Simple LC-MS/MS Methods Using Core–Shell Octadecylsilyl Microparticulate for the Quantitation of Total and Free Daptomycin in Human Plasma :

Low serum albumin levels are very common in critically ill patients, with reported incidences as high as 40-50%. This condition appears to be associated with alterations in the degree of protein binding of many highly protein-bound antibacterials, which lead to altered pharmacokinetics and pharmacodynamics, although this topic is infrequently considered in daily clinical practice. The effects of hypoalbuminaemia on pharmacokinetics are driven by the decrease in the extent of antibacterial bound to albumin, which increases the unbound fraction of the drug. Unlike the fraction bound to plasma proteins, the unbound fraction is the only fraction available for distribution and clearance from the plasma (central compartment). Hence, hypoalbuminaemia is likely to increase the apparent total volume of distribution (V(d)) and clearance (CL) of a drug, which would translate to lower antibacterial exposures that might compromise the attainment of pharmacodynamic targets, especially for time-dependent antibacterials. The effect of hypoalbuminaemia on unbound concentrations is also likely to have an important impact on pharmacodynamics, but there is very little information available on this area. The objectives of this review were to identify the original research papers that report variations in the highly protein-bound antibacterial pharmacokinetics (mainly V(d) and CL) in critically ill patients with hypoalbuminaemia and without renal failure, and subsequently to interpret the consequences for antibacterial dosing. All relevant articles that described the pharmacokinetics and/or pharmacodynamics of highly protein-bound antibacterials in critically ill patients with hypoalbuminaemia and conserved renal function were reviewed. We found that decreases in the protein binding of antibacterials in the presence of hypoalbuminaemia are frequently observed in critically ill patients. For example, the V(d) and CL of ceftriaxone (85-95% protein binding) in hypoalbuminaemic critically ill patients were increased 2-fold. A similar phenomenon was reported with ertapenem (85-95% protein binding), which led to failure to attain pharmacodynamic targets (40% time for which the concentration of unbound [free] antibacterial was maintained above the minimal inhibitory concentration [fT>MIC] of the bacteria throughout the dosing interval). The V(d) and CL of other highly protein-bound antibacterials such as teicoplanin, aztreonam, fusidic acid or daptomycin among others were significantly increased in critically ill patients with hypoalbuminaemia compared with healthy subjects. Increased antibacterial V(d) appeared to be the most significant pharmacokinetic effect of decreased albumin binding, together with increased CL. These pharmacokinetic changes may result in decreased achievement of pharmacodynamic targets especially for time-dependent antibacterials, resulting in sub-optimal treatment. The effects on concentration-dependent antibacterial pharmacodynamics are more controversial due to the lack of data on this topic. In conclusion, altered antibacterial-albumin binding in the presence of hypoalbuminaemia is likely to produce significant variations in the pharmacokinetics of many highly protein-bound antibacterials. Dose adjustments of these antibacterials in critically ill patients with hypoalbuminaemia should be regarded as another step for antibacterial dosing optimization. Moreover, some of the new antibacterials in development exhibit a high level of protein binding although hypoalbuminaemia is rarely considered in clinical trials in critically ill patients. Further research that defines dosing regimens that account for such altered pharmacokinetics is recommended.

The objective of this analysis was to evaluate the relationship between daptomycin exposure and the probability of an elevation in the creatine phosphokinase (CPK) level (hereafter, "CPK elevation") in patients with Staphylococcus aureus bacteremia with or without infective endocarditis. Phase 3 data for patients with S. aureus bacteremia, with or without infective endocarditis, who received intravenous daptomycin (6 mg/kg daily) and in whom pharmacokinetic data were collected were evaluated. On the basis of univariate logistic regression, the relationship between Bayesian post hoc exposure estimates and the probability of a CPK elevation was evaluated. Time to CPK elevation was examined with Kaplan-Meier analysis and Cox proportional hazards regression. Significant relationships between the minimum concentration of drug (C(min)) and area under the plasma concentration time curve and probability of CPK elevation were observed in 108 evaluable patients. Of the 108 patients evaluated, 6 (5.56%) demonstrated a defined CPK elevation, regardless of treatment relationship. C(min) (breakpoint of 24.3 mg/L) was most significantly associated with CPK elevation (P = .002). The probabilities of a CPK elevation with a C(min) 24.3 mg/L and <24.3 mg/L were 0.5 and 0.029, respectively. Increases in C(min), evaluated as a continuous variable, were also significantly associated with CPK elevation (P = .01). Stratified Kaplan-Meier analysis and Cox proportional hazards regression demonstrated C(min) to be a significant predictor of time to a CPK elevation (P .003). The probability of a CPK elevation was 0 and 0.01 after 7 days of treatment in patients with a C(min) 24.3 mg/L or <24.3 mg/L, respectively. After 14 days, the probabilities were 0.5 and 0.025, respectively. This analysis demonstrated that a daptomycin C(min) 24.3 mg/L was associated with an increased probability of a CPK elevation. Clinical trials registration. Clinical trials.gov NCT00093067 .

The purpose of this paper is to establish the pharmacokinetics and safety of escalating, once-daily doses of daptomycin, a novel lipopeptide antibiotic active against gram-positive pathogens, including those resistant to methicillin and vancomycin. This phase 1, multiple-dose, double-blind study involved 24 healthy subjects in three dose cohorts (4, 6, and 8 mg/kg of body weight) who were randomized to receive daptomycin or the control at a 3:1 ratio and administered the study medication by a 30-min intravenous infusion every 24 h for 7 to 14 days. Daptomycin pharmacokinetics was assessed by blood and urine sampling. Safety and tolerability were evaluated by monitoring adverse events (AEs) and laboratory parameters. Daptomycin pharmacokinetics was linear through 6 mg/kg, with a slight ( approximately 20%) nonlinearity in the area under the curve and trough concentration at the highest dose studied (8 mg/kg). The pharmacokinetic parameters measured on the median day of the study period, (day 7) were half-life ( approximately 9 h), volume of distribution ( approximately 0.1 liters/kg), systemic clearance ( approximately 8.2 ml/h/kg), and percentage of the drug excreted intact in urine from 0 to 24 h ( approximately 54%). Daptomycin protein binding (mean amount bound, 91.7%) was independent of the drug concentration. No gender effect was observed. All subjects who received daptomycin completed the study. The frequencies and distributions of treatment-emergent AEs were similar for the subjects who received daptomycin and the control subjects. There were no serious AEs and no pattern of dose-related events. The pharmacokinetics of once-daily administration of daptomycin was linear through 6 mg/kg. For all three doses, plasma daptomycin concentrations were consistent and predictable throughout the dosing interval. Daptomycin was well tolerated when it was administered once daily at a dose as high as 8 mg/kg for 14 days.