Population pharmacokinetics of daptomycin in adult patients undergoing continuous renal replacement therapy

Aim: The objective of this population pharmacokinetic (PK) analysis was to provide guidance for the dosing interval of daptomycin in patients undergoing continuous renal replacement therapy (CRRT).

Methods: A previously published population PK model for daptomycin was updated with data from patients undergoing continuous veno-venous haemodialysis (CVVHD; n = 9) and continuous veno-venous haemodiafiltration (CVVHDF; n = 8). Model-based simulations were performed to compare the 24 h AUC, C_max and C_min of daptomycin following various dosing regimens (4, 6, 8, 10, and 12 mg kg^-1 every [Q] 24 h and Q48 h), with the safety and efficacy exposure references for Staphylococcus aureus bacteraemia/right-sided infective endocarditis.

Results: The previously developed daptomycin structural population PK model could reasonably describe data from the patients on CRRT. The clearance in patients undergoing CVVHDF and CVVHD was estimated at 0.53 and 0.94 l h^-1 , respectively, as compared with 0.75 l h^-1 in patients with creatinine clearance (CrCl) ≥ 30 ml min^-1 . Daptomycin Q24 h dosing in patients undergoing CRRT resulted in optimal exposure for efficacy, with AUC comparable to that in patients with CrCl ≥ 30 ml min^-1 . In contrast, Q48 h dosing was associated with considerably lower AUC_24-48h in all patients for doses up to 12 mg kg^-1 and is therefore inappropriate.

Conclusions: Q24 h dosing of daptomycin up to 12 mg kg^-1 provides comparable drug exposure in patients on CVVHD and in those with CrCl ≥ 30 ml min^-1 . Daily daptomycin use up to 8 mg kg^-1 doses are appropriate for patients on CVVHDF, but higher doses may increase the risk of toxicity.