Population Pharmacokinetics of Cefuroxime in Critically Ill Patients Receiving Continuous Venovenous Hemofiltration With Regional Citrate Anticoagulation and a Phosphate-Containing Replacement Fluid

Janssen, Paddy K.C.; Foudraine, Norbert A.; Burgers, Desiree M. T.; Neef, Kees; Noble, Jos le

doi:10.1097/ftd.0000000000000330

Cited by 13 publications

(16 citation statements)

References 22 publications

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“…The plasma concentration-time curve for cefuroxime was fitted by a two-compartment model, as shown in other studies (22)(23)(24)(25). Cefuroxime is eliminated mainly by renal excretion, and we found that its CL was related to CL CR , but with substantial interindividual variability, which was consistent with findings observed in other studies (22)(23)(24)(25).…”

Section: Discussionsupporting

confidence: 90%

“…The population PK of cefuroxime as a prophylactic antibiotic in cardiac surgery have not been evaluated previously, and studies involving population modeling for this drug are limited (22)(23)(24)(25). In this study, we evaluated the PK profile of cefuroxime in patients undergoing CABG surgery using population modeling and applied the proposed models to Monte Carlo simulations to predict how patient characteristics influence the adequacy of the prophylaxis.…”

Section: Discussionmentioning

confidence: 99%

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Population Pharmacokinetic Model-Based Evaluation of Standard Dosing Regimens for Cefuroxime Used in Coronary Artery Bypass Graft Surgery with Cardiopulmonary Bypass

Alqahtani

Alsultan

Alqattan

et al. 2018

Antimicrob Agents Chemother

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The purpose of this study was to investigate the population pharmacokinetics (PK) of cefuroxime in patients undergoing coronary artery bypass graft (CABG) surgery. In this observational pharmacokinetic study, multiple blood samples were collected over a 48-h interval of intravenous cefuroxime administration. The samples were analyzed by using a validated high-performance liquid chromatography (HPLC) method. Population pharmacokinetic models were developed using Monolix (version 4.4) software. Pharmacokinetic-pharmacodynamic (PD) simulations were performed to explore the ability of different dosage regimens to achieve the pharmacodynamic targets. A total of 468 blood samples from 78 patients were analyzed. The PK for cefuroxime were best described by a two-compartment model with between-subject variability on clearance, the volume of distribution of the central compartment, and the volume of distribution of the peripheral compartment. The clearance of cefuroxime was related to creatinine clearance (CL). Dosing simulations showed that standard dosing regimens of 1.5 g could achieve the PK-PD target of the percentage of the time that the free concentration is maintained above the MIC during a dosing interval () of 65% for an MIC of 8 mg/liter in patients with a CL of 30, 60, or 90 ml/min, whereas this dosing regimen failed to achieve the PK-PD target in patients with a CL of ≥125 ml/min. In conclusion, administration of standard doses of 1.5 g three times daily provided adequate antibiotic prophylaxis in patients undergoing CABG surgery. Lower doses failed to achieve the PK-PD target. Patients with high CL values required either higher doses or shorter intervals of cefuroxime dosing. On the other hand, lower doses (1 g three times daily) produced adequate target attainment for patients with low CL values (≤30 ml/min).

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetic Model-Based Evaluation of Standard Dosing Regimens for Cefuroxime Used in Coronary Artery Bypass Graft Surgery with Cardiopulmonary Bypass

Alqahtani

Alsultan

Alqattan

et al. 2018

Antimicrob Agents Chemother

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“…These methods assume SC and SA are static over time and that CL TM is directly proportional to ow rate across the continuum of CRRT settings. Moreover, the methods for calculating SC and SA have varied dramatically throughout the literature, even among the same authors/groups across different studies [49,[69][70][71][72], resulting in an up to 28% difference in SC/SA values based solely on calculation differences. Through rigorous analysis and thorough statistical justi cation in this study, along with our previous work [58], we have demonstrated that calculation of CL TM by AUC via noncompartmental analyses provides more robust and precise estimations of drug removal by CRRT, and therefore, more reliable dosing recommendations.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and Dialytic Clearance of Apixaban During In Vitro Continuous Renal Replacement Therapy

