International Journal of Antimicrobial Agents 42 (2013) 250–255 Contents lists available at SciVerse ScienceDirect International Journal of Antimicrobial Agents j o ur nal homep age : ht tp://www.elsevier.com/locate/ijantimicag Population pharmacokinetics of daptomycin in patients affected by severe Gram-positive infections Antonello Di Paolo a,∗ , Carlo Tascini b , Marialuisa Polillo a , Giulia Gemignani b , Elisabet I. Nielsen c , Guido Bocci a , Mats O. Karlsson c , Francesco Menichetti b , Romano Danesi a a Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, 56126 Pisa, Italy b Infectious Diseases Unit, Azienda Ospedaliero Universitaria Pisana, Via Paradisa 2, 56124 Pisa, Italy c Department of Pharmaceutical Biosciences, Faculty of Pharmacy, Uppsala University, Box 591, 75124 Uppsala, Sweden a r t i c l e i n f o Article history: Received 23 January 2013 Accepted 8 June 2013 Keywords: Daptomycin Population pharmacokinetics Gram-positive infections a b s t r a c t A population pharmacokinetic analysis of daptomycin was performed based on therapeutic drug monitoring (TDM) data from 58 patients receiving doses of 4–12 mg/kg for the treatment of severe Gram- positive infections. At a daily dose of 8 mg/kg, daptomycin plasma concentrations (mean ± S.D.) were 76.9 ± 9.8 mg/L at the end of infusion and 52.7 ± 15.4 mg/L and 11.4 ± 5.4 mg/L at 0.5 h and 23 h after drug administration, respectively. The final model was a one-compartmental model with first-order elimina- tion, with estimated clearance (CL) of 0.80 ± 0.14 L/h and a volume of distribution (V d ) of 0.19 ± 0.05 L/kg. Creatinine clearance (CL Cr ) was identified as having a significant influence on daptomycin CL, and a decrease in CL Cr of 30 mL/min from the median value (80 mL/min) was associated with a reduction of daptomycin CL from 0.80 L/h to 0.73 L/h. These results confirm that the presence of severe infection may be associated with an altered disposition of daptomycin, with an increased V d . MICs were available in 41 patients and results showed that 38 and 31 subjects achieved AUC/MIC values associated with bacterio- static (>400) and bactericidal effects (>800), respectively. Of note, 31 of these 41 subjects experienced a clinical improvement or were cured. Although daptomycin pharmacokinetics may be influenced by infections, effective AUC/MIC values were achieved in the majority of patients. The present model may be applied in clinical settings for a TDM routine on the basis of a sparse blood sampling protocol. © 2013 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. 1. Introduction Gram-positive bacteria are often responsible for severe and difficult-to-treat infections, characterised by a high mortality rate in hospital settings [1]. The introduction of daptomycin has been a step forward in the treatment of severe infections caused by drug-resistant strains, such as meticillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci [2,3]. Daptomycin has concentration-dependent activity and its effectiveness is best predicted by the ratio of the maximum plasma concentration to the minimum inhibitory concentration (C max /MIC) or the area under the concentration–time curve to the MIC (AUC/MIC) [4]. Daptomycin is characterised by linear pharmacokinetics in healthy volunteers up to doses of 12 mg/kg once daily [5,6], for which effectiveness, safety and tolerability have been documented ∗ Corresponding author. Tel.: +39 050 221 8750; fax: +39 050 221 8758. E-mail addresses: antonello.dipaolo@med.unipi.it, antonello.dipaolo@gmail.com (A. Di Paolo). [7,8]. Furthermore, high drug doses (up to 10 mg/kg) have been safely administered to children [9]. Daptomycin is excreted mainly through the kidneys as an unmodified molecule, and dosage adjust- ments are recommended in patients with compromised renal function. Biliary excretion accounts for only 3% of an administered dose, but since bile concentrations are high a role for daptomycin in the treatment of biliary tree infections has recently been advo- cated [10]. The drug displays a limited volume of distribution (V d ), accounting for ca. 0.1–0.2 L/kg of body weight [11]. Although dap- tomycin has poor penetration into the central nervous system [12], it achieves adequate concentrations in cardiac valve tissues and vegetations [13]. In 2004, the first study investigating the population pharma- cokinetics of daptomycin was published based on data in healthy volunteers and patients enrolled in phase 1 and phase 2/3 studies [14]. The trial demonstrated that renal function, dialysis and sex contributed significantly to the interindividual variability in drug clearance (CL). Interestingly, the peripheral V d was linearly corre- lated with the patient’s body weight and it nearly doubled in the presence of an infection. 0924-8579/$ – see front matter © 2013 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. http://dx.doi.org/10.1016/j.ijantimicag.2013.06.006