Pharmacokinetics of Daily Daptomycin in Critically Ill Patients Undergoing Continuous Renal Replacement Therapy

Abstract

Background: The optimal daptomycin dosing regimen for critically ill patients undergoing continuous renal replacement therapy (CRRT) has still to be established. Methods: Daptomycin pharmacokinetics was determined in 9 patients after administration of 6 mg/kg/day over 5 days. Results: At steady state, which was reached by day 3, the area under the curve over 24 h (AUC24h) was 667.4 ± 356.6 mg·h/l, and the maximum concentration (Cmax) was 66.9 ±25.3 mg/l. Mean CRRT clearance accounted for 48% (range 32-67%) of total clearance (mean 10.2 ml/min, range 6.1-18 ml/min). Significant correlations were observed between Cmax, minimum concentration (Cmin) and AUC24h (R² = 0.91, p < 0.001, and R² = 0.94, p < 0.001) and between albumin plasma concentration and free daptomycin (R² = 0.7, p = 0.009). Conclusion: No significant accumulation occurred with a daily daptomycin dose of 6 mg/kg in patients undergoing CRRT with an effluent flow rate of >30 ml/kg/h. The quantification of trough concentrations (Cmin) appears to be a good surrogate to estimate AUC24h and to monitor daptomycin treatment in patients undergoing CRRT.

Population pharmacokinetics of daptomycin in adult patients undergoing continuous renal replacement therapy

“…Although these results should be interpreted with caution due to the small sample size, the overall estimated higher clearance of daptomycin in CRRT patients is consistent with the CRRT procedure, wherein drugs and waste products are removed more efficiently on a continuous basis than with thrice‐weekly intermittent HD . Previous studies have also shown that clearance of daptomycin by CRRT accounted for approximately 40–50% of the total drug clearance , which is comparable to the amount of drug cleared by the kidneys in patients with normal renal function (34–54%) .…”

“… (5001–5008) and Corti et al . (5009) studies; red dots in part B, observed data from the Corti et al study . CVVHD, continuous veno‐venous haemodialysis; CVVHDF, continuous veno‐venous haemodiafiltration…”

“…In this analysis, demographic and daptomycin PK data from patients on CVVHD ( n = 9) or CVVHDF ( n = 8) included in two published studies by Corti et al . and Khadzhynov et al . were pooled with the PK database of the base model for daptomycin , which had been updated from a previously published and validated PK model for daptomycin .…”

“…In the Corti et al . study, where possible, total combined filtration and dialysate rates were maintained between 30 and 40 ml kg − 1 h −1 . Unless prefilter substitution was necessary, the substitute solutions were supplied after the filter.…”

“…In this analysis, demographic and daptomycin PK data from patients on CVVHD (n = 9) or CVVHDF (n = 8) included in two published studies by Corti et al [16] and Khadzhynov et al [17] were pooled with the PK database of the base model for daptomycin [15], which had been updated from a previously published and validated PK model for daptomycin [18]. In the base model [15], subjects were categorized as having CrCl ≥ 30 ml min À1 (n = 374), CrCl < 30 ml min À1 but noton-dialysis (n = 11), end-stage renal disease on HD Q48 h or thrice weekly (n = 40), and end-stage renal disease on CAPD (n = 14).…”