Article

Single-dose daptomycin pharmacokinetics in chronic haemodialysis patients.

Correspondence and offprint requests to: Bruce A. Mueller; E-mail: .
Nephrology Dialysis Transplantation (Impact Factor: 3.37). 11/2010; 25(11):3803. DOI: 10.1093/ndt/gfq615
Source: PubMed

ABSTRACT 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.
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.
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.
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.

0 Bookmarks
 · 
93 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Critically ill patients with acute kidney injury may be treated with a variety of renal replacement therapies (RRTs). Each of these RRTs has profound yet differing effects on drug dosing. Although the doses of some drugs can be titrated to an immediately observable pharmacodynamic effect, the effects of many drugs, such as antibiotics for example, are not immediately apparent. Attainment of desired pharmacodynamic response is a complex interplay between patient, RRT, and pharmacokinetic factors. In the case of antibiotics, microorganism-specific factors also must be considered. Rational and effective drug dosing in this clinical setting cannot occur until all these issues are addressed by the clinician. Failure to account for the pharmacokinetic influences of critical illness, kidney disease, and choice of intermittent hemodialysis or prolonged intermittent or continuous RRT can contribute to the high mortality rates seen in these patients. Pharmacotherapy considerations for each of these therapies are addressed in this article by applying them to a patient case.
    American Journal of Kidney Diseases 11/2012; · 5.29 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: While the pharmacokinetic (PK) properties of daptomycin in hemodialysis (HD) patients have been evaluated previously by three groups, resultant dosing recommendations have varied. To address this clinical conundrum, this study combined concentration-time data from these PK evaluations and derived uniform dosing recommendations among patients on HD receiving daptomycin. A two compartment model with separate HD and non-HD clearance terms was fit to the PK data from these studies with BigNPAG. Embedded with PK parameters from the population PK analysis, 5,000-subject Monte Carlo simulations (MCS) were performed to identify HD dosing schemes which provide efficacy (cumulative and daily area-under-the-curve [lsqb]AUC[rsqb] values) and toxicity (trough concentrations ≥ 24.3 mg/liter) profiles comparable to simulations employing the daptomycin PK model derived from the Staphylococcus aureus bacteremia-infective endocarditis (SAB-IE) study. Separate HD dosing schemes were sought for the two weekly interdialytic periods (48 and 72 hours). For the 48 hour interdialytic period, intra- and post-HD dosing provided the most isometric cumulative and daily AUCs. For the 72 hour interdialytic period, all HD dosing schemes provided AUC(48-72) values < 50% of SAB-IE AUC(48-72) values. Increasing the parent dose by 50% intra- or post-HD provided comparable AUC(48-72) while maintaining acceptable C(min) values. When efficacy and toxicity profiles were evaluated for each individual study, higher probabilities of C(min) ≥ 24.3 mg/liter were observed in one of the three studies. Given the high probability of C(min) ≥ 24.3 mg/liter in one of the three studies, more intensive creatine phosphokinase (CPK) monitoring may be warranted in HD patients receiving daptomycin.
    Antimicrobial Agents and Chemotherapy 12/2012; · 4.57 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The dosing of drugs in critically ill patients remains challenging. While increased volume of distribution after fluid resuscitation and increased cardiac output can increase clearance of antibiotics, liver failure and renal failure can decrease the clearance of drugs. If an extracorporeal device is used, the dosing of drugs becomes even more difficult. Even in intensive care patients with intact renal function, pharmacokinetics and pharmacodynamics are significantly altered.
    Medizinische Klinik, Intensivmedizin und Notfallmedizin. 05/2014;