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Following oral administration, telithromycin reached maximal concentration at about 1 hour (0.5 - 4 hours).
It has an absolute bioavailability of 57% in both young and elderly subjects.
The rate and extent of absorption are unaffected by food intake, thus KETEK (telithromycin) tablets can be given without regard to food.
In healthy adult subjects, peak plasma telithromycin concentrations of approximately 2 μg/mL are attained at a median of 1 hour after an 800-mg oral dose.
Steady-state plasma concentrations are reached within 2 to 3 days of once daily dosing with telithromycin 800 mg.
Following oral dosing, the mean terminal elimination half-life of telithromycin is 10 hours.
The pharmacokinetics of telithromycin after administration of single and multiple (7 days) once daily 800-mg doses to healthy adult subjects are shown in Table 1.
|Single dose (n=18)||Multiple dose (n=18)|
|Cmax (μg/mL)||1.9 (0.80)||2.27 (0.71)|
|Tmax (h)*||1.0 (0.5-4.0)||1.0 (0.5-3.0)|
|AUC(0-24) (μg•h/mL)||8.25 (2.6)||12.5 (5.4)|
|Terminal t½ (h)||7.16 (1.3)||9.81 (1.9)|
|C24h (μg/mL)||0.03 (0.013)||0.07 (0.051)|
|* Median (min-max) values SD=Standard deviation
Cmax=Maximum plasma concentration
Tmax=Time to Cmax
AUC=Area under concentration vs. time curve
t½=Terminal plasma half-life C24h =Plasma concentration at 24 hours post-dose
In a patient population, mean peak and trough plasma concentrations were 2.9 μg/mL (±1.55), (n=219) and 0.2 μg/mL (±0.22), (n=204), respectively, after 3 to 5 days of KETEK (telithromycin) 800 mg once daily.
Total in vitro protein binding is approximately 60% to 70% and is primarily due to human serum albumin.
Protein binding is not modified in elderly subjects and in patients with hepatic impairment.
The volume of distribution of telithromycin after intravenous infusion is 2.9 L/kg.
Telithromycin concentrations in bronchial mucosa, epithelial lining fluid, and alveolar macrophages after 800 mg once daily dosing for 5 days in patients are displayed in Table 2.
|Hours post-dose||Mean concentration (μg/mL)||Tissue/ Plasma Ratio|
|Tissue or fluid||Plasma|
|Epithelial lining fluid||2||14.89||1.86||8.57|
|*Units in mg/kg|
Telithromycin concentration in white blood cells exceeds the concentration in plasma and is eliminated more slowly from white blood cells than from plasma. Mean white blood cell concentrations of telithromycin peaked at 72.1 μg/mL at 6 hours, and remained at 14.1 μg/mL 24 hours after 5 days of repeated dosing of 600 mg once daily. After 10 days, repeated dosing of 600 mg once daily, white blood cell concentrations remained at 8.9 μg/mL 48 hours after the last dose.
In total, metabolism accounts for approximately 70% of the dose. In plasma, the main circulating compound after administration of an 800-mg radio-labeled dose was parent compound, representing 56.7% of the total radioactivity. The main metabolite represented 12.6% of the AUC of telithromycin. Three other plasma metabolites were quantified, each representing 3% or less of the AUC of telithromycin.
It is estimated that approximately 50% of its metabolism is mediated by CYP 450 3A4 and the remaining 50% is CYP 450-independent.
The systemically available telithromycin is eliminated by multiple pathways as follows: 7% of the dose is excreted unchanged in feces by biliary and/or intestinal secretion; 13% of the dose is excreted unchanged in urine by renal excretion; and 37% of the dose is metabolized by the liver.
There was no significant difference between males and females in mean AUC, Cmax, and elimination half-life in two studies; one in 18 healthy young volunteers (18 to 40 years of age) and the other in 14 healthy elderly volunteers (65 to 92 years of age), given single and multiple once daily doses of 800 mg of KETEK (telithromycin) .
