Transmembrane Clearance Research Articles

After 50 Years of Hepatic Clearance Models, Where Should We Go from Here? Improvements and Implications for Physiologically Based Pharmacokinetic Modeling.

There is overwhelming preference for application of the unphysiologic, well-stirred model (WSM) over the parallel tube model (PTM) and dispersion model (DM) to predict hepatic drug clearance, CLH , despite that liver blood flow is dispersive and closer to the DM in nature. The reasoning is the ease in computation relating the hepatic intrinsic clearance ( CLint ), hepatic blood flow ( QH ), unbound fraction in blood ( fub ) and the transmembrane clearances ( CLin and CLef ) to CLH for the WSM. However, the WSM, being the least efficient liver model, predicts a lower EH that is associated with the in vitro CLint ( Vmax / Km ), therefore requiring scale-up to predict CLH in vivo. By contrast, the miniPTM, a three-subcompartment tank-in-series model of uniform enzymes, closely mimics the DM and yielded similar patterns for CLint versus EH , substrate concentration [S] , and KL / B , the tissue to outflow blood concentration ratio. We placed these liver models nested within physiologically based pharmacokinetic models to describe the kinetics of the flow-limited, phenolic substrate, harmol, using the WSM (single compartment) and the miniPTM and zonal liver models (ZLMs) of evenly and unevenly distributed glucuronidation and sulfation activities, respectively, to predict CLH For the same, given CLint ( Vmax and Km ), the WSM again furnished the lowest extraction ratio ( EH,WSM = 0.5) compared with the miniPTM and ZLM (>0.68). Values of EH,WSM were elevated to those for EH, PTM and EH, ZLM when the Vmax s for sulfation and glucuronidation were raised 5.7- to 1.15-fold. The miniPTM is easily manageable mathematically and should be the new normal for liver/physiologic modeling. SIGNIFICANCE STATEMENT: Selection of the proper liver clearance model impacts strongly on CLH predictions. The authors recommend use of the tank-in-series miniPTM (3 compartments mini-parallel tube model), which displays similar properties as the dispersion model (DM) in relating CLint and [ S ] to CLH as a stand-in for the DM, which best describes the liver microcirculation. The miniPTM is readily modified to accommodate enzyme and transporter zonation.

Anakinra Removal by Continuous Renal Replacement Therapy: An Ex Vivo Analysis.

Patients with sepsis are at significant risk for multiple organ dysfunction, including the lungs and kidneys. To manage the morbidity associated with kidney impairment, continuous renal replacement therapy (CRRT) may be required. The extent of anakinra pharmacokinetics in CRRT remains unknown. The objectives of this study were to investigate the anakinra-circuit interaction and quantify the rate of removal from plasma. The anakinra-circuit interaction was evaluated using a closed-loop ex vivo CRRT circuit. CRRT was performed in three phases based on the method of solute removal: 1) hemofiltration, 2) hemodialysis, and 3) hemodiafiltration. Standard control samples of anakinra were included to assess drug degradation. University research laboratory. None. Anakinra was administered to the CRRT circuit and serial prefilter blood samples were collected along with time-matched control and hemofiltrate samples. Each circuit was run in triplicate to assess inter-run variability. Concentrations of anakinra in each reference fluid were measured by enzyme-linked immunosorbent assay. Transmembrane filter clearance was estimated by the product of the sieving coefficient/dialysate saturation constant and circuit flow rates. Removal of anakinra from plasma occurred within minutes for each CRRT modality. Average drug remaining (%) in plasma following anakinra administration was lowest with hemodiafiltration (34.9%). The average sieving coefficient was 0.34, 0.37, and 0.41 for hemodiafiltration, hemofiltration, and hemodialysis, respectively. Transmembrane clearance was fairly consistent across each modality with the highest during hemodialysis (5.53 mL/min), followed by hemodiafiltration (4.99 mL/min), and hemofiltration (3.94 mL/min). Percent drug remaining within the control samples (93.1%) remained consistent across each experiment, indicating negligible degradation within the blood. The results of this analysis are the first to demonstrate that large molecule therapeutic proteins such as anakinra, are removed from plasma with modern CRRT technology. Current dosing recommendations for patients with severe renal impairment may result in subtherapeutic anakinra concentrations in those receiving CRRT.

