Chemical formula: C₄₃H₆₅N₅O₁₀ Molecular mass: 812.018 g/mol PubChem compound: 3002190
Telithromycin inhibits protein synthesis by interacting with domains II and V of the 23S ribosomal RNA of the 50S ribosome subunit. Furthermore, telithromycin is able to block the formation of the 50S and 30S ribosomal subunits. The affinity of telithromycin for the 50S ribosomal subunits of organisms susceptible to erythromycin A is 10-fold higher than that of erythromycin A.
The AUC/MIC ratio has been shown to be the PK/PD parameter that correlates best with the efficacy of telithromycin.
Telithromycin is a semisynthetic derivative of erythromycin A belonging to the ketolides, a class of antibacterial agents related to macrolides.
Telithromycin does not induce expression of macrolide-lincosamide-streptogramin B (MLSB)- mediated resistance in vitro in Staphylococcus aureus, Streptococcus pneumoniae, or Streptococcus pyogenes.
In some organisms that are resistant to erythromycin A due to inducible expression of the MLSB resistance determinant, the affinity of telithromycin for the 50S ribosomal subunit is more than 20- fold that of erythromycin A.
Telithromycin is not active against organisms that constitutively express the MLSB resistance determinant (cMLSB). The majority of methicillin-resistant S. aureus (MRSA) express cMLSB.
In in vitro studies the activity of telithromycin was reduced against organisms that express the erythromycin erm(B) or mef(A) related resistance mechanisms.
Exposure to telithromycin in vitro did select for pneumococcal mutants with increased MICs of telithromycin, generally resulting in MIC values of ≤1 mg/l.
Streptococcus pneumoniae does not demonstrate cross-resistance between erythromycin A and telithromycin.
Streptococcus pyogenes that show high-level resistance to erythromycin A are cross-resistant to telithromycin.
The recommended European Committee for Antimicrobial Susceptibility Testing (EUCAST) MIC clinical breakpoints are presented below:
| Pathogen | Susceptible | Resistant |
|---|---|---|
| Streptococcus A, B, C, G | ≤0.25 mg/l | >0.5 mg/l |
| Streptococcus pneumoniae | ≤0.25 mg/l | >0.5 mg/l |
| Haemophilus influenzae1 | ≤0.12 mg/l | >8 mg/l |
| Moraxella catarrhalis | ≤0.25 mg/l | >0.5 mg/l |
1 The correlation between macrolide MICs and clinical outcome is weak for H. influenzae. Therefore the MIC breakpoint for telithromycin was set to categorise wild-type H. influenzae as having intermediate susceptibility.
The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.
Following oral administration, telithromycin is fairly rapidly absorbed. A mean maximum plasma concentration of about 2 mg/l is reached within 1-3 hour after dose with once-daily dosing of telithromycin 800 mg. The absolute bioavailability is about 57% after a single dose of 800 mg. The rate and extent of absorption is unaffected by food intake, and thus telithromycin tablets can be given without regard to food. Mean steady-state trough plasma concentrations of between 0.04 and 0.07 mg/l are reached within 3 to 4 days with once-daily dosing of telithromycin 800 mg. At steady-state AUC is approximately 1.5 fold increased compared to the single dose. Mean peak and trough plasma concentrations at steady state in patients were 2.9±1.6 mg/l (range 0.02-7.6 mg/l) and 0.2±0.2 mg/l (range 0.010 to 1.29 mg/l), during a therapeutic 800 mg once-daily dose regimen.
The in vitro protein binding is approximately 60% to 70%. Telithromycin is widely distributed throughout the body. The volume of distribution is 2.9±1.0 l/kg. Rapid distribution of telithromycin into tissues results in significantly higher telithromycin concentrations in most target tissues than in plasma. The maximum total tissue concentration in epithelial lining fluid, alveolar macrophages, bronchial mucosa, tonsils and sinus tissue were 14.9±11.4 mg/l, 318.1±231 mg/l, 3.88±1.87 mg/kg, 3.95±0.53 mg/kg and 6.96±1.58 mg/kg, respectively. The total tissue concentration 24 h after dose in epithelial lining fluid, alveolar macrophages, bronchial mucosa, tonsils and sinus tissue were 0.84±0.65 mg/l, 162±96 mg/l, 0.78±0.39 mg/kg, 0.72±0.29 mg/kg and 1.58±1.68 mg/kg, respectively. The mean maximum white blood cell concentration of telithromycin was 83±25 mg/l.
Telithromycin is metabolised primarily by the liver. After oral administration, two-thirds of the dose is eliminated as metabolites and one-third unchanged. The main circulating compound in plasma is telithromycin. Its principal circulating metabolite represents approximately 13% of telithromycin AUC, and has little antimicrobial activity compared with the parent medicinal product. Other metabolites were detected in plasma, urine and faeces and represent less or equal than 3% of plasma AUC.
