title: Pharmacokinetics and tolerability of amikacin administered as BAY41-6551 aerosol in mechanically ventilated patients with gram-negative pneumonia and acute renal failure.
abstract: BACKGROUND
  BAY41-6551, a drug-device combination in development for adjunctive treatment of Gram-negative pneumonia in intubated and mechanically ventilated patients, consists of amikacin formulated for inhalation coupled with the Pulmonary Drug Delivery System (PDDS) Clinical aerosol delivery platform. Given the predominantly renal clearance of aminoglycosides, understanding systemic amikacin exposure and safety during administration of BAY41-6551 to patients with acute renal failure (ARF) is clinically important.
  
  
  METHODS
  Seven mechanically ventilated patients with Gram-negative pneumonia and ARF receiving continuous veno-venous hemodiafiltration (CVVHDF) were treated with multiple administrations of BAY41-6551 400 mg amikacin twice daily using the PDDS Clinical on-ventilator device [in addition to standard intravenous (i.v.) antimicrobial therapy]. CVVHDF parameters were recorded and a PK analysis was performed using serum, urine, and bronchoalveolar lavage fluid samples.
  
  
  RESULTS
  Maximum serum amikacin concentration [median 1.93 (range: 0.63-3.99) mg/L] and area under the concentration-time curve from zero to 12 h on day 3 [median 19.32 (range 6.32-36.87) mg · h/L] were elevated compared with mechanically ventilated patients with normal renal function; however, serum amikacin trough concentrations were within accepted safety limits. The median amikacin concentration in epithelial lining fluid [887 (range: 406-12,819) mg/L] was similar to that reported previously in mechanically ventilated patients with normal renal function. BAY41-6551 demonstrated acceptable safety and tolerability with most adverse events (AEs) as expected for the patient population. One serious AE of bronchospasm was attributed to the study medication; no reported AEs were related to the PDDS Clinical device.
  
  
  CONCLUSIONS
  CVVHDF appears to provide adequate clearance of systemically absorbed amikacin in mechanically ventilated patients with ARF, suggesting that dose adjustments for BAY41-6551 are probably not necessary for this patient population. Nonetheless, the standard precautionary measures for critically ill patients receiving i.v. amikacin should be followed for patients with ARF who are treated with BAY41-6551.
authors.affiliation: Service de Réanimation Médicale, Hôpital Pitié-Salpêtrière, Paris, France. charles-edouard.luyt@psl.ap-hop-paris.fr
authors.forename: Charles-Edouard
authors.initials: CE
authors.lastname: Luyt
authors.forename: Michael A
authors.initials: MA
authors.lastname: Eldon
authors.forename: Heino
authors.initials: H
authors.lastname: Stass
authors.forename: Dennis
authors.initials: D
authors.lastname: Gribben
authors.forename: Kevin
authors.initials: K
authors.lastname: Corkery
authors.forename: Jean
authors.initials: J
authors.lastname: Chastre
mesh_terms: D058186:Acute Kidney Injury / Q000150:complications; D000336:Aerosols; D000368:Aged; D000583:Amikacin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D016638:Critical Illness; D016503:Drug Delivery Systems; D005260:Female; D005500:Follow-Up Studies; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy*; D017583:Hemodiafiltration / Q000379:methods; D006801:Humans; D008297:Male; D008875:Middle Aged; D018410:Pneumonia, Bacterial / Q000188:drug therapy* / Q000382:microbiology; D012121:Respiration, Artificial; D014018:Tissue Distribution
chemical_list: D000336:Aerosols; D000900:Anti-Bacterial Agents; D000583:Amikacin