ru-66647 and Kidney-Diseases

Telithromycin is the first of the ketolide antibacterials to receive US Food and Drug Administration (FDA) approval for clinical use. It is approved for the treatment of community-acquired pneumonia (CAP), acute exacerbations of chronic bronchitis (AECB), and acute maxillary sinusitis (AMS) in adults.. This article reviews the mechanism of action, in vitro antimicrobial activity, pharmacokinetics and pharmacodynamics, clinical efficacy, safety, and drug-interaction profile of telithromycin.. Relevant studies were identified through a search of the English-language literature indexed on MEDLINE (1990-March 2005) using the terms telithromycin and HMR 3647, a review of the reference lists of identified articles, and a review of the briefing document prepared by the manufacturer of telithromycin for presentation to the FDA Anti-infective Drugs Advisory Committee. A search of abstracts from the Interscience Conference on Antimicrobial Agents and Chemotherapy (2001-2004) also was performed.. The results of in vitro susceptibility studies suggest that telithromycin provides coverage against the key respiratory pathogens, both typical and atypical. In addition, telithromycin may be useful against multidrug-resistant strains of Streptococcus pneumoniae and against Haemophilus influenzae, irrespective of beta-lactamase production. In randomized, double-blind, comparative trials (against amoxicillin, amoxicillin/clavulanate, cefuroxime axetil, clarithromycin, moxifloxacin, or trovafloxacin), telithromycin had comparable efficacy to its comparators in the empiric treatment of CAP (4 studies), AECB (3 studies), and AMS (3 studies). Telithromycin is dosed at 800 mg (two 400-mg tablets) QD in community-acquired respiratory tract infections (RTIs). No dose adjustment is required in the elderly, patients with mild to moderate renal insufficiency, or patients with hepatic insufficiency. The majority of adverse events associated with telithromycin were mild to moderate, with gastrointestinal effects (diarrhea, nausea, vomiting) being the most commonly reported, followed by headache and dizziness. Telithromycin has been associated with elevations in hepatic transaminases and prolongation of the electrocardiographic QTc interval, although the significance of these findings is not known. Telithromycin is also a strong inhibitor of and substrate for the cytochrome P450 (CYP) 3A4 isozyme. Therefore, it is important to monitor for potential drug interactions with medications that prolong the QTc interval or are metabolized by the CYP system.. Telithromycin appears to be a useful option for the empiric treatment of community-acquired RTIs in adults. It may be particularly useful in the outpatient setting in areas with high rates of penicillin- and macrolide-resistant S pneumoniae; it may also be an alternative agent for patients who are allergic to beta-lactams and live in areas with a high prevalence of multidrug-resistant S pneumoniae or for those who have failed to respond to beta-lactam- or macrolide-based therapy.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Area Under Curve; Bacterial Infections; Drug Interactions; Female; Half-Life; Humans; Ketolides; Kidney Diseases; Male; Metabolic Clearance Rate; Microbial Sensitivity Tests; Middle Aged; Randomized Controlled Trials as Topic; Tissue Distribution

The objective of this study was to determine the effect of multiple impairments in drug elimination on the pharmacokinetics and pharmacodynamics (effect on QTc interval), using clarithromycin as a comparator.. Thirty-two subjects aged > or = 60 years with renal impairment who were otherwise medically stable were recruited into this parallel-group study. Following stratification according to creatinine clearance (CL(CR)), subjects were randomized to a five-day treatment with ketoconazole (400 mg once daily) alone, or a five-day treatment with ketoconazole (400 mg once daily) and telithromycin (800 mg once daily) given concomitantly or a five-day treatment with ketoconazole (400 mg once daily) and clarithromycin (500 mg twice daily) given concomitantly. Steady-state pharmacokinetics and safety, including serial electrocardiograms, were assessed.. In subjects with CL(CR) 30 - 80 ml/min, the mean maximal telithromycin concentration at steady state (C(max),ss) was 3.6 mg/l and the steady state area under the plasma concentration-time curve from time zero to 24 hours (AUC(0-24 h) ss) was 33.4 mg x h/l. The mean C(max), ss and AUC(0-12 h)ss for clarithromycin were 6.2 mg/l and 56.1 mg x h/l, respectively. The increases in telithromycin C(max) ss and AUC(0-24 h) ss compared to corresponding data for healthy young subjects were 1.6- and 2.7-fold, respectively, whereas corresponding increases for clarithromycin were 2.2- and 3.3-fold, respectively. In the telithromycin plus ketoconazole group deltaQTc values were equal or < 60 ms. All QTc values were equal or < 450 ms in males and equal or < 470 ms in females.. The increase in telithromycin plasma concentrations during ketoconazole-mediated inhibition of CYP3A4 in subjects aged 60 years or older with renal impairment was similar to that for clarithromycin under the same conditions. Telithromycin was well tolerated and produced no clinically significant prolongations in the QTc interval.

