Objective: To investigate daptomycin pharmacokinetics in critically ill patients receiving continuous venovenous hemodialysis to develop dosing recommendations.
Design: Prospective, open-label pharmacokinetic study.
Setting: Intensive care units located within a teaching medical center.
Patients: Eight adults with known/suspected Gram-positive infections receiving continuous venovenous hemodialysis and daptomycin.
Interventions: 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).
Measurements and Main 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.
From the University of New Mexico College of Pharmacy (AMV), Albuquerque, NM; the Arnold Palmer Hospital for Children (MG), Orlando, FL; the University of Michigan College of Pharmacy (DDD, NNS, BAM), Ann Arbor, MI; the University of Michigan Health System (DDD, MH, BAM), Ann Arbor, MI; the Department of Pharmacy Practice (KMS), Purdue University, Indianapolis, IN; Indiana University (KMS), School of Medicine, Indianapolis, IN; Cubist Pharmaceuticals (LG), Lexington, MA; the University of Michigan Medical School (MH), Ann Arbor, MI; St Louis College of Pharmacy (NNS), St Louis, MO; and Cairo University (NNS), Faculty of Pharmacy, Cairo, Egypt.
Financial grant support was received from Cubist Pharmaceuticals.
The interim analysis of this study was presented in abstract form at the 2008 American Society of Nephrology meeting: Vilay AM, Grio M, DePestel DD, et al: Daptomycin pharmacokinetics in patients treated with continuous venovenous hemodialysis. J Am Soc Nephrol 2008; 19:691A (abstract #SA-PO2581).
This work was conducted at the University of Michigan Health System, Ann Arbor, MI.
Drs. DePestel and Mueller received honoraria/speaking fees from Cubist Pharmaceuticals. Dr. DePestel also received a research grant from Cubist Pharmaceuticals. Dr. Gao is employed by Cubist Pharmaceuticals. The remaining authors have not disclosed any potential conflicts of interest.
New address for Dr. DePestel: Cubist Pharmaceuticals Inc., Lexington, MA.
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