2526. Ex Vivo Assessment of Sulbactam-Durlobactam (SUL-DUR) Clearance during Continuous Renal Replacement Therapy (CRRT)

Abstract Background Optimal dosing of antibiotics in patients on CRRT is complicated by factors that can influence drug adsorption and clearance including filter type, CRRT mode, effluent rate (ER), and the drug’s properties itself. SUL-DUR is a novel combination antibiotic under development for management of Acinetobacter baumannii infections. We sought to characterize SUL and DUR adsorption and transmembrane clearance (CLTM) in an ex vivo CRRT model. Methods CLTM was determined in hemofiltration (CVVH) and hemodialysis (CVVHD) modes using the Prismaflex M100 and HF1400 hemofilter sets. One liter of heparinized bovine blood was allowed to circulate in the Prismaflex CRRT system for 10 minutes. SUL and DUR were then added to achieve a plasma concentration of 30 mg/L, the average maximum concentration achieved in humans following SUL-DUR 1g/1g q6h as a 3h infusion. Pre-filter blood, post-filter blood and effluent samples were collected at 0, 10, 30, and 60 minutes to determine SUL and DUR concentrations. Combinations of filters, modes, and replacement fluid were tested in triplicate at effluent rates of 1, 2 and 3 L/h. The sieving coefficient (SC) for CVVH and the saturation coefficient (SA) for CVVHD were calculated to determine CLTM. Adsorption was measured through a closed loop system bypassing effluent elimination. Multiple linear regression was used to determine SUL and DUR CLTM as a function of ER, filter, and mode. Results SUL and DUR adsorption was minimal at 10% for both drugs. Mean ± standard deviation initial SUL and DUR concentrations were 28.6 ± 2.5 and 27.4 ± 1.9 mg/L, respectively. The overall mean SC/SA across different modes, filters, and ERs was 1.0 and 0.9 for SUL and DUR, respectively. Multiple linear regression demonstrated that the ER was the primary driver (p< 0.001) of CLTM for both drugs based on the equations: SUL CLTM (L/h) = -0.0123 + (1 x ER), R2 = 0.998; DUR CLTM (L/h) = 0.0346 + (0.91 x ER), R2 = 0.958. Conclusion SUL and DUR were efficiently cleared by both CVVH and CVVHD through M100 and HF1400 filters. The clearance of both drugs during CRRT was dependent primarily on the ER. When incorporated into established population pharmacokinetic models, these data can be used to estimate CLTM and devise dosing recommendations for SUL-DUR for patients requiring CRRT. Disclosures Xiaoyi Ye, MD, Sanofi Genzyme: Honoraria David P. Nicolau, PharmD, Allergan: Advisor/Consultant|Allergan: Grant/Research Support|Cepheid: Advisor/Consultant|Cepheid: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Tetraphase: Advisor/Consultant|Tetraphase: Grant/Research Support|Venatorx: Advisor/Consultant|Venatorx: Grant/Research Support|Wockhardt: Advisor/Consultant|Wockhardt: Grant/Research Support Joseph L. Kuti, PharmD, bioMeriuex Inc.: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Merck & Co, Inc: Grant/Research Support|Shionogi Inc: Advisor/Consultant|Shionogi Inc: Grant/Research Support|Shionogi Inc: Honoraria

Pharmacokinetics and dialytic clearance of baricitinib during in vivo continuous venovenous haemodialysis in a patient with COVID-19

