Pharmacokinetics and Absolute Oral Bioavailability of an 800-mg Oral Dose of Telithromycin in Healthy Young and Elderly Volunteers

Perret, Catherine; Lenfant, B.; Weinling, Estelle; Wessels, D. H.; Scholtz, H. E.; Montay, G.; Sultan, Eric

doi:10.1159/000066766

Cited by 50 publications

(30 citation statements)

References 4 publications

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“…Following a single 800-mg dose, the AUC 0-G determined in plasma was 10.83 mg ؒ h/l (7.03-14.64) [18]. These data corroborate the higher drug exposures seen once steady state is achieved, as is the case in our current study.…”

Section: Discussionsupporting

confidence: 90%

Intrapulmonary Concentrations of Telithromycin: Clinical Implications for Respiratory Tract Infections due to <i>Streptococcus pneumoniae</i>

Ong

Dandekar²,

Sutherland³

et al. 2005

Chemotherapy

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Background: Antimicrobial efficacy is dependent on the ability of the agent to reach the site of infection. To assess the bronchopulmonary drug disposition of a novel ketolide, telithromycin (TEL), the epithelial lining fluid (ELF) and alveolar macrophage (AM) concentrations were utilized as a surrogate marker for lung penetration. Methods: Adult subjects scheduled for diagnostic bronchoscopy received oral TEL 800 mg once daily for 5 days. Plasma and bronchoalveolar lavage (BAL) samples were collected 2, 8, 12, or 24 h after the last TEL dose. TEL concentrations in the ELF and AM were determined using a validated HPLC assay. ELF drug concentrations were calculated using the urea dilution method. Results: Seventeen subjects with a mean age 65 ± 13 years and a mean weight of 81 ± 25 kg completed this open-label study. The median (range) TEL concentrations in plasma and ELF, respectively, were 1.09 mg/l (1.00–4.81) and 3.91 mg/l (2.64–9.59) at 2 h (n = 6), 0.48 and 1.09 mg/l at 8 h (n = 1), 0.65 mg/l (0.18–1.55) and 1.81 mg/l (0.61–10.0) at 12 h (n = 5), and 0.11 mg/l (0.09–0.24) and 0.69 mg/l (0.15–1.58) at 24 h (n = 5). The median AM concentrations obtained from these subjects were 53.35 mg/l at 2 h, 32.55 mg/l at 8 h, 65.96 mg/l at 12 h, and 26.43 mg/l at 24 h. Overall TEL was well tolerated. No discontinuation was required due to an adverse event. Conclusions: TEL displayed high intrapulmonary penetration with ELF concentrations exceeding that of plasma at all time points. AM intracellular concentrations were multiple times higher than in the ELF and plasma. These data support the clinical efficacy of TEL against intracellular and extracellular pathogens, particularly with Streptococcus pneumoniae having an MIC₉₀well below achievable concentrations at the site of infection.

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Section: Discussionsupporting

confidence: 90%

Intrapulmonary Concentrations of Telithromycin: Clinical Implications for Respiratory Tract Infections due to <i>Streptococcus pneumoniae</i>

Ong

Dandekar²,

Sutherland³

et al. 2005

Chemotherapy

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“…Telithromycin has potent activities both in vitro and in vivo against common respiratory tract pathogens (2), and its spectrum of activity also extends to atypical and intracellular pathogens (3). The clearance, the volume of distribution, the half-life, the plasma protein binding, the urinary excretion, and the extent of absolute oral bioavailability (F) of telithromycin in humans are 12-16 ml/min/kg, 2.1-4.5 l/kg, 7-23 h, 70%, 19-27% of the dose, and 41-112%, respectively (4)(5)(6). Recently, Lee and Lee (7) reported that telithromycin is primarily metabolized via hepatic microsomal cytochrome P450 (CYP) 3A1/2 in male Sprague-Dawley rats.…”

Section: Introductionmentioning

confidence: 99%

Telithromycin Pharmacokinetics in Rat Model of Diabetes Mellitus Induced by Alloxan or Streptozotocin

Lee

2008

Pharm Res

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“…The bioavailability of telithromycin is approximately 60%, and absorption appears to be rapid, reaching C max (maximum concentration) of 1.9 mg/L in 1 hour [19]. Cethromycin appears to have a dose-dependent absorption with time to C max (t max ) increasing from 0.9 to 5.1 hours with increasing dosage [3••, 19,20].…”

Section: Absorptionmentioning

confidence: 99%

The use of ketolides in treatment of upper respiratory tract infections

Ak²,

Hisanaga³

et al. 2004

Curr Infect Dis Rep

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Recent surveillance studies suggest that the incidence of resistance to macrolide antibiotics in common community-acquired respiratory tract pathogens, particularly Streptococcus pneumoniae and Streptococcus pyogenes, is increasing and limiting the usefulness of these drugs. The ketolides, of which telithromycin is the first to be available for clinical use (but not yet in the United States), represent a new class of antibacterials developed specifically to combat respiratory tract pathogens that have acquired resistance to macrolides. The ketolides possess innovative structural modifications, a 3-keto group and a large N-substituted C11, C12-carbamate side chain. This novel structure allows ketolides, which are inhibitors of protein synthesis, to exert a more effective interaction with domain II of the 23S rRNA, enhancing binding to bacterial ribosomes and allowing binding to macrolide-lincosamide-streptogramin B-resistant ribosomes. This novel chemical structure also promotes greater stability of telithromycin in acid conditions, providing the potential for greater stability in gastric fluid and at cellular/tissue levels. Early clinical trials support the bacteriologic and clinical efficacy of telithromycin in the treatment of upper respiratory tract infections (RTIs) such as streptococcal pharyngitis and acute sinusitis, including infections caused by macrolide-resistant S. pneumoniae and S. pyogenes. Common adverse side effects associated with telithromycin are predominantly gastrointestinal, usually of mild to moderate severity, and rarely involve withdrawal of the drug. Telithromycin represents an attractive option for the empiric treatment of upper RTIs, especially as resistance to macrolides is likely to continue to increase.

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Pharmacokinetics and Absolute Oral Bioavailability of an 800-mg Oral Dose of Telithromycin in Healthy Young and Elderly Volunteers

Cited by 50 publications

References 4 publications

Intrapulmonary Concentrations of Telithromycin: Clinical Implications for Respiratory Tract Infections due to <i>Streptococcus pneumoniae</i>

Intrapulmonary Concentrations of Telithromycin: Clinical Implications for Respiratory Tract Infections due to <i>Streptococcus pneumoniae</i>

Telithromycin Pharmacokinetics in Rat Model of Diabetes Mellitus Induced by Alloxan or Streptozotocin

The use of ketolides in treatment of upper respiratory tract infections

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