scholarly journals Pharmacokinetics and Dialytic Clearance of Isavuconazole during In Vitro and In Vivo Continuous Renal Replacement Therapy

2019 ◽  
Vol 63 (12) ◽  
Author(s):  
M. Biagi ◽  
D. Butler ◽  
X. Tan ◽  
S. Qasmieh ◽  
K. Tejani ◽  
...  
Keyword(s):  
Steady State ◽  
Renal Replacement Therapy ◽  
Continuous Renal Replacement Therapy ◽  
Replacement Therapy ◽  
Organ Transplant ◽  
Solid Organ ◽  
Time Curve ◽  
Minimum Concentration

ABSTRACT 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, the mean (± standard deviation [SD]) plasma PK parameters of isavuconazole were as follows: maximum concentration of drug in serum (Cmax), 4.00 ± 1.45 mg/liter; minimum concentration of drug in serum (Cmin), 1.76 ± 0.76 mg/liter; half-life (t1/2), 48.36 ± 29.78 h; volume of distribution at steady state (Vss), 288.78 ± 182.11 liters, clearance at steady state (CLss), 4.85 ± 3.79 liters/h; and area under the concentration-time curve (AUC), 54.01 ± 20.98 mg · h/liter. 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.

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 Hepatitis E Virus Immunopathogenesis

Pathogens ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 1180
Author(s):  
Kush Kumar Yadav ◽  
Scott P. Kenney
Keyword(s):  
Hepatitis E Virus ◽  
Organ Transplant ◽  
Hepatitis E ◽  
Oral Route ◽  
Solid Organ ◽  
Immunocompromised Patients ◽  
In Vivo Models ◽  
Transplant Patients

Hepatitis E virus is an important emerging pathogen producing a lethal impact on the pregnant population and immunocompromised patients. Starting in 1983, it has been described as the cause for acute hepatitis transmitted via the fecal–oral route. However, zoonotic and blood transfusion transmission of HEV have been reported in the past few decades, leading to the detailed research of HEV pathogenesis. The reason behind HEV being highly virulent to the pregnant population particularly during the third trimester, leading to maternal and fetal death, remains unknown. Various host factors (immunological, nutritional, hormonal) and viral factors have been studied to define the key determinants assisting HEV to be virulent in pregnant and immunocompromised patients. Similarly, chronic hepatitis is seen particularly in solid organ transplant patients, resulting in fatal conditions. This review describes recent advances in the immunopathophysiology of HEV infections in general, pregnant, and immunocompromised populations, and further elucidates the in vitro and in vivo models utilized to understand HEV pathogenesis.

Elimination of fluconazole during continuous renal replacement therapy. An in vitro assessment

2020 ◽  
pp. 039139882097614
Author(s):  
Frédéric J Baud ◽  
Vincent Jullien ◽  
Tarik Abarou ◽  
Benoît Pilmis ◽  
Jean-Herlé Raphalen ◽  
...  
Keyword(s):  
Renal Replacement Therapy ◽  
Continuous Renal Replacement Therapy ◽  
Replacement Therapy ◽  
Central Compartment ◽  
Sieving Coefficient ◽  
Continuous Filtration ◽  
In Vitro Assessment ◽  
The Mean ◽  
Made In

Introduction: Continuous renal replacement therapy (CRRT) efficiently eliminates fluconazole. However, the routes of elimination were not clarified. Adsorption of fluconazole by filters is a pending question. We studied the elimination of fluconazole in a model mimicking a session of CRRT in humans using the NeckEpur® model. Two filters were studied. Methods: The AV1000®-polysulfone filter with the Multifiltrate Pro. Fresenius and the ST150®-polyacrylonitrile filter with the Prismaflex. Baxter-Gambro were studied. Continuous filtration used a flowrate of 2.5 L/h in post-dilution only. Session were made in duplicate. Routes of elimination were assessed using the NeckEpur® model. Results: The mean measured initial fluconazole concentration (mean ± SD) for the four sessions in the central compartment (CC) was 14.9 ± 0.2 mg/L. The amount eliminated from the CC at the end of 6 h-session at a 2.5 L/h filtration flowrate for the AV1000®-polysulfone and the ST150®-polyacrylonitrile filters were 90%–93% and 96%–94%, respectively; the clearances from the central compartment (CC) were 2.5–2.6 and 2.4–2.3 L/h, respectively. The means of the instantaneous sieving coefficient were 0.94%–0.91% and 0.99%–0.91%, respectively. The percentages of the amount eliminated from the CC by filtration/adsorption were 100/0%–95/5% and 100/0%–100/0%, respectively. Conclusion: Neither the ST150®-polyacrylonitrile nor the AV1000®-polysulfone filters result in any significant adsorption of fluconazole.

scholarly journals Pharmacokinetics of BILR 355 after Multiple Oral Doses Coadministered with a Low Dose of Ritonavir

2008 ◽  
Vol 53 (1) ◽  
pp. 95-103 ◽  
Author(s):  
Fenglei Huang ◽  
Kristin Drda ◽  
Thomas R. MacGregor ◽  
Joseph Scherer ◽  
Lois Rowland ◽  
...  
Keyword(s):  
Steady State ◽  
Maximum Concentration ◽  
Dose Range ◽  
Dose Interval ◽  
Phase Ii Trials ◽  
Time Curve ◽  
Minimum Concentration ◽  
Oral Dosing ◽  
Repeated Dosing

ABSTRACT The pharmacokinetics and safety of BILR 355 following oral repeated dosing coadministered with low doses of ritonavir (RTV) were investigated in 12 cohorts of healthy male volunteers with a ratio of 6 to 2 for BILR 355 versus the placebo. BILR 355 was given once a day (QD) coadministered with 100 mg RTV (BILR 355/r) at 5 to 50 mg in a polyethylene glycol solution or at 50 to 250 mg as tablets. BILR 355 tablets were also dosed at 150 mg twice a day (BID) coadministered with 100 mg RTV QD or BID. Following oral dosing, BILR 355 was rapidly absorbed, with the mean time to maximum concentration of drug in serum reached within 1.3 to 5 h and a mean half-life of 16 to 20 h. BILR 355 exhibited an approximately linear pharmacokinetics for doses of 5 to 50 mg when given as a solution; in contrast, when given as tablets, BILR 355 displayed a dose-proportional pharmacokinetics, with a dose range of 50 to 100 mg; from 100 to 150 mg, a slightly downward nonlinear pharmacokinetics occurred. The exposure to BILR 355 was maximized at 150 mg and higher due to a saturated dissolution/absorption process. After oral dosing of BILR 355/r, 150/100 mg BID, the values for the maximum concentration of drug in plasma at steady state, the area under the concentration-time curve from 0 to the dose interval at steady state, and the minimum concentration of drug in serum at steady state were 1,500 ng/ml, 12,500 h·ng/ml, and 570 ng/ml, respectively, providing sufficient suppressive concentration toward human immunodeficiency virus type 1. Based on pharmacokinetic modeling along with the in vitro virologic data, several BILR 355 doses were selected for phase II trials using Monte Carlo simulations. Throughout the study, BILR 355 was safe and well tolerated.

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.

scholarly journals Ceftolozane/Tazobactam Clearance During In Vitro Continuous Renal Replacement Therapy (CRRT)

2016 ◽  
Vol 3 (suppl_1) ◽  
Author(s):  
Weerachai Chaijamorn ◽  
Alexander Shaw ◽  
Susan J. Lewis ◽  
Bruce Mueller
Keyword(s):  
Renal Replacement Therapy ◽  
Continuous Renal Replacement Therapy ◽  
Replacement Therapy
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