Use of pharmacokinetic and pharmacodynamic principles to determine optimal administration of daptomycin in patients receiving standardized thrice-weekly hemodialysis.

Abstract

This study identified optimal daptomycin dosing for patients receiving thrice-weekly hemodialysis (HD). Twelve adult patients on HD received daptomycin at 6 mg/kg of body weight intravenously (i.v.) one time; plasma and dialysate samples were collected over 3 days. A 2-compartment model with separate HD and non-HD clearance terms was fit to the data. A series of 9,999-subject Monte Carlo simulations (MCS) was performed to identify HD dosing schemes providing efficacy and toxicity profiles comparable to those obtained for MCS employing the daptomycin population pharmacokinetic (PK) model derived from patients in the Staphylococcus aureus bacteremia-infective endocarditis (SAB-IE) study. For efficacy, we selected the HD dosing scheme which generated an area-under-the-curve (AUC) exposure profile comparable to that for the SAB-IE population model. For toxicity, we selected HD dosing schemes that minimized trough concentrations of ≥ 24.3 mg/liter. Separate HD dosing schemes were developed for each FDA-approved regimen and for two weekly interdialytic periods (48 and 72 h). Administration of the same parent daptomycin dose intra-HD and post-HD resulted in AUC, maximum concentration of drug in serum (C(max)), and C(min) values most comparable to those for SAB-IE simulations for the 48-hour interdialytic period. In contrast, all candidate HD dosing schemes provided AUC(48-72) values that were at least 50% lower than the SAB-IE AUC(48-72) values. Increasing the parent dose by 50% provided more comparable AUC(48-72) values while maintaining acceptable C(min) values. Administration of the daptomycin parent dose intra-HD or post-HD was optimal for the 48-h interdialytic period. For the 72-h interdialytic period, clinicians should consider increasing the dose by 50% to achieve more comparable AUC(48-72) values.