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 t½ of telithromycin were similar to those obtained in age- and sex-matched healthy subjects. In both studies, an increase in renal elimination was observed in hepatically impaired patients indicating that this pathway may compensate for some of the decrease in metabolic clearance. No dosage adjustment is recommended due to hepatic impairment. (See PRECAUTIONS, General and DOSAGE AND ADMINISTRATION)
In a multiple-dose study, 36 subjects with varying degrees of renal impairment received 400 mg, 600 mg, or 800 mg KETEK (telithromycin) once daily for 5 days. There was a 1.4fold increase in Cmax,ss, and a 1.9-fold increase in AUC (0-24)ss at 800 mg multiple doses in the severely renally impaired group (CLCR < 30 mL/min) compared to healthy volunteers. Renal excretion may serve as a compensatory elimination pathway for telithromycin in situations where metabolic clearance is impaired. Patients with severe renal impairment are prone to conditions that may impair their metabolic clearance. Therefore, in the presence of severe renal impairment (CLCR < 30 mL/min), a reduced dosage of KETEK is recommended. (See DOSAGE AND ADMINISTRATION)
In a single-dose study in patients with end-stage renal failure on hemodialysis (n=10), the mean Cmax and AUC values were similar to normal healthy subjects when KETEK (telithromycin) was administered 2 hours post-dialysis. However, the effect of dialysis on removing telithromycin from the body has not been studied.
The effects of co-administration of ketoconazole in 12 subjects (age ≥ 60 years), with impaired renal function were studied (CLCR= 24 to 80 mL/min). In this study, when severe renal insufficiency (CLCR < 30 mL/min, n=2) and concomitant impairment of CYP 3A4 metabolism pathway were present, telithromycin exposure (AUC (0-24)) was increased by approximately 4- to 5-fold compared with the exposure in healthy subjects with normal renal function receiving telithromycin alone. In the presence of severe renal impairment (CLCR < 30 mL/min), with coexisting hepatic impairment, a reduced dosage of KETEK is recommended. (See PRECAUTIONS, General and DOSAGE AND ADMINISTRATION)
Pharmacokinetic data show that there is an increase of 1.4-fold in exposure (AUC) in 20 patients ≥ 65 years of age with community acquired pneumonia in a Phase III study, and a 2.0-fold increase in exposure (AUC) in 14 subjects ≥ 65 years of age as compared with subjects less than 65 years of age in a Phase I study. No dosage adjustment is required based on age alone.
In vitro interactions
In vitro studies using a model compound have shown that telithromycin may act as an inhibitor for the hepatic uptake transporters OATP1B1 and OATP1B3. Although the clinical relevance of this finding is unknown, it is possible that concomitant administration of telithromycin with drugs that are substrates of OATP family members could result in increased plasma concentrations of the co-administered drug.
In vivo interactions
Studies were performed to evaluate the effect of CYP 3A4 inhibitors on telithromycin and the effect of telithromycin on drugs that are substrates of CYP 3A4 and CYP 2D6. In addition, drug interaction studies were conducted with several other concomitantly prescribed drugs.
CYP 3A4 inhibitors
Itraconazole: A multiple-dose interaction study with itraconazole showed that Cmax of telithromycin was increased by 22% and AUC by 54%.
Ketoconazole: A multiple-dose interaction study with ketoconazole showed that Cmax of telithromycin was increased by 51% and AUC by 95%.
Grapefruit juice: When telithromycin was given with 240 mL of grapefruit juice after an overnight fast to healthy subjects, the pharmacokinetics of telithromycin were not affected.
CYP 3A4 substrates
Cisapride: Steady-state peak plasma concentrations of cisapride (an agent with the potential to increase QT interval) were increased by 95% when co-administered with repeated doses of telithromycin, resulting in significant increases in QTc. (See CONTRAINDICATIONS)
Simvastatin: When simvastatin was co-administered with telithromycin, there was a 5.3-fold increase in simvastatin Cmax, an 8.9-fold increase in simvastatin AUC, a 15-fold increase in the simvastatin active metabolite Cmax, and a 12-fold increase in the simvastatin active metabolite AUC. (See PRECAUTIONS)
In another study, when simvastatin and telithromycin were administered 12 hours apart, there was a 3.4-fold increase in simvastatin Cmax, a 4.0-fold increase in simvastatin AUC, a 3.2-fold increase in the active metabolite Cmax, and a 4.3-fold increase in the active metabolite AUC. (See PRECAUTIONS)
Midazolam: Concomitant administration of telithromycin with intravenous or oral midazolam resulted in 2- and 6-fold increases, respectively, in the AUC of midazolam due to inhibition of CYP 3A4-dependent metabolism of midazolam. (See PRECAUTIONS)
CYP 2D6 substrates
Paroxetine: There was no pharmacokinetic effect on paroxetine when telithromycin was coadministered.
