Pharmacokinetics and Pharmacodynamics of Intravenous Daptomycin during Continuous Ambulatory Peritoneal Dialysis

Abstract

Summary Background and objectives This study sought to (1) characterize the pharmacokinetic (PK) profile of intravenous (IV) daptomycin among patients receiving continuous ambulatory peritoneal dialysis (CAPD); (2) identify optimal IV CAPD dosing schemes; and (3) determine extent of daptomycin penetration into the peritoneal space after IV administration. Design, setting, participants, & measurements A PK study was conducted among eight CAPD patients. Population PK modeling and Monte Carlo simulation (MCS) were used to identify CAPD dosing schemes providing efficacy and toxicity plasma profiles comparable with those obtained from MCS using the daptomycin population PK model derived from patients in the Staphylococcus aureus bacteremia-infective endocarditis (SAB-IE) study. The primary efficacy exposure target was the area under the curve (AUC). For toxicity, the goal was to identify CAPD dosing schemes that minimized plasma trough concentrations in excess of 24.3 mg/L. Finally, peritoneal cavity penetration was determined. Results Administration of IV daptomycin 4 or 6 mg/kg, depending on indication, every 48 h was identified as the optimal CAPD dosing scheme. This regimen provided cumulative (AUC0–48) and daily partitioned (AUC0–24h and AUC24–48h) plasma AUC values similar to the SAB-IE or “typical patient” simulations. In addition, the proportion of patients likely to experience an elevated trough concentration in excess of 24.3 mg/L was similar between every 48 h CAPD dosing and the referent group. Penetration into the peritoneal cavity was 6% of plasma. Conclusions Daptomycin 4 or 6 mg/kg, on the basis of indication, IV every 48 h was found to be the optimal IV CAPD dosing scheme.

Pharmacokinetics of Daptomycin in a Patient with Severe Renal Failure Not Receiving Dialysis

“…Daptomycin total clearance (0.240 Ϯ 0.016 liters/h or 4.00 Ϯ 0.27 ml/h/kg) was reduced by approximately 2-fold compared to that with healthy volunteers (9.0 Ϯ 0.9 ml/h/kg) and by almost 4-fold compared to the value (0.957 Ϯ 0.461 liters/h) reported in patients with preserved renal function who were treated for bacteremia and endocarditis (2). Yet the clearance estimate in our patient was relatively close to the value (0.31 Ϯ 0.17 liters/h) previously observed in patients with minimal kidney function (6). In order to prevent toxicity, the maintenance dose was reduced by half on day 25 by doubling the dosing interval.…”

“…Since daptomycin elimination is linear, administering 5 mg/kg every 24 h or 10 mg/kg every 48 h would result in similar areas under the concentration-time curves (AUCs). The AUC-to-MIC ratio is currently considered the relevant pharmacodynamic target for daptomycin (3), but the optimal threshold AUC/MIC value is still unknown (6). In contrast, CPK elevation related to musculoskeletal adverse events is most likely to occur when the residual concentration (C min ) is Ն24.3 mg/liter (2).…”

Reevaluation of Ceftazidime Dosing Recommendations in Patients on Continuous Ambulatory Peritoneal Dialysis

“…As we have previously described, a three-compartment model with zero-order infusion and first-order intercompartmental transfer and elimination was fit to the data using the Big Non-Parametric Adaptive Grid with adaptive ␥ (BigNPAG) software program (19)(20)(21). In this model, each exchange was included as a separate differential equation in the structural model.…”

Ertapenem Pharmacokinetics and Pharmacodynamics during Continuous Ambulatory Peritoneal Dialysis

“…Pharmacokinetic data were analyzed in a population PK model using the Big Non-Parametric Adaptive Grid with adaptive ␥ (BigNPAG) software program (13). A description of our PK model has been previously published (5). Briefly, the structural PK model was parameterized as a threecompartment model with zero-order infusion and first-order intercompartmental transfer and elimination.…”