ObjectivesTo date, there are no published pharmacokinetic (PK) data for baricitinib in critically ill patients requiring continuous renal replacement therapy. This paper describes in detail the plasma PK and dialytic clearance of baricitinib in a patient infected with coronavirus disease 2019 (COVID-19) requiring continuous renal replacement therapy in order to suggest dosing strategies in this population. MethodsBaricitinib 2 mg daily was used for the treatment of COVID-19 in a critically ill patient on continuous venovenous haemodialysis (CVVHD). Prefiltration plasma drug concentrations of baricitinib were measured at hours 1, 2, 12, and 24 after drug administration. Postfiltration and ultrafiltrate concentrations were collected at hour 24. ResultsPlasma PK parameters of baricitinib in this patient were as follows: maximum plasma concentration (Cmax), 20.98 ng/mL; minimum plasma concentration (Cmin), 9.84 ng/mL; half-life (t1/2), 23.85 h; apparent volume of distribution at the steady state (Vss), 99.42 L; total clearance at the steady state (CLss), 2.89 L/h; and area under the concentration-time curve (AUC0–∞), 692.14 ng · h/mL. The saturation coefficient for baricitinib at 24 h after administration was 0.607. The transmembrane clearance of baricitinib by CVVHD running at a flow rate of 2 L/h was 1.21 L/h, representing 41.9% of the total clearance of baricitinib. ConclusionsIn a critically ill COVID-19 patient on CVVHD, a 2-mg dose of baricitinib achieves a Cmax comparable with healthy subjects, but total clearance was reduced to about 20%. Larger studies exploring multiple patients and dialysis modes are needed to determine the optimal dosing strategy for baricitinib in this patient population.

Adsorption and Clearance of the Novel Fluorescent Tracer Agent MB-102 During Continuous Renal Replacement Therapy: In Vitro Results.

MB-102 is a novel fluorescent tracer agent that is exclusively removed from the body by glomerular filtration. This agent can be detected transdermally to provide a real-time measurement of glomerular filtration rate at the point-of-care and is currently in clinical studies for such. MB-102 clearance during continuous renal replacement therapy (CRRT) is unknown. Its plasma protein binding (~0%), molecular weight (~372 Da) and volume of distribution (15-20 L) suggest that it may be removed by renal replacement therapies. To determine the disposition of MB-102 during CRRT, an in vitro study assessing the transmembrane clearance (CL TM ) and adsorptive clearance of MB-102 was conducted. A validated in vitro bovine blood continuous hemofiltration (HF) and continuous hemodialysis (HD) models were performed using two types of hemodiafilters to evaluate CL TM of MB-102. For HF, three different ultrafiltration rates were evaluated. For HD, four different dialysate flow rates were evaluated. Urea was used as a control. No MB-102 adsorption to the CRRT apparatus or either of hemodiafilters was observed. MB-102 is readily removed by HF and HD. Dialysate and ultrafiltrate flow rates directly influence MB-102 CLTM. Hence MB-102 CLTM should be measurable for critically ill patients receiving CRRT.

Imipenem/Relebactam Ex Vivo Clearance during Continuous Renal Replacement Therapy.

(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.

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

BackgroundTo 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.MethodsApixaban 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.ResultsMean 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.ConclusionFor 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.

Pharmacokinetics and Dialytic Clearance of Isavuconazole During In Vitro and In Vivo Continuous Renal Replacement Therapy.

The pharmacokinetics (PK) and dialytic clearance of isavuconazole in vitro and in 7 solid organ transplant patients undergoing continuous renal replacement therapy (CRRT) were evaluated. In vivo, mean (± SD) plasma PK parameters of isavuconazole were: C max 4.00±1.45 mg/L, C min 1.76±0.76 mg/L, t ½ 48.36±29.78 h, Vss 288.78±182.11 L, CLss 4.85±3.79 L/h, and AUC 54.01±20.98 mg ⋅ h/L. Transmembrane clearance represented just 0.7% of the total isavuconazole clearance. These data suggest that isavuconazole is not readily removed by CRRT and no dose adjustments are necessary.