Topics: Aged; Anti-Bacterial Agents; Antifungal Agents; Area Under Curve; Biological Availability; Clarithromycin; Drug Administration Schedule; Drug Interactions; Electrocardiography; Female; Humans; Ketoconazole; Ketolides; Kidney Diseases; Male; Metabolic Clearance Rate; Middle Aged

The pharmacokinetics and safety of the ketolide telithromycin were evaluated in two separate studies after single and repeat oral dosing in patients with varying degrees of renal impairment and in subjects with normal renal function. The single-dose study was an open-label, nonrandomized, parallel-group design in which all 40 patients received a single oral dose of telithromycin 800 mg. The repeat-dose study was an open-label study with a randomized, balanced, incomplete three-block treatment crossover design. In this study, each of the 36 patients received two of three telithromycin regimens (400, 600, or 800 mg once daily for 5 days), with a washout period of >/= 7 days between treatments. Telithromycin was well tolerated. Adverse events were generally mild in severity, and no serious drug-related adverse events were reported. Plasma exposure to telithromycin (C(max), AUC) showed a tendency to increase with increasing severity of renal impairment in both studies. In patients with severe renal impairment (CL(CR) < 30 mL/min) receiving telithromycin 800 mg in the repeat-dose study, C(max,ss) and AUC((0-24 h)ss) increased 1.5-fold (p < 0.05) to 2.0-fold (p = 0.0005), respectively, compared with healthy subjects. The percentage of dose excreted in urine and renal clearance (CL(R)) of telithromycin was found to decrease significantly with increasing severity of renal impairment in both studies, and CL(R) was found to be independent of telithromycin dose in the repeat-dose study. In conclusion, telithromycin dosage adjustment is not necessary in patients with mild to moderate renal impairment (CL(CR) >/= 30 mL/min). In patients with severe renal impairment (CL(CR) < 30 mL/min), dosage adjustment could be considered.

Topics: Administration, Oral; Adolescent; Adult; Age Factors; Aged; Anti-Bacterial Agents; Area Under Curve; Cross-Over Studies; Electrocardiography; Female; Half-Life; Humans; Ketolides; Kidney Diseases; Macrolides; Male; Metabolic Clearance Rate; Middle Aged; Time Factors

Chronic kidney disease, or renal impairment (RI) can increase plasma levels for drugs that are primarily renally cleared and for some drugs whose renal elimination is not a major pathway. We constructed physiologically based pharmacokinetic (PBPK) models for 3 nonrenally eliminated drugs (sildenafil, repaglinide, and telithromycin). These models integrate drug-dependent parameters derived from in vitro, in silico, and in vivo data, and system-dependent parameters that are independent of the test drugs. Plasma pharmacokinetic profiles of test drugs were simulated in subjects with severe RI and normal renal function, respectively. The simulated versus observed areas under the concentration versus time curve changes (AUCR, severe RI/normal) were comparable for sildenafil (2.2 vs 2.0) and telithromycin (1.6 vs 1.9). For repaglinide, the initial, simulated AUCR was lower than that observed (1.2 vs 3.0). The underestimation was corrected once the estimated changes in transporter activity were incorporated into the model. The simulated AUCR values were confirmed using a static, clearance concept model. The PBPK models were further used to evaluate the changes in pharmacokinetic profiles of sildenafil metabolite by RI and of telithromycin by RI and co-administration with ketoconazole. The simulations demonstrate the utility and challenges of the PBPK approach in evaluating the pharmacokinetics of nonrenally cleared drugs in subjects with RI.

Topics: Area Under Curve; Carbamates; Chronic Disease; Computer Simulation; Drug Interactions; Humans; Ketolides; Kidney Diseases; Models, Biological; Piperazines; Piperidines; Purines; Sildenafil Citrate; Sulfones

Telithromycin is the first ketolide anti bacterial approved for treating community-acquired pneumonia, acute exacerbations of chronic bronchitis, and acute bacterial sinusitis in adults. The purpose of this article is to review the main pharmacokinetic properties of telithromycin and their application to the treatment of these infections.. Sources of information were identified through a Medline search (up to March 2005).. The absolute oral bioavailability of telithromycin is approximately 57%, which is unaffected by food intake. At the recommended 800 mg once-daily oral dosing regimen, telithromycin reaches a steady-state concentration of approximately 2 microg/mL in plasma and has an elimination half-life of approximately 10 hours. Telithromycin shows extensive tissue distribution and penetrates effectively into bronchopulmonary tissue and epithelial lining fluid. Since elimination of telithromycin occurs via multiple pathways--the highest proportion (70%) through metabolism--impairment of a single pathway has a limited impact on telithromycin exposure. Dose adjustments are unnecessary in elderly patients or in individuals with hepatic impairment or mild to moderate renal impairment. A reduced dose could be recommended in patients with severe renal impairment. Telithromycin is metabolized primarily in the liver, approximately half of which is via the cytochrome P450 (CYP) 3A4 system. Telithromycin AUC(0-24 h) increased by 1.5- to 2.0-fold in the presence of itraconazole and ketoconazole. Administration of telithromycin with drugs metabolized via CYP3A4 may result in increased exposure to the co-administered drug, as shown for simvastatin (5.3-fold) and midazolam (6-fold). Co-administration of telithromycin minimally increases (1.2- to 1.4-fold) exposure to theophylline, digoxin, and metoprolol. Although telithromycin does not affect the pharmacokinetics of warfarin, consideration should be given to monitoring prothrombin times/INR in patients receiving telithromycin and oral anticoagulants simultaneously.. 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.

Topics: Aged; Anti-Bacterial Agents; Biological Availability; Bronchitis; Community-Acquired Infections; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Drug Interactions; Humans; Ketolides; Kidney Diseases; Pneumonia; Respiratory Tract Infections; Sinusitis