Ex vivo Ceftolozane/Tazobactam Clearance during Continuous Renal Replacement Therapy

2017 ◽  
Vol 44 (1) ◽  
pp. 16-23 ◽  
Author(s):  
Weerachai Chaijamorn ◽  
Alexander R. Shaw ◽  
Susan J. Lewis ◽  
Bruce A. Mueller
Keyword(s):  
Renal Replacement Therapy ◽  
Continuous Renal Replacement Therapy ◽  
Replacement Therapy ◽  
Important Determinant ◽  
Ex Vivo ◽  
Pharmacokinetic Parameters ◽  
No Adsorption ◽  
Continuous Hemofiltration ◽  
Flow Rates ◽  
Dosing Regimens

Background/Aims: To determine ceftolozane/tazobactam transmembrane clearances (CLTM) in continuous hemofiltration (CHF) and continuous hemodialysis (CHD) and to determine optimal ceftolozane/tazobactam dosing regimens for patients receiving continuous renal replacement therapy (CRRT). Method: Validated, ex vivo CHF and CHD bovine blood models using polysulfone (HF1400) and AN69 (Multiflow 150-M) hemofilters were used to evaluate adsorption and CLTM at different effluent flow rates. Monte Carlo simulations (MCS) using pharmacokinetic parameters from published studies and CLTM from this study were used to generate ceftolozane/tazobactam dosing for patients receiving CRRT. Results: CHF and CHD CLTM did not differ at equivalent effluent rates. CLTM approximated effluent flow rates. No adsorption of ceftolozane/tazobactam occurred for either hemofilter. Effluent flow was the most important determinant of MCS-derived doses. Conclusion: CRRT clearances of ceftolozane/tazobactam depended on effluent flow rates but not hemofilter types. MCS-derived ceftolozane/tazobactam doses of 750 (500/250)-1,500 (1,000/500) mg every 8 h met pharmacodynamic targets for virtual patients receiving CRRT at contemporary effluent rates.

scholarly journals Imipenem/Relebactam Ex Vivo Clearance during Continuous Renal Replacement Therapy

Antibiotics ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1184
Author(s):  
Soo Min Jang ◽  
Lenar Yessayan ◽  
Michael Dean ◽  
Gabrielle Costello ◽  
Ravi Katwaru ◽  
...  
Keyword(s):  
Renal Replacement Therapy ◽  
Continuous Renal Replacement Therapy ◽  
Replacement Therapy ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Ex Vivo ◽  
Continuous Hemofiltration ◽  
Flow Rates ◽  
Drug Dosing ◽  
Dialysate Flow

(1) Purpose of this study: determination of adsorption and transmembrane clearances (CLTM) of imipenem and relebactam in ex vivo continuous hemofiltration (CH) and continuous hemodialysis (CHD) models. These clearances were incorporated into a Monte Carlo Simulation (MCS), to develop drug dosing recommendations for critically ill patients requiring continuous renal replacement therapy (CRRT); (2) Methods: A validated ex vivo bovine blood CH and CHD model using two hemodiafilters. Imipenem/relebactam and urea CLTM at different ultrafiltrate/dialysate flow rates were evaluated in both CH and CHD. MCS was performed to determine dose recommendations for patients receiving CRRT; (3) Results: Neither imipenem nor relebactam adsorbed to the CRRT apparatus. The CLTM of imipenem, relebactam, and urea approximated the effluent rates (ultrafiltrate/dialysate flow rates). The types of hemodiafilter and effluent rates did not influence CLTM except in a dialysis flow rate of 1 L/h and 6 L/h in the CHD with relebactam (p < 0.05). Imipenem and relebactam 200 mg/100 mg every 6 h were sufficient to meet the standard time above the MIC pharmacodynamic targets in the modeled CRRT regimen of 25 kg/mL/h. (4) Conclusions: Imipenem and relebactam are not removed by adsorption to the CRRT apparatus, but readily cross the hemodiafilter membrane in CH and CHD. Dosage adjustment of imipenem/relebactam is likely required for critically ill patients receiving CRRT.

scholarly journals Imipenem dosing recommendations for patients undergoing continuous renal replacement therapy: systematic review and Monte Carlo simulations

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Dhakrit Rungkitwattanakul ◽  
Taniya Charoensareerat ◽  
Pathakorn Kerdnimith ◽  
Nutsinee Kosumwisaisakul ◽  
Piyakamol Teeranaew ◽  
...  
Keyword(s):  
Systematic Review ◽  
Monte Carlo ◽  
Renal Replacement Therapy ◽  
Monte Carlo Simulations ◽  
Continuous Renal Replacement Therapy ◽  
Replacement Therapy ◽  
Optimal Dose ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Dosing Regimens

