Observational study to determine the optimal dose of daptomycin based on pharmacokinetic/pharmacodynamic analysis

Abstract

High doses of daptomycin (DAP) (>6 mg/kg/day) have been preliminarily recommended in recent practical guidelines for methicillin-resistant Staphylococcus aureus infection, to achieve better clinical effects. While such doses can elevate the plasma trough concentration (Cmin) of DAP, there is an associated risk of creatine phosphokinase (CPK) elevation warranting further investigation. In the current study relationships between DAP Cmin and CPK elevation were investigated, and optimal DAP doses were determined. Plasma DAP concentrations were measured in 20 patients. Logistic regression analysis was performed to assess relationships between DAP Cmin and CPK elevation, then a population pharmacokinetic model of DAP was developed. To determine an optimal DAP dose a Monte Carlo simulation (MCS) was performed to minimize the risk of CPK elevation and maximize the probability of successful treatment. In logistic regression analysis DAP Cmin was significantly associated with CPK elevation (odds ratio 1.21, p = 0.048). With respect to dose-dependent increases in the probability of CPK elevation and exposure to DAP, MCS estimated an optimal DAP dose of 4–6 mg/kg/day, corresponding to a minimum inhibitory concentration (MIC) of ≤0.5 μg/mL. For an MIC of 1 μg/mL, MCS estimated an optimal DAP dose of 10 mg/kg/day. However, the probability of CPK elevation associated with high doses of DAP was higher than that associated with the approved doses. In cases where high doses of DAP are administered, close CPK monitoring is required and therapeutic drug monitoring of DAP may be desirable.