Tigecycline in critically ill patients on continuous renal replacement therapy: a population pharmacokinetic study

Abstract Objectives The dosing regimen of daptomycin for critically ill patients undergoing continuous renal replacement therapy (CRRT) remains controversial. The goal of this study was to provide guidance for optimal daptomycin therapy in CRRT patients with Staphylococcus aureus infections. Methods Individual concentration data of 32 CRRT subjects pooled from previously published studies were used to construct the population pharmacokinetic model for daptomycin. Model-based simulations were performed to evaluate the efficacy and risk of toxicity for daptomycin doses of 4, 6 and 8 mg/kg, q24h or q48h, under CRRT doses of 25, 30 and 35 mL/h/kg. Efficacy was assessed by the bacteriostatic and bactericidal AUC/MIC targets and drug exposure-based efficacy references. Toxicity was estimated by safety exposure references and the trough concentration threshold. Results A two-compartment model adequately described the pharmacokinetics of daptomycin. Efficacy analysis demonstrated that q48h dosing is associated with an extremely low probability of bactericidal target attainment on every second day after dosing and q24h dosing is preferred for a high probability of bactericidal target attainment. Toxicity evaluation showed that 8 mg/kg q24h has a high probability for reaching the toxicity-related concentration threshold, while 6 mg/kg q24h gives a satisfactory risk–benefit balance. The studied CRRT doses had a limited impact on efficacy and a CRRT dose of 30–35 mL/h/kg may lower the risk of toxicity. Conclusions The model predicted that the combination of 6 mg/kg q24h daptomycin dose and CRRT dose of 30–35 mL/h/kg would achieve the best balance of efficacy and safety.

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Influence of Renal Replacement Modalities on Amikacin Population Pharmacokinetics in Critically Ill Patients on Continuous Renal Replacement Therapy

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00828-16 ◽

2016 ◽

Vol 60 (8) ◽

pp. 4901-4909 ◽

Cited By ~ 13

Author(s):

Claire Roger ◽

Steven C. Wallis ◽

Laurent Muller ◽

Gilbert Saissi ◽

Jeffrey Lipman ◽

...

Keyword(s):

Renal Replacement Therapy ◽

Continuous Renal Replacement Therapy ◽

Replacement Therapy ◽

Critically Ill ◽

Rate Constant ◽

Critically Ill Patients ◽

Drug Distribution ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

The Mean

ABSTRACTThe objective of this study was to describe amikacin pharmacokinetics (PK) in critically ill patients receiving equal doses (30 ml/kg of body weight/h) of continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodiafiltration (CVVHDF). Patients receiving amikacin and undergoing CVVH or CVVHDF were eligible. Population pharmacokinetic analysis and Monte Carlo simulation were undertaken using the Pmetrics software package for R. Sixteen patients (9 undergoing CVVH, 11 undergoing CVVHDF) and 20 sampling intervals were analyzed. A two-compartment linear model best described the data. Patient weight was the only covariate that was associated with drug clearance. The mean ± standard deviation parameter estimates were 25.2 ± 17.3 liters for the central volume, 0.89 ± 1.17 h−1for the rate constant for the drug distribution from the central to the peripheral compartment, 2.38 ± 6.60 h−1for the rate constant for the drug distribution from the peripheral to the central compartment, 4.45 ± 2.35 liters/h for hemodiafiltration clearance, and 4.69 ± 2.42 liters/h for hemofiltration clearance. Dosing simulations for amikacin supported the use of high dosing regimens (≥25 mg/kg) and extended intervals (36 to 48 h) for most patients when considering PK/pharmacodynamic (PD) targets of a maximum concentration in plasma (Cmax)/MIC ratio of ≥8 and a minimal concentration of ≤2.5 mg/liter at the end of the dosing interval. The mean clearance of amikacin was 1.8 ± 1.3 liters/h by CVVHDF and 1.3 ± 1 liters/h by CVVH. On the basis of simulations, a strategy of an extended-interval high loading dose of amikacin (25 mg/kg every 48 h) associated with therapeutic drug monitoring (TDM) should be the preferred approach for aminoglycoside treatment in critically ill patients receiving continuous renal replacement therapy (CRRT). (This study is a substudy of a trial registered at ClinicalTrials.gov under number NCT01403220.)

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