Steady-State Plasma and Intrapulmonary Pharmacokinetics and Pharmacodynamics of Cethromycin

Abstract

The objective of this study was to determine the steady-state plasma and intrapulmonary pharmacokinetic parameters of orally administered cethromycin in healthy volunteers. The study design included administering 150 or 300 mg of cethromycin once daily to 25 or 35 healthy adult subjects, respectively, for a total of five doses. Standardized and timed bronchoalveolar lavage (BAL) was performed after the last dose. Blood was obtained for drug assay prior to the first and last dose, at multiple time points following the last dose, and at the time of BAL. Cethromycin was measured in plasma, BAL, and alveolar cell (AC) by using a combined high-performance liquid chromatography-mass spectrometric technique. Plasma, epithelial lining fluid (ELF), and AC pharmacokinetics were derived by noncompartmental methods. C max /90% minimum inhibitory concentration (MIC 90 ) ratios, area under the concentration-time curve (AUC)/MIC 90 ratios, intrapulmonary drug exposure ratios, and percent time above MIC 90 during the dosing interval (%T > MIC 90 ) were calculated for recently reported respiratory pathogens. The kinetics were nonlinear, i.e., not proportional to dose. In the 150-mg-dose group, the C max (mean ؎ standard deviations), AUC 0-24 , and half-life for plasma were 0.181 ؎ 0.084 g/ml, 0.902 ؎ 0.469 g · h/ml, and 4.85 ؎ 1.10 h, respectively; for ELF the values were 0.9 ؎ 0.2 g/ml, 11.4 g · h/ml, and 6.43 h, respectively; for AC the values were 12.7 ؎ 6.4 g/ml, 160.8 g · h/ml, and 10.0 h, respectively. In the 300-mg-dose group, the C max (mean ؎ standard deviations), AUC 0-24 , and half-life for plasma were 0.500 ؎ 0.168 g/ml, 3.067 ؎ 1.205 g · h/ml, and 4.94 ؎ 0.66 h, respectively; for ELF the values were 2.7 ؎ 2.0 g/ml, 24.15 g · h/ml, and 5.26 h, respectively; for AC the values were 55.4 ؎ 38.7 g/ml, 636.2 g · h/ml, and 11.6 h, respectively. We concluded that the C max /MIC 90 ratios, AUC/MIC 90 ratios, %T > MIC 90 values, and extended plasma and intrapulmonary half-lives provide a pharmacokinetic rationale for once-daily administration and are favorable for the treatment of cethromycin-susceptible pulmonary infections.Cethromycin is an investigational ketolide antibiotic that is active against common respiratory pathogens, such as Streptococcus pneumoniae, Mycoplasma pneumoniae, Chlamydia pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, group A streptococci, and Streptococcus viridans (14,15,17,18,29). Cethromycin is also active, in vitro and in a murine model, against Mycobacterium avium infection (10), and related macrolides are active against other mycobacteria (12, 21). Doses of cethromycin ranging from 100 to 1,200 mg have been administered to humans in phase I clinical studies. The plasma elimination half-life (t 1/2 ) ranges from 3.6 to 6.7 h (R. S. Pradhan, L. E. Gustavson, D. D. Londo, Y. Shang, J. Zhang, and M. Paris, Abstr. 40th Intersci. Conf. Antimicrob. Agents Chemother., abstr. 2138, 2000). The maximum concentration of drug in serum (C max ), area under the concentration-time curve from 0 to 24...

Cellular Uptake and Efflux of Azithromycin, Erythromycin, Clarithromycin, Telithromycin, and Cethromycin

“…In addition, our results demonstrate the selective in vitro behaviors of compounds that in vivo are all widely distributed throughout the body (5,7,25,30). Extensive accumulation in vitro of established macrolide antibacterials within cells shows in general an inverse correlation with serum concentrations in vivo.…”

Intrapulmonary pharmacokinetics and pharmacodynamics of high-dose levofloxacin in healthy volunteer subjects

“…In the 20 subjects who received the 1000 mg dose, standardised bronchoscopy, BAL and clinical monitoring [38,39] were performed in the GCRC at either 3, 4, 8, 12 or 24 h after initiation of the 2-h infusion of the last dose of levofloxacin. In the four subjects who received the 750 mg dose, standardised bronchoscopy, BAL and clinical monitoring were performed in the GCRC at 4 h after initiation of the 2-h infusion of the last dose.…”

Interpretation of Antibiotic Concentration Ratios Measured in Epithelial Lining Fluid

“…Measured ELF concentrations of macrolides (azithromycin and clarithromycin) and ketolides (telithromycin and cethromycin) and their derived AUCs were consistently higher than serum levels by as much as 10-fold (15,19,21,27,44,55,57,60,72,77,78,80,(86)(87)(88) (Table 3). In addition, when protein binding of the antibiotics in serum was considered, the ratios became even higher.…”

“…Measurements at steady state were preferred over those at non-steady-state conditions. Under the criteria, the following antibiotics from a total of 45 publications, 44 original articles, and 1 review article were included in the evaluation: 3 beta-lactams (amoxicillin, cefdinir, and meropenem) (22,32,34), 2 macrolides (azithromycin and clarithromycin) (15,19,21,44,53,77,80,(86)(87)(88), 2 ketolides (cethromycin and telithromycin) (27,57,60,72,78), 13 fluoroquinolones (3-5, 8, 9, 15, 33, 45, 51, 52, 79, 87, 91, 93, 97, 99, 100), linezolid (26,54), tigecycline (23), 2 rifamycins (rifampin and rifapentine) (18,31,103), 4 other antituberculosis antibiotics (ethambutol, ethionamide, isoniazid, and pyrazinamide) (20,24,29,30), and an antifungal azole (itraconazole) (25).…”