To support daptomycin dosing recommendations in patients with Staphylococcus aureus bacteraemia (SAB) and severe renal impairment using simulations from a population pharmacokinetic model for daptomycin.A population pharmacokinetic model was developed using 4875 daptomycin plasma concentrations from 442 subjects. Daptomycin 24 h AUC and Cmax were then simulated for subjects with a CL(CR) < 30 mL/min [with or without haemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD)] for different dosing frequencies (every 24 h, every 48 h and three times weekly) with doses of 4 mg/kg and 6 mg/kg. These results were compared with efficacy and safety exposure references based on daily dosing to understand the implications of less frequent dosing (for example, higher exposures on day 1 versus day 2) and to evaluate the 4 mg/kg versus 6 mg/kg regimens.Substantially more patients with SAB and severe renal impairment were underexposed (24 h AUCs compared with an efficacy reference of 6 mg/kg/day, CLCR ≥ 30 mL/min, pivotal trial population) at 4 mg/kg every 48 h compared with 6 mg/kg. Cmax results also favoured 6 mg/kg every 48 h over 4 mg/kg every 48 h. Both exposure metrics at 6 mg/kg every 48 h also stayed below the defined safety limits (based on 12 mg/kg/day, CL(CR) >80 mL/min, the highest dose in controlled clinical trials).For patients with SAB and CLCR <30 mL/min, or receiving HD or CAPD, the dose recommendation of 6 mg/kg every 48 h provides appropriate daptomycin exposure for this indication; this will not be the case for patients receiving 4 mg/kg every 48 h.

作者：Ricardo L, Chaves；Abhijit, Chakraborty；David, Benziger；Stacey, Tannenbaum

来源：The Journal of antimicrobial chemotherapy 2014 年 69卷 1期