Population pharmacokinetics of daptomycin in critically ill patients

• Published in: International journal of antimicrobial agents Vol. 52; no. 2; pp. 158 - 165
• Main Authors: Soraluce, A., Asín-Prieto, E., Rodríguez-Gascón, A., Barrasa, H., Maynar, J., Carcelero, E., Soy, D., Isla, A.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.08.2018
• Subjects: Acute Kidney Injury - pathology; Acute Kidney Injury - therapy; Aged; Aged, 80 and over; Anti-Bacterial Agents - blood; Anti-Bacterial Agents - pharmacokinetics; Area Under Curve; blood; Continuous renal replacement therapies; creatinine; Creatinine - blood; Critical Illness; Critically ill; Daptomycin; Daptomycin - blood; Daptomycin - pharmacokinetics; data analysis; Drug Administration Schedule; Drug Dosage Calculations; Female; Gram-positive bacteria; Humans; Infectious Disease; Intensive Care Units; Male; Microbial Sensitivity Tests; Middle Aged; minimum inhibitory concentration; Monte Carlo Method; patients; pharmacodynamics; Pharmacokinetic/pharmacodynamic analysis; Pharmacokinetics; Prospective Studies; Renal Dialysis - instrumentation; Renal Dialysis - methods; therapeutics; toxicity; Pharmacokinetics; Critically ill; Continuous renal replacement therapies; Daptomycin; Pharmacokinetic/pharmacodynamic analysis
• ISSN: 0924-8579; 1872-7913; 1872-7913
• DOI: 10.1016/j.ijantimicag.2018.03.008

•A population PK model for daptomycin in critically ill patients was performed.•Daptomycin clearance depended on creatinine clearance and extracorporeal clearance.•PK/PD analysis showed that with the approved dosages, patients are often underdosed.•Dosage should consider renal function and the use of renal replacement therapies. Daptomycin has shown activity against a wide range of Gram-positive bacteria; however, the approved dosages usually seem insufficient for critically ill patients. The aim of this study was to develop a population pharmacokinetic model for daptomycin in critically ill patients and to estimate the success of the therapy by applying pharmacokinetic/pharmacodynamic (PK/PD) criteria. Sixteen intensive care unit patients were included, four of whom underwent continuous renal replacement therapies (CRRT). Blood and, when necessary, effluent samples were drawn after daptomycin administration at previously defined time points. A population approach using NONMEM 7.3 was performed to analyse data. Monte Carlo simulations were executed to evaluate the suitability of different dosage regimens. The probabilities of achieving the PK/PD target value associated with treatment success (ratio of the area under the plasma concentration-time curve over 24 h divided by the minimum inhibitory concentration (AUC24/MIC ≥ 666)) and to reach daptomycin concentrations linked to toxicity (minimum concentration at steady-state (Cminss) ≥ 24.3 mg/L) were calculated. The pharmacokinetics of daptomycin was best described by a one-compartment model. Elimination was conditioned by the creatinine clearance (Clcr) and also by the extra-corporeal clearance when patients were subjected to continuous renal replacement therapy (CRRT). The PK/PD analysis confirmed that 280- and 420-mg/d dosages would not be enough to achieve high probabilities of target attainment for MIC values ≥ 1 mg/L in patients with Clcr ≥ 60 mL/min or in subjects with lower Clcrs but receiving CRRT. In these patients, higher dosages (560–840 mg/d) should be needed. When treating infections due to MIC values ≥ 4 mg/L, even the highest dose would be insufficient.