Daptomycin pharmacokinetics in critically ill patients receiving continuous venovenous hemodialysis.
OBJECTIVE
To investigate daptomycin pharmacokinetics in critically ill patients receiving continuous venovenous hemodialysis to develop dosing recommendations.


METHODS
Prospective, open-label pharmacokinetic study.


METHODS
: Intensive care units located within a teaching medical center.


METHODS
Eight adults with known/suspected Gram-positive infections receiving continuous venovenous hemodialysis and daptomycin.


METHODS
Daptomycin at 8 mg/kg intravenously over 30 mins. Serial blood and effluent samples were collected over the next 48 hrs. Daptomycin protein binding was determined by equilibrium dialysis. Daptomycin continuous venovenous hemodialysis transmembrane clearance was determined by dividing daptomycin effluent by serum concentrations and multiplying by mean effluent production rate for each subject. Equations describing a two-compartment, open-pharmacokinetic model were fitted to each subject's daptomycin concentration-time data and pharmacokinetic parameters were determined by standard methods. Serum concentration-time profiles were simulated for two daptomycin regimens (8 mg/kg every 48 hrs and 4 mg/kg every 24 hrs).


RESULTS
A total of 7.7 ± 0.6 mg/kg (mean ± sd) of daptomycin was administered, resulting in an observed peak concentration of 81.2 ± 19.0 μg/mL. Daptomycin steady-state volume of distribution (0.23 ± 0.14 L/kg) and free fraction (17.5% ± 5.0%) were increased in critically ill subjects receiving continuous venovenous hemodialysis compared with previous values reported in healthy volunteers. Daptomycin transmembrane clearance (6.3 ± 2.9 mL/min) accounted for more than half of total clearance (11.3 ± 4.7 mL/min). Simulations demonstrated 8 mg/kg daptomycin every 48 hrs would result in higher peak (88.8 ± 20.0 μg/mL vs. 53.0 ± 12.3 μg/mL) and lower trough concentrations (7.2 ± 5.2 μg/mL vs. 12.3 ± 5.1 μg/mL) than 4 mg/kg every 24 hrs.


CONCLUSIONS
Daptomycin at 8 mg/kg every 48 hrs in critically ill patients receiving continuous venovenous hemodialysis resulted in good drug exposure, achieved high peak concentrations to maximize daptomycin's concentration-dependent activity, and resulted in trough concentration that would minimize the risk of myopathy. CLINICALTRIALS.GOV IDENTIFIER: NCT00663403.
Vilay
A Mary
AM
University of New Mexico College of Pharmacy, Albuquerque, NM, USA. mvilay@salud.unm.edu
Grio
Maricor
M
Depestel
Daryl D
DD
Sowinski
Kevin M
KM
Gao
Lihong
L
Heung
Michael
M
Salama
Noha N
NN
Mueller
Bruce A
BA
D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016470:Bacteremia / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality / Q000628:therapy; D003131:Combined Modality Therapy; D016638:Critical Illness / Q000401:mortality / Q000628:therapy*; D017576:Daptomycin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D016908:Gram-Positive Bacterial Infections / Q000175:diagnosis / Q000188:drug therapy / Q000401:mortality; D006784:Hospitals, Teaching; D006801:Humans; D007262:Infusions, Intravenous; D007362:Intensive Care Units; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D006435:Renal Dialysis / Q000379:methods*; D018570:Risk Assessment; D016019:Survival Analysis; D016896:Treatment Outcome
D000900:Anti-Bacterial Agents; D017576:Daptomycin