Metoprolol: When metoprolol was co-administered with telithromycin, there was an increase of approximately 38% on the Cmax and AUC of metoprolol, however, there was no effect on the elimination half-life of metoprolol. Telithromycin exposure is not modified with concomitant single-dose administration of metoprolol. (See PRECAUTIONS: DRUG INTERACTIONS)
Other drug interactions
Digoxin: The plasma peak and trough levels of digoxin were increased by 73% and 21%, respectively, in healthy volunteers when co-administered with telithromycin. However, trough plasma concentrations of digoxin (when equilibrium between plasma and tissue concentrations has been achieved) ranged from 0.74 to 2.17 ng/mL. There were no significant changes in ECG parameters and no signs of digoxin toxicity. (See PRECAUTIONS)
Theophylline: When theophylline was co-administered with repeated doses of telithromycin, there was an increase of approximately 16% and 17% on the steady-state Cmax and AUC of theophylline. Co-administration of theophylline may worsen gastrointestinal side effects such as nausea and vomiting, especially in female patients. It is recommended that telithromycin should be taken with theophylline 1 hour apart to decrease the likelihood of gastrointestinal side effects.
Sotalol: Telithromycin has been shown to decrease the Cmax and AUC of sotalol by 34% and 20%, respectively, due to decreased absorption.
Warfarin: When co-administered with telithromycin in healthy subjects, there were no pharmacodynamic or pharmacokinetic effects on racemic warfarin.
Oral contraceptives: When oral contraceptives containing ethinyl estradiol and levonorgestrel were co-administered with telithromycin, the steady-state AUC of ethinyl estradiol did not change and the steady-state AUC of levonorgestrel was increased by 50%. The pharmacokinetic/pharmacodynamic study showed that telithromycin did not interfere with the antiovulatory effect of oral contraceptives containing ethinyl estradiol and levonorgestrel.
Ranitidine, antacid: There was no clinically relevant pharmacokinetic interaction of ranitidine or antacids containing aluminum and magnesium hydroxide on telithromycin.
Telithromycin belongs to the ketolide class of antibacterials and is structurally related to the macrolide family of antibiotics. Telithromycin concentrates in phagocytes where it exhibits activity against intracellular respiratory pathogens. In vitro, telithromycin has been shown to demonstrate concentration-dependent bactericidal activity against isolates of Streptococcus pneumoniae (including multi-drug resistant isolates [MDRSP*]).
*MDRSP=Multi-drug resistant Streptococcus pneumoniae includes isolates known as PRSP (penicillin-resistant Streptococcus pneumoniae), and are isolates resistant to two or more of the 2nd following antimicrobials: penicillin, generation cephalosporins (e.g., cefuroxime), macrolides, tetracyclines, and trimethoprim/sulfamethoxazole.
Mechanism of action
Telithromycin blocks protein synthesis by binding to domains II and V of 23S rRNA of the 50S ribosomal subunit. By binding at domain II, telithromycin retains activity against gram-positive cocci (e.g., Streptococcus pneumoniae) in the presence of resistance mediated by methylases (erm genes) that alter the domain V binding site of telithromycin. Telithromycin may also inhibit the assembly of nascent ribosomal units.
Mechanism of resistance
Staphylococcus aureus and Streptococcus pyogenes with the constitutive macrolide-lincosamidestreptogramin B (cMLSB) phenotype are resistant to telithromycin.
Mutants of Streptococcus pneumoniae derived in the laboratory by serial passage in subinhibitory concentrations of telithromycin have demonstrated resistance based on L22 riboprotein mutations (telithromycin MICs are elevated but still within the susceptible range), one of two reported mutations affecting the L4 riboprotein, and production of K-peptide. The clinical significance of these laboratory mutants is not known.
Telithromycin does not induce resistance through methylase gene expression in erythromycininducibly resistant bacteria, a function of its 3-keto moiety. Telithromycin has not been shown to induce resistance to itself.
List of Microorganisms
Telithromycin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical settings as described in the INDICATIONS AND USAGE section.
Aerobic gram-positive microorganisms
Streptococcus pneumoniae (including multi-drug resistant isolates [MDRSP*])
*MDRSP=Multi-drug resistant Streptococcus pneumoniae includes isolates known as PRSP (penicillin-resistant S. pneumoniae), and are isolates resistant to two or more of the following antimicrobials: penicillin, 2nd generation cephalosporins (e.g., cefuroxime), macrolides, tetracyclines, and trimethoprim/sulfamethoxazole.