Ex vivo Rezafungin Adsorption and Clearance During Continuous Renal Replacement Therapy

Background/Aims: To determine adsorption and transmembrane clearances (CL_TM) of rezafungin, a novel long-acting echinocandin, in continuous venovenous hemofiltration (CVVH). Methods: A validated ex vivo bovine blood CVVH model using polysulfone and AN69 hemodiafilters was used to evaluate urea and rezafungin CL_TM at 3 different ultrafiltrate flow rates. Rezafungin adsorption to the CRRT apparatus was determined for each hemodiafilter. Results: The sieving coefficient (S_C) from CVVH with 3 different ultrafiltrate flow rates was 0 for both HF1400 and Multiflow-150 hemodiafilters, while urea S_C was approximately 1 at all flow rates. Hemodiafilter type and ultrafiltrate flow rate did not influence CL_TM. Rezafungin adsorption to the CVVH apparatus was not observed for either hemodiafilter. Conclusion: Rezafungin is not removed by CVVH by membrane adsorption or via CL_TM. Ultrafiltrate flow rates and hemodiafilter types are unlikely to influence rezafungin CL_TM. No dosage adjustment of rezafungin is likely required for critically ill patients receiving CVVH.

Influence of hemodialysis on regadenoson clearance in an in vitro hemodialysis model

BackgroundRegadenoson is a novel pharmacological stress agent whose disposition during hemodialysis is not known. The purpose of this study was to determine the clearance of regadenoson under varying dialytic conditions using an in vitro hemodialysis model. Methods and ResultsWhole human blood was used to analyze the effect of hemodialysis on the clearance of regadenoson. Regadenoson transmembrane clearance (CLD) was assessed for both a standard permeability and a high permeability polysulfone hemodialyzer with blood/dialysate flow rates of 300/600 and 400/800 mL/min. A two-tailed, paired Student’s t test was used to compare regadenoson CLD between hemodialyzer types and flow rates. The mean ± SD regadenoson CLD values ranged between 62.5 ± 11.8 and 89.1 ± 24.0 mL/min for all dialytic conditions. There was no significant difference in regadenoson CLD between hemodialyzer types and flow rates (p > .05). ConclusionsHemodialysis enhances the clearance of regadenoson independent of hemodialyzer permeability and blood/dialysate flow rate. This clearance is modest relative to total body clearance and is unlikely to produce a clinically significant outcome.

Acetaminophen clearance during ex vivo continuous renal replacement therapies.

Intravenous acetaminophen is an adjuvant to opioid use in critically ill and surgical patients requiring continuous renal replacement therapy (CRRT). The objective of this study was to determine the ex vivo transmembrane clearance of intravenous acetaminophen during continuous hemofiltration and hemodialysis. Transmembrane clearance was assessed using a validated ex vivo bovine blood model for CRRT using an F8 or HF1400 hemodiafilter. Ultrafiltrate and dialysate flow rates were 1, 2, and 3L/h. Urea and acetaminophen clearances were calculated and compared. Acetaminophen was readily cleared by continuous hemofiltration with both hemodiafilters. Acetaminophen clearance rates were 92-98% of ultrafiltrate production rates. Similarly, dialytic acetaminophen clearances approximated dialysate flow rates for both hemodiafilters. Acetaminophen is readily cleared by CRRT. Patients receiving CRRT and acetaminophen may require increased doses for adequate pain control.

