title: Clinical and pharmacokinetic considerations for the use of daptomycin in patients with Staphylococcus aureus bacteraemia and severe renal impairment.
abstract: OBJECTIVE
  To support daptomycin dosing recommendations in patients with Staphylococcus aureus bacteraemia (SAB) and severe renal impairment using simulations from a population pharmacokinetic model for daptomycin.
  
  
  METHODS
  A population pharmacokinetic model was developed using 4875 daptomycin plasma concentrations from 442 subjects. Daptomycin 24 h AUC and Cmax were then simulated for subjects with a CL(CR) < 30 mL/min [with or without haemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD)] for different dosing frequencies (every 24 h, every 48 h and three times weekly) with doses of 4 mg/kg and 6 mg/kg. These results were compared with efficacy and safety exposure references based on daily dosing to understand the implications of less frequent dosing (for example, higher exposures on day 1 versus day 2) and to evaluate the 4 mg/kg versus 6 mg/kg regimens.
  
  
  RESULTS
  Substantially more patients with SAB and severe renal impairment were underexposed (24 h AUCs compared with an efficacy reference of 6 mg/kg/day, CLCR ≥ 30 mL/min, pivotal trial population) at 4 mg/kg every 48 h compared with 6 mg/kg. Cmax results also favoured 6 mg/kg every 48 h over 4 mg/kg every 48 h. Both exposure metrics at 6 mg/kg every 48 h also stayed below the defined safety limits (based on 12 mg/kg/day, CL(CR) >80 mL/min, the highest dose in controlled clinical trials).
  
  
  CONCLUSIONS
  For patients with SAB and CLCR <30 mL/min, or receiving HD or CAPD, the dose recommendation of 6 mg/kg every 48 h provides appropriate daptomycin exposure for this indication; this will not be the case for patients receiving 4 mg/kg every 48 h.
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Ricardo L
authors.initials: RL
authors.lastname: Chaves
authors.forename: Abhijit
authors.initials: A
authors.lastname: Chakraborty
authors.forename: David
authors.initials: D
authors.lastname: Benziger
authors.forename: Stacey
authors.initials: S
authors.lastname: Tannenbaum
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016470:Bacteremia / Q000150:complications* / Q000188:drug therapy* / Q000382:microbiology; D017576:Daptomycin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D010949:Plasma / Q000737:chemistry; D006435:Renal Dialysis; D051437:Renal Insufficiency / Q000150:complications* / Q000628:therapy; D013203:Staphylococcal Infections / Q000150:complications* / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000900:Anti-Bacterial Agents; D017576:Daptomycin
keywords: continuous ambulatory peritoneal dialysis; dosing; haemodialysis