Aerobic gram-negative microorganisms
Chlamydophila (Chlamydia) pneumoniae
The following in vitro data are available, but their clinical significance is unknown.
At least 90% of the following microorganisms exhibit in vitro minimum inhibitory concentrations (MICs) less than or equal to the susceptible breakpoint for telithromycin. However, the safety and efficacy of telithromycin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.
Aerobic gram-positive microorganisms
Staphylococcus aureus (methicillin and erythromycin susceptible isolates
Streptococcus pyogenes (erythromycin susceptible isolates only)
Streptococci (Lancefield groups C and G)
Susceptibility Test Methods
When available, the clinical microbiology laboratory should provide cumulative results of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.
Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antibacterial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on dilution methods (broth or agar dilution)1,3 or equivalent with standardized inoculum and concentrations of telithromycin powder. The MIC values should be interpreted according to criteria provided in Table 3.
Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antibiotics. One such standardized procedure2,3 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 15 μg telithromycin to test the susceptibility of microorganisms to telithromycin. Disc diffusion zone sizes should be interpreted according to criteria in Table 3.
Table 3: Susceptibility Test Result Interpretive Criteria
|Pathogen||Minimal Inhibitory Concentrations (μg/mL)||Disk Diffusion (zone diameters in mm)|
|Streptococcus pneumoniae||≤ 1||2||≥ 4||≥ 19||16-18||≤ 15|
|Haemophilus influenzae||≤ 4||8||≥ 16||≥ 15||12-14||≤ 11|
A report of “Susceptible” indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antibacterial compound in the blood reaches the concentrations usually achievable. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.
Standardized susceptibility test procedures require the use of quality control microorganisms to determine the performance of the test procedures1,2,3. Standard telithromycin powder should provide the MIC ranges for the quality control organisms in Table 4. For the disk diffusion technique, the 15-μg telithromycin disk should provide the zone diameter ranges for the quality control organisms in Table 4.
Table 4: Acceptable Quality Control Ranges for Telithromycin
|QC Strain||Minimum Inhibitory Concentrations (μg/mL)||Disk Diffusion (Zone diameter in mm)|
|Streptococcus pneumoniae ATCC 49619||0.004-0.03||27-33|
|Haemophilus influenzae ATCC 49247||1.0-4.0||17-23|
|ATCC = American Type Culture Collection|
Community-acquired pneumonia (CAP)
KETEK (telithromycin) was studied in four randomized, double-blind, controlled studies and four open-label studies for the treatment of community-acquired pneumonia. Patients with mild to moderate CAP who were considered appropriate for oral outpatient treatment were enrolled in these trials. Patients with severe pneumonia were excluded based on any one of the following: ICU admission, need for parenteral antibiotics, respiratory rate > 30/minute, hypotension, altered mental status, < 90% oxygen saturation by pulse oximetry, or white blood cell count < 4000/mm³. Total number of clinically evaluable patients in the telithromycin group included 2016 patients.
Table 6: CAP: Clinical cure rate at post-therapy follow-up
|Controlled Studies||Patients (n)||Clinical cure rate|
|KETEK vs. clarithromycin 500 mg BID for 10 days||162||156||88.3%||88.5%|
|KETEK vs. trovafloxacin* 200 mg QD for 7 to 10 days||80||86||90.0%||94.2%|
|KETEK vs. amoxicillin 1000 mg TID for 10 days||149||152||94.6%||90.1%|
|KETEK for 7 days vs. clarithromycin 500 mg BID for 10 days||161||146||88.8%||91.8%|
|*This study was stopped prematurely after trovafloxacin was restricted for use in hospitalized patients with severe infection.|
Clinical cure rates by pathogen from the four CAP controlled clinical trials in microbiologically evaluable patients given KETEK (telithromycin) for 7-10 days or a comparator are displayed in Table 7.
