title: Effect of ketoconazole on the pharmacokinetics and safety of telithromycin and clarithromycin in older subjects with renal impairment.
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 > 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.
  
  
  RESULTS
  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.
  
  
  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.
authors.affiliation: Aventis, Global Biopharmaceutics and Clinical Pharmacokinetics, Drug Metabolism and Pharmacokinetics, 1041 Route 202 - 206, Bridgewater, NJ 08807-0800, USA. junshi88@yahoo.com
authors.forename: J
authors.initials: J
authors.lastname: Shi
authors.forename: S
authors.initials: S
authors.lastname: Chapel
authors.forename: G
authors.initials: G
authors.lastname: Montay
authors.forename: P
authors.initials: P
authors.lastname: Hardy
authors.forename: J S
authors.initials: JS
authors.lastname: Barrett
authors.forename: D
authors.initials: D
authors.lastname: Sica
authors.forename: S K
authors.initials: SK
authors.lastname: Swan
authors.forename: R
authors.initials: R
authors.lastname: Noveck
authors.forename: B
authors.initials: B
authors.lastname: Leroy
authors.forename: V O
authors.initials: VO
authors.lastname: Bhargava
mesh_terms: D000368:Aged; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D000935:Antifungal Agents / Q000494:pharmacology*; D019540:Area Under Curve; D001682:Biological Availability; D017291:Clarithromycin / Q000009:adverse effects / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology*; D048628:Ketolides / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D007674:Kidney Diseases / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged
chemical_list: D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D048628:Ketolides; D017291:Clarithromycin; C106791:telithromycin; D007654:Ketoconazole