Pharmacokinetic Variability of Daptomycin during Prolonged Therapy for Bone and Joint Infections

Abstract

The interindividual and intraindividual variabilities in daptomycin pharmacokinetics were investigated in 23 patients (69 pharmacokinetic profiles) who were treated for several months for bone and joint infections. Population daptomycin clearance was significantly influenced by renal function and was significantly higher in male than in female patients. We observed significant intraindividual changes in daptomycin clearance, which were uncorrelated with changes in renal function, suggesting that therapeutic drug monitoring is important in patients receiving prolonged daptomycin therapy. Daptomycin is a cyclic lipopeptide that has been proposed as an alternative therapeutic option in patients with prosthetic joint infection caused by Staphylococcus or Enterococcus species in the latest Infectious Diseases Society of America (IDSA) guidelines (1).The population pharmacokinetics (PK) of daptomycin have been described in various groups of patients in previous publications (2-5). However, little information exists on the PK of daptomycin in patients with bone and joint infections (BJI). Also, previous population studies did not investigate daptomycin PK over prolonged therapy, and, to our knowledge, no study has reported the intraindividual PK variability of this drug.(This work was presented in part at the 54th ICAAC Meeting, Washington, DC, 5 to 9 September 2014, and at the 34th RICAI meeting, Paris, France, 13 to 15 December 2014.)We performed a retrospective analysis of PK data collected in 23 patients who were treated with daptomycin for BJI in Lyon Center in 2012 and 2013. Therapeutic drug monitoring (TDM) of daptomycin was performed regularly in those patients throughout therapy, roughly every month, to ensure sufficient exposure and to prevent drug accumulation. This project was reviewed by our local institutional review board (CPP Sud-Est III), and a waiver was obtained, as this was a noninterventional study.On each TDM occasion, a daptomycin PK profile was obtained based on three concentrations usually measured at predose (trough level), 0.5 to 1 h, and 5 to 6 h postdose. A total of 203 daptomycin plasma concentrations and 69 individual PK profiles were determined for the 23 individuals. The exact daptomycin doses, dosing times, dose intervals, blood sampling times, and plasma concentrations were recorded for each subject on each occasion. All patients received daptomycin as a 30-min infusion. The dose interval was 24 h, except for 6 profiles from 4 patients in whom it was 48 h because of renal impairment. Other data available on each occasion included age, sex, height, weight, serum creatinine, estimated glomerular filtration rate (eGFR) provided by the 4-variable modification of diet in renal disease (MDRD) equation (6), and concomitant use of rifampin (10 profiles from 3 patients).Daptomycin concentrations were determined by using a highperformance liquid chromatography assay with a photodiode array detector. Concentrations were calculated at two wavelengths (260 and 360 nm), and a spectral analysis was ...

Clinical Pharmacokinetics of Daptomycin

“…In two studies, clearance has been shown to be 20-44% lower for female subjects than for male subjects. [56,80,81] However, in some other studies, difference of clearance between genders was not significant. [82,101] It may be hypothesized that gender could be a better descriptor of the influence of body size on the clearance of daptomycin, but this requires further investigation.…”

“…Clearance and therefore AUC decrease while and t 1/2 increases with decreasing renal function. [27,[80][81][82] Compared with critically ill patients with normal renal function (creatinine clearance, CLcr=120 mL/min), urinary excretion dropped from 61% to 21% while AUC jumped by 2-folds in critically ill patients with severe renal insufficiency (CLcr=20 mL/min).…”

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