Andrews¹,

Benken²,

Tan³

et al. 2020

Preprint

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Objective: To evaluate the transmembrane clearance (CLTM) of apixaban during modeled in vitro continuous renal replacement therapy (CRRT), assess protein binding and circuit adsorption, and provide initial dosing recommendations. Design: In vitro pharmacokinetic (PK) study.Setting: University research laboratory.Subjects: Not applicable. Interventions: Apixaban was added to the CRRT circuit and serial, undiluted pre-filter bovine blood samples were collected along with analogous post-filter blood and effluent samples. All experiments were performed in duplicate using continuous veno-venous hemofiltration (CVVH) and hemodialysis (CVVHD) modes, with varying filter types (M150 and HF1400), flow rates (2 and 4 L/h), and point of CVVH replacement fluid dilution (pre, post, and pre/post filter). Concentrations of apixaban and urea were quantified via liquid chromatography-tandem mass spectrometry. Plasma PK parameters for apixaban were estimated via noncompartmental analysis in WinNonlin. CLTM was calculated via the estimated area under the curve (AUC) and by the product of the sieving/saturation coefficient (SC/SA) and flow rate. Two and three-way ANOVA models were built to assess the effects of mode, filter type, flow rate, and point of dilution on CLTM by each method. Optimal doses were suggested by matching the AUC observed in vitro to the systemic exposure demonstrated in Phase 2/3 studies of apixaban. Linear regression was then utilized to provide dosing estimations for flow rates from 0.5-5 L/h. Measurements and Main Results: Mean adsorption to the HF1400 and M150 filters differed significantly at 38% and 13%, respectively, while mean (±SD) percent protein binding was 70.81±0.01%. Effect of CVVH point of replacement fluid dilution did not differ across filter types, although CLTM was consistently significantly higher during CRRT with the HF1400 filter compared to the M150. The three-way ANOVA demonstrated improved fit when CLTM values calculated by AUC were used (adjusted R2 0.87 vs. 0.52), and therefore, these values were used to generate optimal dosing recommendations. Linear regression revealed significant effects of filter type and flow rate on CLTM by AUC, suggesting doses of 5-10 mg BID may be needed for flow rates ranging from 0.5-5 L/h respectively. Conclusion: CLTM of apixaban during CRRT resulted in estimated dosing recommendations ranging from 5 mg BID for flow rates ≤3 L/h up to 7.5-10 mg BID for rates >3 L/h, depending on filter type, in order to match target systemic exposure thresholds. The safety and efficacy of these proposed dosing regimens warrants further investigation in clinical studies.

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“…Pharmacokinetic studies of cefuroxime have been limited to measurements of total concentrations . To our knowledge, only one study is published on the analysis of unbound concentrations of cefuroxime.…”

Section: Introductionmentioning

confidence: 99%

“…2,3 Pharmacokinetic studies of cefuroxime have been limited to measurements of total concentrations. [4][5][6] To our knowledge, only one study is published on the analysis of unbound concentrations of cefuroxime. However, analysis was performed by high-performance liquid chromatography (HPLC) ultraviolet detection.…”

Section: Introductionmentioning

confidence: 99%

Quantification of total and unbound cefuroxime in plasma by ultra‐performance liquid chromatography tandem mass spectrometry in a cohort of critically ill patients with hypoalbuminemia and renal failure

Raaij

Mabelis

Shudofsky

et al. 2019

Clinical Laboratory Analysis

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Background Pharmacokinetic studies of cefuroxime by ultra‐performance liquid chromatography tandem mass spectrometry (UPLC‐MS/MS) have been limited to measurements of total concentrations. Here, we developed a robust method for quantifying total and unbound cefuroxime concentrations using UPLC‐MS/MS and ultrafiltration in critically ill patients with hypoalbuminemia and renal failure. Methods Method validation included accuracy, linearity, precision, repeatability, recovery, and limit of quantification (LOQ). Feasibility of the method was performed on samples obtained from randomly selected intensive care unit (ICU) patients. Total and unbound cefuroxime concentrations were quantified using UPLC‐MS/MS. Sampling times were categorized as trough (180‐1 min prior to administration), peak (10‐30 min after administration), mid (30‐360 min after administration), and continuous (sampling during administration). Pharmacokinetic/pharmacodynamic (PK/PD) targets were unbound cefuroxime concentrations above 4 times the minimum inhibitory concentration (32 mg/L). Results Intra‐assay and inter‐assay precision was <3%. Recovery was 99.7%‐100.3%, and LOQ was 0.1 mg/L. We included 11 patients (median age 72 years (range 54‐77). Median albumin serum concentrations and eGFR were 19 g/L (range 11‐40 g/L) and 48 mL/min/1.73 m2 (range 7‐115 mL/min/1.73 m2), respectively. Median trough and mid concentrations of total cefuroxime were 22.27 mg/L (range 5.42‐54.03 mg/L) and 71.49 mg/L (range 53.87‐73.86 mg/L), and median unbound fraction was 75.42% (range 27.36%‐99.75%). Median unbound cefuroxime concentrations were 11.94 mg/L (range 3.85‐32.39 mg/L) (trough) and 55.62 mg/L (range 10.03‐62.62 mg/L) (mid). Conclusion The method is precise and accurate according to ISO 15189 and within the clinical range of cefuroxime (0.5‐100 mg/L). The method was applied in ICU patients and is suitable for TDM on unbound cefuroxime concentrations.

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Population Pharmacokinetics of Cefuroxime in Critically Ill Patients Receiving Continuous Venovenous Hemofiltration With Regional Citrate Anticoagulation and a Phosphate-Containing Replacement Fluid

Cited by 13 publications

References 22 publications

Population Pharmacokinetic Model-Based Evaluation of Standard Dosing Regimens for Cefuroxime Used in Coronary Artery Bypass Graft Surgery with Cardiopulmonary Bypass

Population Pharmacokinetic Model-Based Evaluation of Standard Dosing Regimens for Cefuroxime Used in Coronary Artery Bypass Graft Surgery with Cardiopulmonary Bypass

Pharmacokinetics and Dialytic Clearance of Apixaban During In Vitro Continuous Renal Replacement Therapy

Quantification of total and unbound cefuroxime in plasma by ultra‐performance liquid chromatography tandem mass spectrometry in a cohort of critically ill patients with hypoalbuminemia and renal failure

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