Daptomycin Exposure and the Probability of Elevations in the Creatine Phosphokinase Level: Data from a Randomized Trial of Patients with Bacteremia and Endocarditis

Background. The objective of this analysis was to evaluate the relationship between daptomycin exposure and the probability of an elevation in the creatine phosphokinase (CPK) level (hereafter, "CPK elevation") in patients with Staphylococcus aureus bacteremia with or without infective endocarditis. Methods. Phase 3 data for patients with S. aureus bacteremia, with or without infective endocarditis, who received intravenous daptomycin (6 mg/kg daily) and in whom pharmacokinetic data were collected were evaluated. On the basis of univariate logistic regression, the relationship between Bayesian post hoc exposure estimates and the probability of a CPK elevation was evaluated. Time to CPK elevation was examined with Kaplan-Meier analysis and Cox proportional hazards regression. Results. Significant relationships between the minimum concentration of drug (C-min) and area under the plasma concentration time curve and probability of CPK elevation were observed in 108 evaluable patients. Of the 108 patients evaluated, 6 (5.56%) demonstrated a defined CPK elevation, regardless of treatment relationship. C-min (breakpoint of 24.3 mg/L) was most significantly associated with CPK elevation (P = .002). The probabilities of a CPK elevation with a C-min >= 24.3 mg/L and <24.3 mg/L were 0.5 and 0.029, respectively. Increases in C-min, evaluated as a continuous variable, were also significantly associated with CPK elevation (P = .01). Stratified Kaplan-Meier analysis and Cox proportional hazards regression demonstrated C min to be a significant predictor of time to a CPK elevation (P <= .003). The probability of a CPK elevation was 0 and 0.01 after 7 days of treatment in patients with a C-min >= 24.3 mg/L or <24.3 mg/L, respectively. After 14 days, the probabilities were 0.5 and 0.025, respectively. Conclusions. This analysis demonstrated that a daptomycin C-min >= 24.3 mg/L was associated with an increased probability of a CPK elevation.