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PHARMACOKINETICS AND PHARMACODYNAMICS |
From Aventis, Bridgewater, New Jersey (Dr. Shi, Dr. Chapel, Dr. Barrett, Dr. Leroy, Dr. Bhargava); Aventis, Vitry-sur-Seine, France (Dr. Montay, Dr. Hardy); Radiant Research, Austin, Texas (Dr. Sack); Orlando Clinical Research Center, Orlando, Florida (Dr. Marbury); DaVita Clinical Research and Hennepin County Medical Center, Minneapolis, Minnesota (Dr. Swan); Clinical Research Center, New Orleans, Louisiana (Dr. Vargas); and Aster, Paris, France (Dr. Leclerc).
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 (Cmax, AUC) showed a tendency to increase with increasing severity of renal impairment in both studies. In patients with severe renal impairment (CLCR < 30 mL/min) receiving telithromycin 800 mg in the repeat-dose study, Cmax,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 (CLR) of telithromycin was found to decrease significantly with increasing severity of renal impairment in both studies, and CLR 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 (CLCR 30 mL/min). In patients with severe renal impairment (CLCR < 30 mL/min), dosage adjustment could be considered.
Key Words: Pharmacokinetics • ketolide • telithromycin • safety • renal impairment
Address for reprints: Jun Shi, Aventis Pharmaceuticals, Biopharmaceutics, 1041 Route 202-206, P.O. Box 6800, Mail Code: BW-M-303B, Bridgewater, NJ 08807-0800.
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