Clearance of ceftazidime-avibactam in an in vitro continuous venovenous hemodialysis model

Abstract Background Optimal dosing of ceftazidime-avibactam (C-A) in critically ill patients on continuous renal replacement therapy (CRRT) is unknown. The objective of this study was to evaluate the adsorption and transmembrane clearance (CLTM) of C-A in an in vitro continuous venovenous hemodialysis (CVVHD) model to guide dosing in the absence of clinical data. Methods CVVHD was simulated with bovine blood (200 mL/minute) on a Prismaflex dialysis unit with polysulfone (HF1400) and AN69 (M150) hemofilters at dialysate flow rates (Qd) of 2 and 4 L/hours. Pre-hemofilter plasma samples were collected at 0, 5, 10, 20, 30, 45, and 60 mins after C-A addition; postfilter and dialysate samples were collected at 10 and 45 mins for saturation coefficient (SA) calculation. Adsorption was determined by total drug recovery in dialysate and plasma after 120 mins of dialysis at 2 L/hours. CLTM was calculated as the product of SA and Qd (CLTM-SA) and by elimination rate constant (CLTM-ke) derived from the slope of log-linear concentration-time plots. Results Mean (± SD) SA and CLTM values for C-A from duplicate experiments are in Table 1. CLTM was not affected by filter type, and increased linearly with Qd when calculated by two different methods. Avibactam CLTM was higher than ceftazidime CLTM with each filter and rate. Adsorption affected 17.3% and 20.2% of C-A for HF1400 and AN69 filters, respectively. Conclusion Significant Qd- dependent clearance of C-A was observed in in vitro CVVHD. CLTM of ceftazidime was slightly higher than previous reports and may reflect the larger surface area of contemporary filters in this study. The more rapid clearance of avibactam, particularly at higher flow rates, suggests that dose adjustments should focus on ensuring adequate avibactam exposure during CVVHD. Disclosures L. H. Danziger, Allergan: Investigator, Research grant.

Ex vivo Ceftolozane/Tazobactam Clearance during Continuous Renal Replacement Therapy

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.

Tedizolid Adsorption and Transmembrane Clearance during in vitro Continuous Renal Replacement Therapy

Background/Aims: To study transmembrane clearance (CL_TM) and adsorption of tedizolid, a novel oxazolidinone antibiotic, in continuous hemofiltration (CVVH) and continuous hemodialysis (CVVHD). Methods: In vitro CVVH/CVVHD models with polysulfone and AN69 hemodiafilters were used. Tedizolid CL_TM during CVVH/CVVHD was assessed at various ultrafiltrate (Quf) and dialysate rates (Qd). Tedizolid adsorption was tested in a recirculating CVVH model over 4 h. Results: In CVVH, CL_TM did not differ between filter types. In CVVHD, tedizolid CL_TM was significantly higher with the polysulfone hemodiafilter at Qd 6 l/h (p < 0.02). Tedizolid exhibited irreversible adsorption to the CRRT apparatus and bound significantly higher to the polysulfone hemodiafilter. Conclusion: Tedizolid's CL_TM is dependent on Qd, Quf, and hemodiafilter type. At conventional CRRT rates, tedizolid CL_TM appears modest relative to total body clearance and is unlikely to require dose adjustments. CRRT adsorption in the clinical setting is likely less than what we observed in this in vitro, continuously recirculating blood model.

Iohexol Transmembrane Clearance during Modeled Continuous Renal Replacement Therapy

Background/Aims: Urea clearance during continuous renal replacement therapy (CRRT) is not representative of middle molecular weight solute clearances. We aimed to characterize iohexol, molecular weight 821 Da, clearance during continuous hemofiltration (CH) and continuous hemodialysis (CHD). Methods: Using an in vitro model, iohexol sieving coefficients (SC) and saturation coefficients (SA) were determined with the M100 membrane at ultrafiltration/dialysate rates of 1, 2, 3, 4, and 6 l/h. Iohexol transmembrane clearance was calculated using the measured SC and SA. Results: During CH, the value of iohexol SC remained approximately 1 at all ultrafiltration rates studied. In contrast, during CHD iohexol the mean SA was 1.02 ± 0.05 at a dialysate rate 1 l/h and decreased significantly with higher dialysate rates to a mean SA of 0.57 ± 0.12 at a dialysate rate of 6 l/h. Conclusions: At higher effluent flow rates, CH was more effective in removing iohexol than CHD. CH transmembrane clearance of iohexol appears to approximate the ultrafiltration rate.

