Telithromycin is the first ketolide, which is a new class of
antibacterial agents related to the
macrolides that have structural modifications permitting dual binding to bacterial
ribosomal RNA so that activity is retained against Streptococcus pneumoniae with
macrolide-lincosamide-
streptogramin(B) resistance. Clinical experience in infectious patients has shown that oral
telithromycin 800mg once daily for 5-10 days is effective for the treatment of community-acquired upper and lower
respiratory tract infections. Absorption of
telithromycin in humans is estimated to be > or = 90%. Prior to entering the systemic circulation,
telithromycin undergoes first-pass metabolism (mainly by the liver). Its absolute bioavailability is 57% and is unaffected by food. The volume of distribution of
telithromycin after
intravenous infusion is 2.9 L/kg.
Telithromycin is 60-70% bound to
serum proteins and has extensive diffusion into a range of target
biological tissues, achieving concentrations above its minimum inhibitory concentration (MIC) against key respiratory pathogens throughout the dosing interval. After entering the systemic circulation,
telithromycin is eliminated by multiple pathways (7% by biliary and/or intestinal excretion, 13% by renal excretion and 37% by hepatic metabolism).
Telithromycin is metabolised via
cytochrome P450 (CYP) 3A4 and non-CYP pathways. The identified metabolites show minimal antibacterial activity compared with the parent
drug. In healthy subjects receiving
telithromycin 800 mg once daily, the peak plasma concentration achieved is 2.27 microg/mL. Plasma concentrations of
telithromycin show a biphasic decrease over time, with an initial disposition half-life of 2.9 hours and a terminal elimination half-life of approximately 10 hours after multiple dose administration. Steady-state plasma concentrations are achieved within 2-3 days of once-daily administration. Owing to elimination by multiple pathways there is a small increase in exposure when one of these elimination pathways is impaired, as indicated by the results of studies in special patient populations (e.g. those with hepatic or renal impairment). Dosage reductions may be recommended in patients with severe renal impairment. Inhibition of
CYP3A4 by potent inhibitors such as
itraconazole and
ketoconazole results in a 54% and 95% increase in
telithromycin area under the plasma concentration-time curve, respectively. The potential for
telithromycin to inhibit the
CYP3A4 pathway is similar to that of
clarithromycin. The once-daily administration of
telithromycin is likely to limit the potential for drug interactions and clinically significant increases in exposure. In phase III clinical trials, the
telithromycin 800 mg once-daily dose has been shown to provide close to the maximum antimicrobial activity against S. pneumoniae, Haemophilus influenzae and Staphylococcus aureus in patients with community-acquired
pneumonia. In conclusion,
telithromycin has a well characterised and reproducible pharmacokinetic profile, with pharmacokinetic/pharmacodynamic relationships supporting an oral dosage regimen of 800 mg once daily.