Pharmacokinetic/Pharmacodynamic Evaluation of Fixed-Dose Daptomycin

Specific Aims Despite receiving FDA approval in 2003, the optimal dosing strategy for intravenous (IV) daptomycin (Cubicin®) has yet to be elucidated in clinical practice. Early clinical trials and package labeling utilize a dosing schematic of daptomycin 4-6 mg/kg/day administered every 24 hours. Since approval, ample clinical data has recognized that higher doses of daptomycin, ranging from 8-12 mg/kg/day, improve efficacy and treatment outcomes while maintaining drug tolerability. Additionally, the Clinical and Laboratory Standards Institute (CLSI) has updated the minimum inhibitory concentration (MIC) breakpoint for Enterococcus faecium such that an MIC of <=4 is considered “susceptible, dose-dependent” with the recommendation that a dose of 8-12 mg/kg/day be used to achieve such dose-dependent susceptibility. There has been a dramatic swing in the paradigm of daptomycin dosing within the last two decades. As greater understanding surrounding therapeutic outcomes and efficacy has emerged, so have concerns surrounding the appropriateness of weight-based dosing schematics. Clinical data suggest that an area under the curve in a 24-hour period to minimum inhibitory concentration ratio (AUC24:MIC) of at least 666 represents the pharmacokinetic/pharmacodynamic (PK/PD) efficacy target for daptomycin in Staphylococcus aureus infections. The well-established relationship between AUC, total daily dose (TDD), and clearance (i.e. AUC = total daily dose/CL) exemplifies potential concerns with daptomycin dosing, as obese patients receive larger total daily doses of daptomycin without a proportional increase in daptomycin clearance based on their weight, putting them at risk for daptomycin-induced skeletal muscle toxicity (Figure 1). As daptomycin clearance is not impacted by body weight, it is perplexing that a weight- based dosing schematic is currently employed for patients with serious Gram-positive infections. As daptomycin clearance is unaffected by weight, significant concerns surrounding the weight-based dosing of daptomycin exist, particularly for patients at the extremes of weight. Specifically, patients who are overweight may experience higher rates of musculoskeletal toxicity while underweight patients may experience higher rates of treatment failure. Fixed dosing of daptomycin has been proposed to mitigate such complications and optimize PK/PD parameters, thus improving treatment Figure 1: Pharmacokinetic Equations for outcomes. However, evidence supporting this approach in a real-world Calculation of Daptomycin Area under the Curve clinical population is extremely limited as pharmacokinetic data surrounding fixed dosing of daptomycin in human patients has not yet been published. While Monte Carlo simulations have justified the feasibility of using fixed dosing of daptomycin, prospective studies in a clinical setting are needed to characterize pharmacokinetic parameters associated with fixed dosing. In addition, defining the achievement of PK/PD efficacy targets and the incidence of elevated trough concentrations from a safety perspective is prudent with this novel dosing approach. The primary objective of this study is to prospectively characterize the pharmacokinetic parameters associated with fixed dosing of daptomycin within a non-critically ill patient population with suspected or confirmed Staphylococcus aureus infections. This study will also evaluate the attainment of AUC24:MIC ≥666 and incidence of elevated Cmin >24.3 mg/L utilizing fixed dosing of daptomycin. Overall, this study is expected to provide critical information regarding the optimal dosing strategies of daptomycin. Since this will be the first human study evaluating the pharmacokinetics with fixed dosing of daptomycin, this data will be useful in informing future fixed dosing studies. Additionally, the outcomes described below will be stratified based on each patient’s weight classification. Specific Aim I: Evaluate attainment of PK/PD efficacy target (AUC24 ≥ 666 mg*hr/L) and incidence of supratherapeutic trough concentrations (Cmin >24.3 mg/L) in non-critically ill patients receiving fixed dosing of IV daptomycin. Hypothesis: We predict that the majority (>90%) and minority (<10%) of all patients enrolled and evaluated following initiation of daptomycin 750 mg administered IV every 24 hours will have a calculated steady-state AUC24:MIC ≥666 and Cmin >24.3, respectively. Sub-Aim IA: Compare attainment of AUC24 ≥666 mg*hr/L calculated using first-order equations (with concentrations obtained at steady state) in a subgroup analysis of patients stratified according to the following weight classifications: (1) total body weight (TBW) >85 kg, (2) TBW 65- 85 kg, and (3) TBW <65 kg. Hypothesis: We predict that there will be no difference in rate of therapeutic attainment of AUC24 ≥ 666 mg*hr/L between any of the three TBW classifications. Sub-Aim IB: Compare incidence of Cmin >24.3 mg/L calculated using first-order equations (with concentrations obtained at steady state) in a subgroup analysis of patients stratified according to the following weight classifications: (1) total body weight (TBW) >85 kg, (2) TBW 65-85 kg, and (3) TBW <65 kg. Hypothesis: We predict that there will be no difference in the occurrence of supratherapeutic Cmin >24.3 mg/L between any of the three TBW classifications. Specific Aim II: Characterize pharmacokinetic parameters associated with fixed dosing of daptomycin in non-critically ill patients utilizing daptomycin concentrations obtained at steady-state and calculated using first-order pharmacokinetic equations. Hypothesis: We predict that this study will provide the information necessary to describe the elimination rate constant (k), half-life (t1/2), volume of distribution (Vd), clearance (CL) peak concentration (Cmax), trough concentration (Cmin), and exposure (AUC24:MIC) for patients receiving fixed dosing of IV daptomycin. The results of this study will provide much needed real-world evidence surrounding the efficacy (AUC24 ≥666 mg*hr/L) and safety (Cmin >24.3) of IV daptomycin administered using a fixed dose. Given the latitude of our data set, results indicating the optimal method for dosing of IV daptomycin could be rapidly translated into clinical practice. As PK/PD optimization of daptomycin is essential to prevent mortality and reduce morbidity associated with infectious sequalae, a greater understanding of the optimal dosing method is warranted to improve therapeutic success and subsequent patient outcomes.