Trimethoprim and Sulfamethoxazole Transmembrane Clearance during Modeled Continuous Renal Replacement Therapy

Background/Aims: There is limited data regarding trimethoprim (TMP)/sulfamethoxazole (SMX) continuous renal replacement therapy (CRRT) dosing. We aimed to estimate TMP/SMX transmembrane clearance (CLtm) during continuous hemofiltration (CH) and continuous hemodialysis (CD) to guide dosing. Methods: Using an in vitro model, TMP/SMX sieving coefficients (SC) and saturation coefficients (SA) were determined with high-flux polyarylethersulfone and polyacrylonitrile-sodium methallyl sulfonate copolymer hemodiafilters at ultrafiltration/dialysate rates of 1, 2, 3, and 6 l/h. TMP/SMX CLtm was calculated using measured SC and SA. TMP/SMX CRRT doses were modeled using CLtm and published TMP/SMX pharmacokinetic parameters. Results: TMP SC/SA during CH/CD were significantly higher than SMX SC/SA. During modeling, TMP 10 mg/kg/day and its corresponding SMX dose, 50 mg/kg/day, resulted in steady state TMP/SMX peak concentrations associated with efficacy against Pneumocystis jirovecii. Conclusions: CRRT resulted in greater TMP CLtm than SMX. TMP 10 mg/kg/day divided q12h may be an appropriate initial dose to consider in patients undergoing CRRT.

Management of digoxin therapy using pharmacokinetics in a patient undergoing continuous venovenous hemofiltration

The management of digoxin therapy using pharmacokinetics in a patient undergoing continuous venovenous hemofiltration (CVVH) is reported. A 46-year-old African-American woman with New York Heart Association class IV, American College of Cardiology- American Heart Association stage D heart failure arrived from an outside facility with complaints of dyspnea after minimal exertion, orthopnea, and lower-extremity edema. A transthoracic echocardiogram revealed an estimated left ventricular ejection fraction of 15%. The patient subsequently required left ventricular assist device placement on hospital day 5 as a potential bridge to transplantation. A total digoxin loading dose of 500 μg i.v. (8.2 μg/kg) was given in two divided doses six hours apart. The next morning, the serum digoxin concentration was 1.9 ng/mL, and the patient was started on a maintenance digoxin dosage of 125 μg i.v. daily. On postoperative day (POD) 20, the patient developed acute kidney injury, and CVVH was initiated. The sieving coefficient (Sc), transmembrane clearance (CLtm), digoxin concentration in ultrafiltration fluid (Cuf), and need for supplemental digoxin were determined to account for CVVH- associated digoxin loss. After 14 days of CVVH, the patient's clinical condition improved, and CVVH was transitioned to intermittent hemodialysis. On POD 66, the patient was discharged to an extended-care facility without adverse reactions related to digoxin therapy. Analysis of serum digoxin concentration and digoxin Cuf values suggested that digoxin was cleared by CVVH, allowed calculation of Sc and CLtm values, and facilitated determination of digoxin requirements in a critically ill patient requiring CVVH.

Vibration Enhances Clearance of Solutes With Varying Molecular Weights During In Vitro Hemodialysis

This proof of concept pilot study was performed to determine whether vibration can increase solute clearance when applied to an in vitro dialysis model. Urea, creatinine, gentamicin, and vancomycin transmembrane clearances were calculated at a blood flow rate of 200 ml/min, dialysate flow rates of 2 and 8 L/hr, and no concurrent ultrafiltration at various vibration intensities. Dialyzer integrity was determined by measuring transmembrane pressure, filter drop pressure, and albumin clearance, and by visually inspecting the dialysate. Comparing the highest vibration modality with no vibration, the median percentage increase in urea, creatinine, gentamicin, and vancomycin clearance was 18% (all p < 0.005). The transmembrane clearance of albumin was negligible for all experiments. When measuring transmembrane pressure and filter drop pressure, no significant differences were found between nonvibration and vibration dialysis. The addition of vibration during dialysis increased transmembrane clearance for solutes with molecular weights of 60-1450 Daltons.

