Abstract

Objective: 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. Methods: Thirty-two subjects aged ³ 60 years with renal impairment who were otherwise medically stable were recruited into this parallel-group study. Following stratification according to creatinine clearance (CLCR), 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. Results: In subjects with CLCR 30 – 80 ml/min, the mean maximal telithromycin concentration at steady state (Cmax,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 ´ h/l. The mean Cmax,ss and AUC(0–12 h)ss for clarithromycin were 6.2 mg/l and 56.1 mg ´ h/l, respectively. The increases in telithromycin Cmax,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 DQTc values were equal or < 60 ms. All QTc values were equal or < 450 ms in males and equal or < 470 ms in females. Conclusions: 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.

Author Details

Authors

• J. Shi
• S. Chapel
• G. Montay
• P. Hardy
• J.S. Barrett
• D. Sica
• S.K. Swan
• R. Noveck
• B. Leroy
• V.O. Bhargava

Departments

• ¹ Aventis, Bridgewater, NJ, USA,
• ² Aventis, Vitry-sur-Seine, France,
  
• ³ Medical College of Virginia, Richmond, VA,
• ⁴ DaVita Clinical Research
  and Hennepin County Medical Center, Minneapolis, MN, and
  
• ⁵ Clinical Research Center, New Orleans, LA, USA

Address

J. Shi
Aventis
Global Biopharmaceutics and Clinical Pharmacokinetics
Drug Metabolism and Pharmacokinetics
1041 Route 202 – 206
Bridgewater, NJ 08807-0800, USA
Email: [email protected]

Citation