Antibiotic Dosing for Critically Ill Adult Patients Receiving Intermittent Hemodialysis, Prolonged Intermittent Renal Replacement Therapy, and Continuous Renal Replacement Therapy: An Update

Hoff, Brian M; Maker, Jenana H.; Dager, William E.; Heintz, Brett H.

doi:10.1177/1060028019865873

Cited by 99 publications

(99 citation statements)

References 99 publications

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“…Finally, we also assessed the effect of protein binding and adsorption on the clearance of apixaban during CRRT. Although protein binding is known to be one of the most important factors affecting drug removal during CRRT [76], exceedingly few agents have available data regarding binding to bovine plasma as these animals are not typically utilized in the drug development process [77]. As the measured protein binding of apixaban in bovine plasma in our study was within ~25% of that observed in healthy volunteers, it is unlikely that this signi cantly altered our optimal dosing recommendations.…”

Section: Discussionmentioning

confidence: 73%

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

Andrews

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 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 2.5-7.5 mg BID may be needed for flow rates ranging from 0.5-5 L/h, respectively. Conclusion: For CRRT flow rates most commonly employed in clinical practice, the standard labeled 5 mg BID dose of apixaban is predicted to achieve target systemic exposure thresholds. The safety and efficacy of these proposed dosing regimens warrants further investigation in clinical studies.

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Section: Discussionmentioning

confidence: 73%

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

Andrews

Benken²,

Tan³

et al. 2020

Preprint

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“…The effect of different CRRT‐techniques, convection vs diffusion, modes and settings on pharmacokinetics of antibiotics including vancomycin is not finally established 18‐20 . Although several population pharmacokinetic‐pharmacodynamic (PK‐PD) models for vancomycin exist, many are based on smaller, often retrospective studies, and are not updated regarding CRRT‐filters, mode and CRRT‐dose, with few and not consecutively collected vancomycin levels 17,21,22 .…”

Section: Introductionmentioning

confidence: 99%

Factors increasing the risk of inappropriate vancomycin therapy in ICU patients: A prospective observational study

Helset

Nordøy

Sporsem

et al. 2020

Acta Anaesthesiol Scand

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Background Vancomycin trough levels are frequently subtherapeutic in intensive care unit (ICU) patients. The aim of this study was to identify patients at risk of therapeutic failure defined as vancomycin area‐under‐the‐curve0‐24/minimum inhibitory concentration (AUC0‐24/MIC) <400, and to examine possible effects of different MICs, the variability in renal clearance and continuous renal replacement therapy (CRRT), and the relevance of vancomycin therapy. Methods A prospective observational study of ICU patients ≥18 years at initiation of vancomycin therapy was conducted from May 2013 to October 2015. The patients were divided into four groups according to renal function and CRRT‐mode as follows: normal‐ or augmented renal clearance and continuous venovenous hemodialysis or ‐hemofiltration. Vancomycin peak and trough levels were measured at 24, 48, and 72 hours after therapy initiation. Relevance of vancomycin therapy was retrospectively evaluated based on microbiological results. Results Eighty‐three patients were included, median age 54.5 years, 74.5% male, SAPS II score 46, and 90 day mortality 28%. Vancomycin therapy was initiated on ICU‐day 8 (IQR, 5‐12), with a median treatment time of 7.5 (IQR, 5‐12) days. AUC0‐24/MIC > 400 was reached in 81% and 8% with MIC = 1 and 2 mg/L respectively. The CRRT groups had higher AUC0‐24/MIC‐ratios than the non‐CRRT groups (P < .001). Augmented renal clearance increased the risk of AUC0‐24/MIC < 400, independent of MIC‐value. Initiation of vancomycin therapy was retrospectively considered relevant in 28 patients (34%). Conclusion A MIC‐value >1 mg/L and augmented renal clearance, were factors increasing the risk of therapeutic failure. Vancomycin treatments could have been omitted or shortened in most of these patients.

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“…Finally, we also assessed protein binding, adsorption, and the effects of point of replacement uid dilution on drug removal. Although protein binding is known to be one of the most important factors affecting drug removal during CRRT [80], exceedingly few agents have available data regarding binding to bovine plasma as these animals are not typically utilized in the drug development process [81]. As such, it is crucial to directly measure this for appropriate clinical translation of in vitro results.…”

Section: Discussionmentioning

confidence: 99%

“…In our study, we observed degrees of lter adsorption high enough to potentially effect drug dosing during CRRT in addition to ltration, particularly for the HF1400 lter. Although the effect of point of replacement uid dilution during CVVH is largely ignored from CRRT dosing recommendations [80,82], the impact can be signi cant, especially at high ow rates [52], and warrants thorough evaluation such as ours during in vitro studies.…”

Section: Discussionmentioning

confidence: 99%

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

Andrews¹,

Benken²,

Tan³

et al. 2020

Preprint

View full text Add to dashboard Cite

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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Antibiotic Dosing for Critically Ill Adult Patients Receiving Intermittent Hemodialysis, Prolonged Intermittent Renal Replacement Therapy, and Continuous Renal Replacement Therapy: An Update

Cited by 99 publications

References 99 publications

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

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

Factors increasing the risk of inappropriate vancomycin therapy in ICU patients: A prospective observational study

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

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