Pharmacokinetics and pharmacodynamics of intravenous daptomycin during continuous ambulatory peritoneal dialysis

Abstract

Background and objectives: This study sought to (1) characterize the pharmacokinetic (PK) profile of intravenous (i.v.) daptomycin among patients receiving continuous ambulatory peritoneal dialysis (CAPD); (2) identify optimal i.v. CAPD dosing schemes; and (3) determine extent of daptomycin penetration into the peritoneal space after i.v. 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 i.v. daptomycin 4 or 6 mg/kg, depending on indication, every 48 h was identified as the optimal CAPD dosing scheme. This regimen provided cumulative (AUC(0-48)) and daily partitioned (AUC(0-24 h) and AUC(24-48 h)) 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, i.v. every 48 h was found to be the optimal i.v. CAPD dosing scheme.

Figure 1.

Three-compartment pharmacokinetic model with zero-order infusion and first-order intercompartmental transfer and elimination. X₁ and X₂, amount of drug in the central and peripheral compartments, respectively; X₃, X₄, and X₅, amount of drug in the first, second, and third peritoneal exchanges, respectively; CL, nondialytic clearance from central compartment (liters/h); V_c, volume of the central compartment (liters); k₁₂ and k₂₁, first-order intercompartmental transfer-rate constants between central and peripheral compartments (inverse hours); k₁₃ and k₃₁, first-order intercompartmental transfer-rate constants between central and peritoneal compartments; CONEX₁ and CONEX₂, amount of daptomycin remaining in peritoneal compartment after drainage of first and second study dwells, respectively (mg); R₁, time-delimited zero-order drug input rate (piece-wise input function) into the central compartment (mg/h).

Figure 2.

(a) Mean ± SD simulated daptomycin concentrations in plasma after a single 4 mg/kg dose. (b) Mean ± SD simulated daptomycin concentrations in plasma after a single 6 mg/kg dose. (c) Mean ± SD simulated daptomycin concentrations in peritoneal fluid after a single 4 mg/kg dose. (d) Mean ± SD simulated daptomycin concentrations in peritoneal fluid after a single 6 mg/kg dose.

Figure 3.

(a) Mean cumulative plasma AUC values for 4 mg/kg daptomycin. (b) Mean partitioned plasma AUC values for 4 mg/kg daptomycin. (c) Mean cumulative plasma AUC values for 6 mg/kg daptomycin. (d) Mean partitioned plasma AUC values for 6 mg/kg daptomycin.