A Fixed versus Weight-Based Dosing Strategy of Daptomycin May Improve Safety in Obese Adults.

Abstract

To compare daptomycin exposures and predicted safety outcomes with a simulated weight-based and fixed dose in morbidly obese and nonobese subjects. We performed a nonparametric population pharmacokinetic analysis of daptomycin concentration-time data from a prior obese and nonobese kidney function-matched cohort of healthy adult volunteers. Monte Carlo simulations were performed to compare the maximum concentrations (Cmax ), minimum concentrations (Cmin ), and area under the curve (AUC) with the standard daptomycin 6 mg/kg/day dose or a 500-mg daily fixed dose in obese and nonobese subjects. The probability of exceeding a daptomycin Cmin target (24.3 mg/L or higher) associated with creatine phosphokinase (CPK) elevations was computed with the two regimens. No significant differences were observed in clearance, volume of distribution at steady state, or terminal half-life between the morbidly obese and nonobese PK models. Daptomycin 6 mg/kg/day resulted in AUC, Cmax , and Cmin values that were ~2-fold higher in morbidly obese subjects relative to nonobese individuals. In contrast, fixed dosing (500 mg/day) resulted in relatively isometric exposures. The fraction of simulated morbidly obese subjects with a Cmin target associated with CPK elevations was 10.8% with 6 mg/kg/day and 2.0% at the 500 mg/day dosage. Weight-based maintenance dosing of daptomycin is less likely to yield bioequivalent exposures in morbidly obese subjects and provides credence for the evaluation of fixed maintenance doses across adult body size to improve safety.