Telithromycin is metabolised both by CYP450 isoenzymes and non-CYP enzymes. The major CYP450 enzyme involved in the metabolism of telithromycin is CYP3A4. Telithromycin is an inhibitor of CYP3A4 and CYP2D6, but has no or limited effect on CYP1A, 2A6, 2B6, 2C8, 2C9, 2C19 and 2E1.
After oral administration of radiolabelled telithromycin, 76% of the radioactivity was recovered from faeces, and 17% from the urine. Approximately one-third of telithromycin was eliminated unchanged; 20% in faeces and 12% in urine. Telithromycin displays moderate non-linear pharmacokinetics. The non-renal clearance is decreased as the dose is increased. The total clearance (mean ±SD) is approximately 58±5 l/h after an intravenous administration with renal clearance accounting for about 22% of this. Telithromycin displays a tri-exponential decay from plasma, with a rapid distribution half-life of 0.17 h. The main elimination half-life of telithromycin is 2-3 h and the terminal, less important, half-life is about 10 h at the dose 800 mg once daily.
In a multiple-dose study, 36 subjects with varying degrees of renal impairment, a 1.4-fold increase in Cmax,ss, and a 2-fold increase in AUC(0-24)ss at 800 mg multiple doses in the severe renally impaired group (CLCR < 30 ml/min) compared to healthy volunteers were observed and a reduced dosage of telithromycin is recommended. Based on observed data, a 600 mg daily dose is approximately equivalent with the target exposure observed in healthy subjects. Based on simulation data, an alternating daily dosing regimen of 800 mg and 400 mg in patients with severe renal impairment can approximate the AUC in healthy subjects receiving 800 mg once daily.
The effect of dialysis on the elimination of telithromycin has not been assessed.
In a single-dose study (800 mg) in 12 patients and a multiple-dose study (800 mg) in 13 patients with mild to severe hepatic insufficiency (Child Pugh Class A, B and C), the Cmax, AUC and t1/2 of telithromycin were similar compared to those obtained in age- and sex-matched healthy subjects. In both studies, higher renal elimination was observed in the hepatically impaired patients. Due to limited experience in patients with decreased metabolic capacity of the liver, telithromycin should be used with caution in patients with hepatic impairment.
In subjects over 65 (median 75 years), the maximum plasma concentration and AUC of telithromycin were increased approximately 2-fold compared with those achieved in young healthy adults. These changes in pharmacokinetics do not necessitate dosage adjustment.
Limited data, obtained in paediatric patients 13 to 17 years of age, showed that telithromycin concentrations in this age group were similar to the concentrations in patients 18 to 40 years of age.
The pharmacokinetics of telithromycin is similar between males and females.
Repeated dose toxicity studies of 1, 3 and 6 month duration with telithromycin conducted in rat, dog and monkey showed that the liver was the principal target for toxicity with elevations of liver enzymes, and histological evidence of damage. These effects showed a tendency to regress after cessation of treatment. Plasma exposures based on free fraction of active substance, at the no observed adverse effect levels ranged from 1.6 to 13 times the expected clinical exposure.
Phospholipidosis (intracellular phospholipid accumulation) affecting a number of organs and tissues (e.g., liver, kidney, lung, thymus, spleen, gall bladder, mesenteric lymph nodes, GI-tract) has been observed in rats and dogs administered telithromycin at repeated doses of 150 mg/kg/day or more for 1 month and 20 mg/kg/day or more for 3-6 months. This administration corresponds to free active substance systemic exposure levels of at least 9 times the expected levels in human after 1 month and less than the expected level in humans after 6 months, respectively. There was evidence of reversibility upon cessation of treatment. The significance of these findings for humans is unknown.
In similarity to some macrolides, telithromycin caused a prolongation of QTc interval in dogs and on action potential duration in rabbit Purkinje fibers in vitro. Effects were evident at plasma levels of free drug 8 to 13 times the expected clinical level. Hypokalaemia and quinidine had additive/supraadditive effects in vitro while potentiation was evident with sotalol. Telithromycin, but not its major human metabolites, had inhibitory activity on HERG and Kv1.5 channels.
Reproduction toxicity studies showed reduced gamete maturation in rat and adverse effects on fertilization. Slight reductions in fertility indices were seen in rats at parentally toxic doses higher than 150 mg/kg. At high doses embryotoxicity was apparent and an increase in incomplete ossification and in skeletal anomalies was seen. Studies in rats and rabbits were inconclusive with respect to potential for teratogenicity; there was equivocal evidence of adverse effects on foetal development at high doses.
Telithromycin, and its principal human metabolites, were negative in tests on genotoxic potential in vitro and in vivo. No carcinogenicity studies have been conducted with telithromycin.
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