Single-dose daptomycin pharmacokinetics in chronic haemodialysis patients.
BACKGROUND
Daptomycin has concentration-dependent antibacterial activity against Gram-positive bacteria. Its use is increasing in haemodialysis units. The manufacturer recommends a 4-6-mg/kg dose administered every 48 hrs for patients receiving haemodialysis. However, there are no published data about daptomycin pharmacokinetics and clearance during haemodialysis. The recommended dosing regimen would conflict with asymmetric thrice-weekly haemodialysis, which yields two ~44-hr and one ~68-hr interdialytic periods. This is the first study to evaluate daptomycin pharmacokinetics in haemodialysis patients, assess the extent of daptomycin dialytic removal and model serum concentrations at 44 and 68 hrs.


METHODS
Six otherwise healthy subjects on chronic haemodialysis (55.3 +/- 16.1 years old, three females, 66.2 +/- 14.2 kg) received a single 6-mg/kg dose of daptomycin post-haemodialysis infused over 30 minutes. Serial blood samples were collected for ~44 hrs (pre-next haemodialysis) and throughout the subsequent haemodialysis session with a high permeability haemodialyser. Individual pharmacokinetic parameters determined by compartmental analysis were used to model trough serum concentrations at 44 and 68 hrs with 6-, 8- and 10-mg/kg post-haemodialysis doses.


RESULTS
The haemodialysis session in this trial yielded mean urea and daptomycin reduction ratios of 79.6 +/- 5.8% and 57.6 +/- 9.2%, respectively. Daptomycin half-life was 19.4 +/- 6.5 and 3.8 +/- 1.1 hrs 'off' and 'on haemodialysis', respectively, with minimal rebound 1 hr post-haemodialysis. All modelled trough concentrations at 44 and 68 hrs at all doses exceed typical minimum inhibitory concentration (MIC(90)) values for Staphylococcus aureus and Enterococcus faecalis.


CONCLUSIONS
Daptomycin serum concentrations declined by ~50% after a 4-hr haemodialysis session with a high permeability haemodialyser. A 6-mg/kg i.v. post-haemodialysis thrice-weekly dose should result in sufficient pre-haemodialysis daptomycin serum concentrations even after a 68-hr interdialytic period.
Salama
Noha N
NN
University of Michigan College of Pharmacy, Department of Clinical, Social & Administrative Sciences, Ann Arbor, MI, USA.
Segal
Jonathan H
JH
Churchwell
Mariann D
MD
Patel
Jignesh H
JH
Gao
Lihong
L
Heung
Michael
M
Mueller
Bruce A
BA
D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics*; D002853:Chromatography, Liquid; D003198:Computer Simulation; D017576:Daptomycin / Q000493:pharmacokinetics*; D005260:Female; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy*; D006207:Half-Life; D006801:Humans; D007676:Kidney Failure, Chronic / Q000382:microbiology* / Q000628:therapy; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D011446:Prospective Studies; D006435:Renal Dialysis; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D000900:Anti-Bacterial Agents; D017576:Daptomycin