.
Background: This two-way, randomized, single-dose, crossover study determined the pharmacokinetics and absolute oral bioavailability of telithromycin in young and elderly healthy subjects. Methods: Twelve young (18–40 years) and 12 elderly (>65 years and ≤85 years) subjects received a single 800-mg oral dose of telithromycin or an intravenous infusion of 400 mg (young subjects) or 480 mg (elderly subjects) of telithromycin over 2.5 h in two treatment periods, separated by a 1-week washout period. The plasma concentrations and pharmacokinetic parameters of telithromycin and its major metabolite, RU 76363, were determined. Absolute oral bioavailability was calculated using the area under the plasma concentration-time curve (AUC) from zero hours to infinity. Results: The absolute oral bioavailability of telithromycin was 57% in both young and elderly subjects. The AUC for the metabolite was lower after intravenous infusion of telithromycin, indicating first-pass loss following oral administration. Telithromycin was well tolerated in both groups of subjects. Conclusions: Telithromycin has an absolute oral bioavailability of 57% in young and elderly subjects and is well tolerated.
Three pharmacokinetic studies involving single oral doses of cefpodoxime proxetil in healthy volunteers are reported. The first study was to determine the absolute bioavailability of cefpodoxime, the second was to study the relationship between the oral dose of cefpodoxime proxetil and pharmacokinetic parameters of cefpodoxime, and the third was to compare the pharmacokinetics of cefpodoxime in healthy young and elderly volunteers. Half the dose of cefpodoxime orally administered as cefpodoxime proxetil in tablet form reaches the systemic circulation, while 80% of the cefpodoxime absorbed is excreted unchanged in urine. The volume of distribution is large (32.3 l). The pharmacokinetics of cefpodoxime were linear in young and elderly subjects after 100 and 200 mg oral doses, which are those used therapeutically. The Cmax was about 1.4 mg/l (after 100 mg) and 2.6 mg/l (after 200 mg). Deviation from linearity appeared at 400 mg and the effect was confirmed at 800 mg. The differences between young and elderly subjects were negligible, with the exception of the half-life which increased by only 14%, from 2.67 to 3 h. Dosage adjustment is therefore not necessary in the elderly.
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