Longitudinal Hemodiafilter Performance in Modeled Continuous Renal Replacement Therapy

Background/Aims: With advanced anticoagulation, many institutions operate continuous renal replacement therapy (CRRT) circuits longer than manufacturers’ recommendations. This extended use may change hemodiafilter performance and clearance properties. However, hemodiafilter performance over time has not been assessed. We investigated solute clearance over time in modeled CRRT. Methods: In vitro continuous hemofiltration (CH) and continuous hemodialysis (CD) were operated for 48 h using AN69 polyacrylonitrile, cellulose triacetate, F70 polysulfone, and Optiflux F160NR polysulfone hemodiafilters with citrated bovine blood. Urea, creatinine, gentamicin, vancomycin, and albumin clearances were assessed in CH (ultrafiltration rates = 1 and 3 l/h). Clearances of urea, creatinine, gentamicin, and albumin, were assessed in CD with dialysate flow rate of 2 l/h. Results: Solute CH clearances were significantly higher at 3 l/h. Only creatinine and gentamicin clearances were affected by time. Creatinine CD clearance significantly declined at 48 h for all hemodiafilters, especially polysulfone hemodiafilters. Conclusions: CRRT duration affects solute transmembrane clearance. Clinicians should consider hemodiafilter age when assessing hemodialysis dose or drug clearance.

Daptomycin pharmacokinetics in critically ill patients receiving continuous venovenous hemodialysis

To investigate daptomycin pharmacokinetics in critically ill patients receiving continuous venovenous hemodialysis to develop dosing recommendations. Prospective, open-label pharmacokinetic study. : Intensive care units located within a teaching medical center. Eight adults with known/suspected Gram-positive infections receiving continuous venovenous hemodialysis and daptomycin. Daptomycin at 8 mg/kg intravenously over 30 mins. Serial blood and effluent samples were collected over the next 48 hrs. Daptomycin protein binding was determined by equilibrium dialysis. Daptomycin continuous venovenous hemodialysis transmembrane clearance was determined by dividing daptomycin effluent by serum concentrations and multiplying by mean effluent production rate for each subject. Equations describing a two-compartment, open-pharmacokinetic model were fitted to each subject's daptomycin concentration-time data and pharmacokinetic parameters were determined by standard methods. Serum concentration-time profiles were simulated for two daptomycin regimens (8 mg/kg every 48 hrs and 4 mg/kg every 24 hrs). A total of 7.7 ± 0.6 mg/kg (mean ± sd) of daptomycin was administered, resulting in an observed peak concentration of 81.2 ± 19.0 μg/mL. Daptomycin steady-state volume of distribution (0.23 ± 0.14 L/kg) and free fraction (17.5% ± 5.0%) were increased in critically ill subjects receiving continuous venovenous hemodialysis compared with previous values reported in healthy volunteers. Daptomycin transmembrane clearance (6.3 ± 2.9 mL/min) accounted for more than half of total clearance (11.3 ± 4.7 mL/min). Simulations demonstrated 8 mg/kg daptomycin every 48 hrs would result in higher peak (88.8 ± 20.0 μg/mL vs. 53.0 ± 12.3 μg/mL) and lower trough concentrations (7.2 ± 5.2 μg/mL vs. 12.3 ± 5.1 μg/mL) than 4 mg/kg every 24 hrs. Daptomycin at 8 mg/kg every 48 hrs in critically ill patients receiving continuous venovenous hemodialysis resulted in good drug exposure, achieved high peak concentrations to maximize daptomycin's concentration-dependent activity, and resulted in trough concentration that would minimize the risk of myopathy. CLINICALTRIALS.GOV IDENTIFIER: NCT00663403.