Clinical and pharmacokinetic considerations for the use of daptomycin in patients with Staphylococcus aureus bacteraemia and severe renal impairment.

OBJECTIVES

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.

METHODS

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.

RESULTS

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).

CONCLUSIONS

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.