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Daptomycin, a lipopeptide antibiotic with excellent activity against Gram-positive bacteria, is excreted primarily by the kidneys. Development of effective chromatographic methodologies for the determination of daptomycin in human specimens is necessary for clinical use. This study developed a simple and validated ultra-high-performance liquid chromatography method coupled to ultraviolet detection for determination of daptomycin in human plasma and urine. After the pretreatments involving protein precipitation, the supernatants were separated using a 2.3 µm particle size octadecylsilyl column, and the run time was 1 min. The calibration curves were linear over the concentration ranges of 2-200 mg/L for plasma and 25-300 mg/L for urine. Intra- and inter-assay precision and accuracy values of plasma were within 13.5 and 92-100% and within 10.7 and 100-107%, respectively. Those of urine were within 5.0 and 101-104% and within 3.7 and 100-101%, respectively. The validated method was applied to the determination of plasma and urine samples in patients receiving 4-6 mg/kg of intravenous daptomycin, resulting in sufficient sensitivity for evaluating the plasma exposure and urinary excretion. In conclusion, the present method with acceptable analytical performance can be helpful for evaluating the pharmacokinetic disposition of daptomycin in clinical settings., (Copyright © 2013 John Wiley & Sons, Ltd.)

A 13-min LC-MS method was developed for the determination of daptomycin, a new potent antibiotic, in peritoneal fluid, blood plasma, and urine of patients receiving renal replacement therapy. Chromatography was performed on a C(18) column and detection was performed by a single-quadrupole mass spectrometer coupled to LC via an electrospray interface (ESI). The column effluent was also monitored at 370 nm using a photodiode-array detector. The developed method provided a linear dynamic range for concentrations from 0.5 microg mL(-1) to 100 microg mL(-1). Method precision and accuracy were found to be satisfactory for clinical application, thus the method was successfully used for the analysis of daptomycin in pharmacokinetic studies. The drug was preventively administered against Gram-positive infections to 19 clinical patients undergoing peritoneal dialysis. Peritoneal fluid, blood plasma, and urine samples were collected at 13 time points over a period of 48 h. Clinical samples were analysed following simple sample-preparation procedures and daptomycin was unambiguously detected and quantified.

Daptomycin pharmacokinetics were evaluated for burn patients. Burn patients had decreases in the maximum concentration of the drug in serum (44%) and the area under the concentration-time curve (47%) and increases in the volume of distribution (64%) and total clearance (77%) compared to healthy volunteers. In burn patients, daptomycin at 10 to 12 mg/kg of body weight/day would be required to achieve drug exposures similar to those for healthy volunteers receiving 6 mg/kg.

The present study characterized the single-dose pharmacokinetics of daptomycin dosed as 4 mg/kg of total body weight (TBW) in seven morbidly obese and seven age-, sex-, race-, and serum creatinine-matched healthy subjects. The glomerular filtration rate (GFR) was measured for both groups following a single bolus injection of [(125)I]sodium iothalamate. Noncompartmental analysis was used to determine the pharmacokinetic parameters, and these values were normalized against TBW, ideal body weight (IBW), and fat-free weight (FFW) for comparison of the two groups. All subjects enrolled in this study were female, and the mean (+/-standard deviation) body mass index was 46.2 +/- 5.5 kg/m(2) or 21.8 +/- 1.9 kg/m(2) for the morbidly obese or normal-weight group, respectively. The maximum plasma concentration and area under the concentration-time curve from dosing to 24 h were approximately 60% higher (P < 0.05) in the morbidly obese group than in the normal-weight group, and these were a function of the higher total dose received in the morbidly obese group. No differences in daptomycin volume of distribution (V), total clearance, renal clearance, or protein binding were noted between the two groups. Of TBW, FFW, or IBW, TBW provided the best correlation to V. In contrast, TBW overestimated GFR through creatinine clearance calculations using the Cockcroft-Gault equation. Use of IBW in the Cockcroft-Gault equation or use of the four-variable modification of diet in renal disease equation best estimated GFR in morbidly obese subjects. Further studies of daptomycin pharmacokinetics in morbidly obese patients with acute bacterial infections and impaired renal function are necessary to better predict appropriate dosage intervals.