Abstract Background The appropriate dosing of imipenem for critically ill AKI patients undergoing CRRT remains scarce. Purpose This study aimed to (1) gather the available published pharmacokinetic studies conducted in septic patients receiving continuous renal replacement therapy (CRRT) and (2) to define the optimal imipenem dosing regimens in these populations via Monte Carlo simulations. Methods The databases of PubMed, Embase, and ScienceDirect were searched from inception to May 2020. We used the Medical Subject Headings of “Imipenem,” “CRRT,” and “pharmacokinetics” or related terms or synonym to identify the studies for systematic reviews. A one-compartment pharmacokinetic model was conducted to predict imipenem levels for the initial 48 h of therapy. The pharmacodynamic target was 40% of free drug level above 4 times of the MIC (40% fT > 4 MIC). The dose that achieved at least 90% of the probability of target attainment was defined as an optimal dose. Results Eleven articles were identified and included for our systematic review. The necessary pharmacokinetic parameters such as the volume of distribution and the CRRT clearance were mentioned in 100 and 90.9%, respectively. None of the current studies reported the complete necessary parameters. A regimen of 750 mg q 6 h was the optimal dose for the predilution-CVVH and CVVHD modality with two effluent rates (25 and 35 mL/kg/h) for the pharmacodynamic target of 40% fT > 4MIC. Conclusions None of the current studies showed the complete necessary pharmacokinetic parameters for drug dosing. Pharmacodynamic target significantly contributed to imipenem dosing regimens in these patients. Different effluent rates and types of CRRT had minimal impact on dosing regimens. Clinical validation of the recommendation is necessary.

scholarly journals Pharmacokinetics and dialytic clearance of apixaban during in vitro continuous renal replacement therapy

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Lauren Andrews ◽  
Scott Benken ◽  
Xing Tan ◽  
Eric Wenzler
Keyword(s):  
Renal Replacement Therapy ◽  
Linear Regression ◽  
Protein Binding ◽  
Continuous Renal Replacement Therapy ◽  
Replacement Therapy ◽  
Flow Rate ◽  
Systemic Exposure ◽  
Flow Rates ◽  
Filter Type

Abstract Background 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. Methods Apixaban was added to the CRRT circuit and serial pre-filter bovine blood samples were collected along with 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, flow rates, and point of CVVH replacement fluid dilution. Concentrations of apixaban and urea were quantified via liquid chromatography-tandem mass spectrometry. Plasma pharmacokinetic parameters for apixaban were estimated via noncompartmental analysis. 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 analysis of variance (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 utilized to provide dosing estimations for flow rates from 0.5–5 L/h. Results Mean adsorption to the HF1400 and M150 filters differed significantly at 38 and 13%, respectively, while mean (± standard deviation, SD) percent protein binding was 70.81 ± 0.01%. Effect of CVVH point of 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 twice daily (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.

scholarly journals Cefepime population pharmacokinetics and target attainment in critically ill patients on continuous renal replacement therapy

2021 ◽  
Author(s):  
Mohammad H. Al-Shaer ◽  
Carolyn D. Philpott ◽  
Christopher A. Droege ◽  
Joshua D. Courter ◽  
Daniel P. Healy ◽  
...  
Keyword(s):  
Steady State ◽  
Renal Replacement Therapy ◽  
Continuous Renal Replacement Therapy ◽  
Replacement Therapy ◽  
Bacterial Infections ◽  
Population Pharmacokinetic ◽  
Target Attainment ◽  
Icu Patients ◽  
Flow Rates ◽  
Good Target

Sepsis causes half of acute kidney injuries in the intensive care unit (ICU). ICU patients may need continuous renal replacement therapy (CRRT) which will affect their antimicrobial exposure. We aim to build a cefepime population pharmacokinetic (PK) model in CRRT ICU patients and perform simulations to assess target attainment. Patients who were ≥18 years old, admitted to the ICU, and received cefepime 2 g every 8 hours as 4-hour infusion while on CRRT were enrolled prospectively. Samples were collected from the predialyzer, postdialyzer ports, and effluent fluid at times 1, 2, 3, 4, and 8 hours after the first dose and at steady state. Age, sex, weight, urine output, and CRRT parameters were recorded. Pmetrics was used for population PK and simulations. The target exposure was 100% fT>MIC. Ten patients were included and their mean age was 53 years and weight 119 kg. Seventy percent were males. Cefepime was described by a five-compartment model. The downtime was applied to the CRRT flow rates which were used to describe the rates of transfer between the compartments. At MIC of ≤8 mg/L, cefepime 2g intermittent infusion every 8 hours achieved good target attainment both early in therapy and at steady state. Only extended and continuous infusion regimens achieved good target attainment at MIC 16 mg/L. In conclusion, cefepime 2g infused over 30 minutes followed by 2g extended infusion every 8 hours achieved good target attainment at MIC ≤16 mg/L with different CRRT flow rates and may be considered in resistant bacterial infections.

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