Table 7: CAP: Clinical cure rate by pathogen at post-therapy
follow-up (17-24 days)
|Streptococcus pneumoniae||73/78 (93.6%)||63/70 (90.0%)|
|Haemophilus influenzae||39/47 (83.0%)||42/44 (95.5%)|
|Moraxella catarrhalis||12/14 (85.7%)||7/9 (77.8%)|
|Chlamydophila (Chlamydia) pneumoniae||23/25 (92.0%)||18/19 (94.7%)|
|Mycoplasma pneumoniae||22/23 (95.7%)||20/22 (90.9%)|
Clinical cure rates for patients with CAP due to Streptococcus pneumoniae were determined from patients in controlled and uncontrolled trials. Of 333 evaluable patients with CAP due to Streptococcus pneumoniae, 312 (93.7%) achieved clinical success. Only patients considered appropriate for oral outpatient therapy were included in these trials. More severely ill patients were not enrolled. Blood cultures were obtained in all patients participating in the clinical trials of mild to moderate community-acquired pneumonia. In a limited number of outpatients with incidental pneumococcal bacteremia treated with KETEK (telithromycin) , a clinical cure rate of 88% (67/76) has been observed. KETEK (telithromycin) is not indicated for the treatment of severe community-acquired pneumonia or suspected pneumococcal bacteremia.
Clinical cure rates for patients with CAP due to multi-drug resistant Streptococcus pneumoniae (MDRSP*) were determined from patients in controlled and uncontrolled trials. Of 36 evaluable patients with CAP due to MDRSP, 33 (91.7%) achieved clinical success.
*MDRSP: Multi-drug resistant Streptococcus pneumoniae includes isolates known as PRSP (penicillin-resistant Streptococcus pneumoniae), and are isolates resistant to two or more of the following antibiotics: penicillin, 2nd generation cephalosporins, e.g., cefuroxime, macrolides, tetracyclines and trimethoprim/sulfamethoxazole.
Table 8: Clinical cure rate for 36 evaluable patients with
MDRSP treated with KETEK (telithromycin) in studies of community-acquired pneumonia
|Screening Susceptibility||Clinical Success in Patients||Evaluable MDRSP|
|2nd generation cephalosporin-resistant||20/22||90.9|
|a n = the number of patients successfully
treated; N = the number with resistance to the listed drug of the 36 evaluable
patients with CAP due to MDRSP.
b Includes isolates tested for resistance to either tetracycline or doxycycline.
Visual Adverse Events
Table 9 provides the incidence of all treatment-emergent visual adverse events in controlled Phase III studies by age and gender. The group with the highest incidence was females under the age of 40, while males over the age of 40 had rates of visual adverse events similar to comparator-treated patients.
Table 9: Incidence of All Treatment-Emergent Visual Adverse
Events in Controlled Phase III Studies
|Female ≤ 40||2.1% (14/682)||0.0% (0/534)|
|Female > 40||1.0% (7/703)||0.35% (2/574)|
|Male ≤ 40||1.2% (7/563)||0.48% (2/417)|
|Male > 40||0.27% (2/754)||0.33% (2/614)|
|Total||1.1% (30/2702)||0.28% (6/2139)|
|* Includes all comparators combined|
Repeated dose toxicity studies of 1, 3, and 6 months' 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. There was evidence of reversibility after cessation of treatment. Plasma exposures based on free fraction of drug at the no observed adverse effect levels ranged from 1 to 10 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 with the administration of telithromycin in rats at repeated doses of 900 mg/m²/day (1.8x the human dose) or more for 1 month, and 300 mg/m²/day (0.61x the human dose) or more for 3-6 months. Similarly, phospholipidosis has been observed in dogs with telithromycin at repeated doses of 3000 mg/m²/day (6.1x the human dose) or more for 1 month and 1000 mg/m²/day (2.0x the human dose) or more for 3 months. The significance of these findings for humans is unknown.
Pharmacology/toxicology studies showed an effect both in prolonging QTc interval in dogs in vivo and in vitro action potential duration (APD) in rabbit Purkinje fibers. These effects were observed at concentrations of free drug at least 8.8 (in dogs) times those circulating in clinical use. In vitro electrophysiological studies (hERG assays) suggested an inhibition of the rapid activating component of the delayed rectifier potassium current (IKr) as an underlying mechanism.
1. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically – Sixth Edition; Approved Standard, NCCLS Document M7-A6, Vol. 23, No. 2, NCCLS, Wayne, PA, January, 2003.
2. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests - Eighth Edition; Approved Standard, NCCLS Document M2-A8, Vol. 23, No. 1, NCCLS, Wayne, PA, January, 2003.
3. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Susceptibility Testing: Twelfth Informational Supplement; Approved Standard, NCCLS Document M2-A8 and M7-A6, Vol. 23, No. 1, NCCLS, Wayne, PA, January, 2004.
Last reviewed on RxList: 1/27/2011
This monograph has been modified to include the generic and brand name in many instances.
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