Pharmacokinetics of telithromycin: application to dosing in the treatment of community-acquired respiratory tract infections

Ciervo, Carman A.; Shi, Jun Yi

doi:10.1185/030079905x65466

Cited by 9 publications

(7 citation statements)

References 26 publications

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“…16 CYP3A TDI was assessed using human liver microsomes with midazolam as a probe substrate for CYP3A. Compounds were evaluated for time-and concentration-dependent inhibition of midazolam metabolism, and K I and k inact values were determined.…”

Section: Resultsmentioning

confidence: 99%

“…15 The measured human liver microsomal extraction ratio (ER) of 1 was 0.7, consistent with the relatively high clearance observed in human. 16 CYP3A TDI was assessed using human liver microsomes with midazolam as a probe substrate for CYP3A. Compounds were evaluated for time-and concentration-dependent inhibition of midazolam metabolism, and K I and k inact values were determined.…”

Section: Resultsmentioning

confidence: 99%

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Discovery of Azetidinyl Ketolides for the Treatment of Susceptible and Multidrug Resistant Community-Acquired Respiratory Tract Infections

Magee

Ripp

et al. 2009

J. Med. Chem.

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Respiratory tract bacterial strains are becoming increasingly resistant to currently marketed macrolide antibiotics. The current alternative telithromycin (1) from the newer ketolide class of macrolides addresses resistance but is hampered by serious safety concerns, hepatotoxicity in particular. We have discovered a novel series of azetidinyl ketolides that focus on mitigation of hepatotoxicity by minimizing hepatic turnover and time-dependent inactivation of CYP3A isoforms in the liver without compromising the potency and efficacy of 1.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Discovery of Azetidinyl Ketolides for the Treatment of Susceptible and Multidrug Resistant Community-Acquired Respiratory Tract Infections

Magee

Ripp

et al. 2009

J. Med. Chem.

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“…Although clinicians should be aware of a potential interaction with simvastatin and erythromycin or clarithromycin, telithromycin has also been shown to increase serum levels of simvastatin several-fold in healthy subjects when coadministered with the statin. 31 Azithromycin does not affect CYP3A4 metabolism, as measured by midazolam clearance, 14 and is therefore probably a safer alternative for coadministration with statins metabolized by CYP3A4. However, one case report has described lovastatin-induced rhabdomyolysis after concurrent administration of azithromycin.…”

Section: Discussionmentioning

confidence: 99%

Simvastatin‐Associated Rhabdomyolysis After Coadministration of Macrolide Antibiotics in Two Patients

Molden¹,

Andersson²

2007

Pharmacotherapy

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Two men, aged 83 and 78 years, who received stable therapy with simvastatin 80 mg/day were hospitalized 1-2 weeks after completion of short-term treatment with erythromycin and clarithromycin, respectively. Both patients were admitted with myalgia, muscle weakness, functional disability (inability to raise arms and legs), and serum creatine kinase levels more than 60 times the upper limit of normal (ULN). Substantial elevations in aspartate aminotransferase (> 30 times the ULN) and alanine aminotransferase (> 7 times the ULN) levels were also observed. Rhabdomyolysis was diagnosed in both patients. Both recovered, but the combined events resulted in almost 40 days of hospitalization, the cost of which is considerable. According to the Naranjo adverse drug reaction probability scale, the likelihood that the rhabdomyolysis was secondary to a simvastatin-macrolide interaction was probable. Four cases of rhabdomyolysis after therapy with combined simvastatin and clarithromycin have been reported previously, but this is apparently the first report of rhabdomyolysis after coadministration of erythromycin. The interacting mechanism likely was inhibited cytochrome P450 (CYP) 3A4 metabolism and possibly P-glycoprotein transport of simvastatin as well. Previous reports of simvastatin-clarithromycin-related events involved additional drugs that inhibited CYP3A4 and P-glycoprotein. However, this was not the situation with our two patients. To prevent future events, it is crucial that clinicians recognize the interaction risk associated with concurrent use of simvastatin and clarithromycin or erythromycin. The risk could be managed by temporary interruption of simvastatin treatment or administration of a noninteracting antimicrobial agent.

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“…66 Telithromycin, when administered with the CYP3A4 substrates simvastatin and midazolam, inhibited their metabolism resulting in elevated levels of those drugs. 78 Telithromycin concentrations have increased with concomitant administration of CYP3A4 inhibitors, such as itraconazole and ketoconazole. [78][79][80] A case report of telithromycininduced digoxin toxicity suggests telithromycin may inhibit drug transport by P-glycoprotein.…”

Section: Drug Interactionsmentioning

confidence: 99%

“…78 Telithromycin concentrations have increased with concomitant administration of CYP3A4 inhibitors, such as itraconazole and ketoconazole. [78][79][80] A case report of telithromycininduced digoxin toxicity suggests telithromycin may inhibit drug transport by P-glycoprotein. 81 Telithromycin also has the ability to prolong the corrected QT (QTc) interval and increase the risk of ventricular arrhythmias and torsade de pointes, particularly with concomitant administration of other drugs with this effect.…”

Section: Drug Interactionsmentioning

confidence: 99%

Cethromycin: A Promising New Ketolide Antibiotic for Respiratory Infections

2010

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Community-acquired pneumonia remains the primary infectious cause of death in the United States. At current levels of antimicrobial resistance, conventional agents are at risk of becoming less effective, and the need for new agents is pressing. Cethromycin is a new ketolide antibiotic being investigated for use in respiratory tract infections. To review its pharmacology, in vitro susceptibilities, pharmacokinetics, efficacy, safety, and drug interactions, we conducted a MEDLINE search restricted to English-language articles citing cethromycin or ABT-773 (its original designation) from 1990-May 2009. Additional data sources were identified from the references of selected articles. All published trials and available poster data citing cethromycin were selected for review. In vitro, cethromycin displays more potent antibacterial effects than its predecessor telithromycin. Cethromycin exhibits potent inhibition of both gram-positive and gram-negative respiratory pathogens. A new drug application for cethromycin was submitted to the United States Food and Drug Administration in 2008 for the treatment of community-acquired pneumonia. Clinical trial data in the treatment of respiratory tract infections support cethromycin's efficacy. The limited safety data have not included any reports of hepatotoxicity. If cethromycin proves to be safe with regard to hepatotoxicity, it has great promise as an alternative to current standard therapy for community-acquired respiratory infections, especially pneumonia. Given current resistance levels, cethromycin could provide more reliable coverage against common respiratory pathogens than traditional agents in the beta-lactam and macrolide classes.

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Pharmacokinetics of telithromycin: application to dosing in the treatment of community-acquired respiratory tract infections

Abstract: Overall, the pharmacokinetic/pharmaco dynamic properties of telithromycin indicate that this ketolide antibacterial is a valuable and convenient treatment option for community-acquired respiratory tract infections.

Cited by 9 publications

References 26 publications

Discovery of Azetidinyl Ketolides for the Treatment of Susceptible and Multidrug Resistant Community-Acquired Respiratory Tract Infections

Discovery of Azetidinyl Ketolides for the Treatment of Susceptible and Multidrug Resistant Community-Acquired Respiratory Tract Infections

Simvastatin‐Associated Rhabdomyolysis After Coadministration of Macrolide Antibiotics in Two Patients

Cethromycin: A Promising New Ketolide Antibiotic for Respiratory Infections

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