Clinical pharmacokinetics of telithromycin, the first ketolide antibacterial.

Telithromycin is the first ketolide, which is a new class of antibacterial agents related to the macrolides that have structural modifications permitting dual binding to bacterial ribosomal RNA so that activity is retained against Streptococcus pneumoniae with macrolide-lincosamide-streptogramin(B) resistance. Clinical experience in infectious patients has shown that oral telithromycin 800mg once daily for 5-10 days is effective for the treatment of community-acquired upper and lower respiratory tract infections. Absorption of telithromycin in humans is estimated to be > or = 90%. Prior to entering the systemic circulation, telithromycin undergoes first-pass metabolism (mainly by the liver). Its absolute bioavailability is 57% and is unaffected by food. The volume of distribution of telithromycin after intravenous infusion is 2.9 L/kg. Telithromycin is 60-70% bound to serum proteins and has extensive diffusion into a range of target biological tissues, achieving concentrations above its minimum inhibitory concentration (MIC) against key respiratory pathogens throughout the dosing interval. After entering the systemic circulation, telithromycin is eliminated by multiple pathways (7% by biliary and/or intestinal excretion, 13% by renal excretion and 37% by hepatic metabolism). Telithromycin is metabolised via cytochrome P450 (CYP) 3A4 and non-CYP pathways. The identified metabolites show minimal antibacterial activity compared with the parent drug. In healthy subjects receiving telithromycin 800 mg once daily, the peak plasma concentration achieved is 2.27 microg/mL. Plasma concentrations of telithromycin show a biphasic decrease over time, with an initial disposition half-life of 2.9 hours and a terminal elimination half-life of approximately 10 hours after multiple dose administration. Steady-state plasma concentrations are achieved within 2-3 days of once-daily administration. Owing to elimination by multiple pathways there is a small increase in exposure when one of these elimination pathways is impaired, as indicated by the results of studies in special patient populations (e.g. those with hepatic or renal impairment). Dosage reductions may be recommended in patients with severe renal impairment. Inhibition of CYP3A4 by potent inhibitors such as itraconazole and ketoconazole results in a 54% and 95% increase in telithromycin area under the plasma concentration-time curve, respectively. The potential for telithromycin to inhibit the CYP3A4 pathway is similar to that of clarithromycin. The once-daily administration of telithromycin is likely to limit the potential for drug interactions and clinically significant increases in exposure. In phase III clinical trials, the telithromycin 800 mg once-daily dose has been shown to provide close to the maximum antimicrobial activity against S. pneumoniae, Haemophilus influenzae and Staphylococcus aureus in patients with community-acquired pneumonia. In conclusion, telithromycin has a well characterised and reproducible pharmacokinetic profile, with pharmacokinetic/pharmacodynamic relationships supporting an oral dosage regimen of 800 mg once daily.

Effects of itraconazole or grapefruit juice on the pharmacokinetics of telithromycin.

STUDY OBJECTIVE: To determine whether coadministration of the cytochrome P450 3A4 (CYP3A4) inhibitors itraconazole or grapefruit juice will modify the pharmacokinetic profile of telithromycin, and to assess the safety of telithromycin. DESIGN: Two single-center, open-label studies; the itraconazole study was nonrandomized, sequential, and multiple dose, and the grapefruit juice study was randomized, two-period crossover, and single dose. SETTING: Two clinical investigative centers in the United States. SUBJECTS: Thirty-four healthy, nonsmoking male volunteers aged 18-45 years. INTERVENTION: All patients received telithromycin 800 mg/day; 18 patients received concomitant itraconazole 200 mg/day, and 16 received concomitant single-dose, single-strength grapefruit juice. MEASUREMENTS AND MAIN RESULTS: Standard pharmacokinetic and safety measurements were performed. Itraconazole given concomitantly with telithromycin increased the steady-state area under the plasma concentration-time curve from 0-24 hours of telithromycin by 53.8% (p<0.0001). Coadministration of grapefruit juice did not affect telithromycin pharmacokinetic parameters, and telithromycin was well tolerated in both studies. CONCLUSION: Only modest changes in the pharmacokinetics of telithromycin were seen with concomitant administration of itraconazole. Telithromycin pharmacokinetics were unaffected by concomitant administration of grapefruit juice.

Pharmacokinetics and safety of the ketolide telithromycin in patients with renal impairment.

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.

The pharmacokinetics and pharmacodynamics of enoxaparin in obese volunteers.

OBJECTIVES: The objective of this study was to compare the pharmacokinetics of the low-molecular-weight heparin enoxaparin in obese and nonobese volunteers, by means of two administration regimens. METHODS: Enoxaparin was administered subcutaneously (1.5 mg/kg once daily for 4 days) and in a single 6-hour infusion (1.5 mg/kg) to 24 obese volunteers and 24 age-, sex-, and height-matched nonobese volunteers in a randomized, open-label, 2-way crossover design. Blood plasma was assessed for anti-Xa and anti-IIa activity and activated partial thromboplastin time. RESULTS: After subcutaneous administration, steady-state exposure was achieved after the second dose in nonobese volunteers and after the third dose in obese volunteers. Time to maximum anti-Xa activity was 1 hour longer in obese volunteers, but maximum anti-Xa activity was similar in both groups. For anti-Xa activity, exposure at steady-state was 16% higher in obese volunteers than in nonobese volunteers (90% confidence interval, 108%-125%). After intravenous infusion, total body clearance and volume of distribution at steady state were higher in obese volunteers than in nonobese volunteers, but when adjusted for weight, these values were about 10% lower in obese volunteers. Anti-IIa activity after subcutaneous administration did not differ significantly between obese and nonobese volunteers. Pharmacodynamic analysis of activated partial thromboplastin time showed similar results in obese and nonobese volunteers after both intravenous and subcutaneous administration. No deaths or serious adverse events occurred during the study. CONCLUSIONS: Enoxaparin was well tolerated when administered subcutaneously or intravenously, and there appears to be no need to modify the currently recommended dose for obese volunteers.

Lack of effect of food on the bioavailability of a new ketolide antibacterial, telithromycin.

Telithromycin is an innovative antibacterial designed for the treatment of community-acquired respiratory tract infections. This study assessed the effect of food on the bioavailability of a single oral dose of telithromycin 800 mg in healthy male subjects. Male volunteers aged 18-45 y were recruited for an open-label, single-dose, 2-period, cross-over study. In each trial period, subjects received a single oral dose of telithromycin 800 mg after an overnight fast, or after a standard high-fat breakfast. A washout period of 6-8 d separated the 2 study periods. All 18 subjects recruited (mean age 30.7 y) completed the study. Telithromycin was rapidly absorbed, reaching maximum plasma concentrations within a median of 2.50 and 2.25 h in the fasting and non-fasting states, respectively. There was no statistical difference between the non-fasting and fasting states for any of the pharmacokinetic parameters measured. The mean plasma telithromycin concentration versus time profiles for the non-fasting and fasting phases were almost superimposable. For the maximum plasma concentration and area under the curve from time 0 to infinity, the 90% confidence intervals for the mean non-fasting:fasting ratios were 83-116 and 101-123 mg x h/l, respectively; these are within 80-125% of the bioequivalence range. Telithromycin was well tolerated. The bioavailability, rate and extent of absorption of the new ketolide antibacterial telithromycin were unaffected by food.