Pharmacokinetics of the New Ketolide Telithromycin (HMR 3647) Administered in Ascending Single and Multiple Doses

Abstract

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.

Cellular Uptake and Efflux of Azithromycin, Erythromycin, Clarithromycin, Telithromycin, and Cethromycin

“…The slow release from the cells that was observed leads to prolonged retention of the substance in the body and probably influences the terminal half-life of the drug and, subsequently, the dosing regimen. The terminal half-lives after a single oral dose are about 40 h for azithromycin (7) and about 7 h for telithromycin (27), which thus allow once-daily dosing. On the other hand, clarithromycin and erythromycin, which have terminal half-lives of 4 h and 3 h, respectively (30), require multiple doses daily.…”

Quantitative Analysis of Gentamicin, Azithromycin, Telithromycin, Ciprofloxacin, Moxifloxacin, and Oritavancin (LY333328) Activities against Intracellular Staphylococcus aureus in Mouse J774 Macrophages

“…The lowest drug concentrations investigated (0.5 mg/liter for azithromycin, 0.06 mg/liter for telithromycin) correspond to the MICs (in broth) of the drugs for the strain of S. aureus used in this study; note that for azithromycin, the peak concentration observed for patients receiving a conventional dose (500 mg) did not exceed 0.4 mg/liter (24); for telithromycin, the highest concentration investigated (2 mg/liter) corresponds to the C max observed for patients after administration of a conventional dose (800 mg) (42). Each point corresponds to the mean value for three independent determinations.…”

Pharmacodynamic Profile of Telithromycin against Macrolide- and Fluoroquinolone-Resistant Streptococcus pneumoniae in a Neutropenic Mouse Thigh Model

“…As a result, while the pharmacodynamic parameter most predictive of outcome (i.e., AUC/MIC) remains constant in the absence or the presence of neutrophils, the magnitude of drug exposure required to produce any given reduction in bacterial density is substantially reduced in the immunocompetent host. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]1998) evaluated the impacts of neutrophils on the bacteriostatic activity of telithromycin and a structurally related ketolide against S. pneumoniae strains with various macrolide susceptibilities in the murine thigh infection model and reported that the potencies of the ketolides are enhanced (1.8-to 24-fold) in the presence of neutrophils. Moreover, although neutropenic conditions were used in the present study, the enhanced in vivo potency of another ketolide, ABT-773, against pneumococci in immunocompetent hosts has also recently been demonstrated (5).…”

“…Mouse serum samples were analyzed by HPLC to quantitate the telithromycin concentrations (16). Serum samples to which an internal standard (moxifloxacin; Bayer Corp., West Haven, Conn.) was added were deproteinized by the addition of acetonitrile and centrifugation.…”