title: Daptomycin pharmacokinetics in adult oncology patients with neutropenic fever.
abstract: Daptomycin is the first antibacterial agent of the cyclic lipopeptides with in vitro bactericidal activity against gram-positive organisms, including vancomycin-resistant enterococci, methicillin-resistant staphylococci, and glycopeptide-resistant Staphylococcus aureus. The pharmacokinetics of daptomycin were determined in 29 adult oncology patients with neutropenic fever. Serial blood samples were drawn at 0, 0.5, 1, 2, 4, 8, 12, and 24 h after the initial intravenous infusion of 6 mg/kg of body weight daptomycin. Daptomycin total and free plasma concentrations were determined by high-pressure liquid chromatography. Concentration-time data were analyzed by noncompartmental methods. The results (presented as means +/- standard deviations and ranges, unless indicated otherwise) were as follows: the maximum concentration of drug in plasma (C(max)) was 49.04 +/- 12.42 microg/ml (range, 21.54 to 75.20 microg/ml), the 24-h plasma concentration was 6.48 +/- 5.31 microg/ml (range, 1.48 to 29.26 microg/ml), the area under the concentration-time curve (AUC) from time zero to infinity was 521.37 +/- 523.53 microg.h/ml (range, 164.64 to 3155.11 microg.h/ml), the volume of distribution at steady state was 0.18 +/- 0.05 liters/kg (range, 0.13 to 0.36 liters/kg), the clearance was 15.04 +/- 6.09 ml/h/kg (range, 1.90 to 34.76 ml/h/kg), the half-life was 11.34 +/- 14.15 h (range, 5.17 to 83.92 h), the mean residence time was 15.67 +/- 20.66 h (range, 7.00 to 121.73 h), and the median time to C(max) was 0.6 h (range, 0.5 to 2.5 h). The fraction unbound in the plasma was 0.06 +/- 0.02. All patients achieved C(max)/MIC and AUC from time zero to 24 h (AUC(0-24))/MIC ratios for a bacteriostatic effect against Streptococcus pneumoniae. Twenty-seven patients (93%) achieved a C(max)/MIC ratio for a bacteriostatic effect against S. aureus, and 28 patients (97%) achieved an AUC(0-24)/MIC ratio for a bacteriostatic effect against S. aureus. Free plasma daptomycin concentrations were above the MIC for 50 to 100% of the dosing interval in 100% of patients for S. pneumoniae and 90% of patients for S. aureus. The median time to defervescence was 3 days from the start of daptomycin therapy. In summary, a 6-mg/kg intravenous infusion of daptomycin every 24 h was effective and well tolerated in neutropenic cancer patients.
authors.affiliation: Department of Pharmacy Services, Oregon Health & Science University, Portland, 97239, USA.
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Bubalo
authors.forename: Myrna Y
authors.initials: MY
authors.lastname: Munar
authors.forename: Ganesh
authors.initials: G
authors.lastname: Cherala
authors.forename: Brandon
authors.initials: B
authors.lastname: Hayes-Lattin
authors.forename: Richard
authors.initials: R
authors.lastname: Maziarz
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000009:adverse effects; D019540:Area Under Curve; D001681:Biological Assay; D017576:Daptomycin / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D005006:Ethnicity; D005260:Female; D005334:Fever / Q000139:chemically induced / Q000150:complications*; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008875:Middle Aged; D009369:Neoplasms / Q000150:complications* / Q000378:metabolism; D009503:Neutropenia / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism; D009767:Obesity, Morbid / Q000378:metabolism; D012727:Sex Characteristics; D013211:Staphylococcus aureus / Q000187:drug effects; D013296:Streptococcus pneumoniae / Q000187:drug effects; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D017576:Daptomycin