In silico comparison of protein-bound uremic toxin removal by hemodialysis, hemodiafiltration, membrane adsorption, and binding competition

Maheshwari, Vaibhav; Thijssen, Stephan; Tao, Xia; Fuertinger, Doris; Kappel, Franz; Kotanko, Peter

doi:10.1038/s41598-018-37195-1

Cited by 28 publications

(47 citation statements)

References 41 publications

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“…Although we fully acknowledge the overall low solute clearances, we strongly believe that this finding does not invalidate the broader insight, namely that the infusion of ibuprofen as a displacer increases the dialytic removal of p-cresyl sulfate and indoxyl sulfate (and to a lesser extent, of tryptophan as well). This notion is supported by several strands of evidence, such as (1) this study with its internally-consisted proteinbound uremic toxin dialysate and blood levels shows a distinct increase in their dialysate levels and dialysatesided clearances, respectively (our clinical research study rejects the null hypothesis of no ibuprofen effect with reasonably robust P values of ,0.001); (2) in vitro experiments (20) that show the clearance-enhancing effects of several displacers on protein-bound uremic toxin dissolved in artificial albumin solutions; (3) ex vivo experiments (19) that confirm the augmented dialytic removal of protein-bound uremic toxin from human blood undergoing hemodialysis combined with displacer infusions; and (4) mathematical modeling of protein-bound uremic toxin removal with and without displacer infusions (29,30). In summary, this is the first-in-man study of displaceraugmented hemodialysis.…”

Section: Discussionmentioning

confidence: 99%

Removal of Protein-Bound Uremic Toxins during Hemodialysis Using a Binding Competitor

Madero

Cano

Campos

et al. 2019

CJASN

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Background and objectivesCurrent hemodialysis techniques fail to efficiently remove the protein-bound uremic toxins p-cresyl sulfate and indoxyl sulfate due to their high degree of albumin binding. Ibuprofen, which shares the same primary albumin binding site with p-cresyl sulfate and indoxyl sulfate, can be infused during hemodialysis to displace these toxins, thereby augmenting their removal.Design, setting, participants, & measurementsWe infused 800 mg ibuprofen into the arterial bloodline between minutes 21 and 40 of a conventional 4-hour high-flux hemodialysis treatment. We measured arterial, venous, and dialysate outlet concentrations of indoxyl sulfate, p-cresyl sulfate, tryptophan, ibuprofen, urea, and creatinine before, during, and after the ibuprofen infusion. We report clearances of p-cresyl sulfate and indoxyl sulfate before and during ibuprofen infusion and dialysate concentrations of protein-bound uremic toxins normalized to each patient’s average preinfusion concentrations.ResultsWe studied 18 patients on maintenance hemodialysis: age 36±11 years old, ten women, and mean vintage of 37±37 months. Compared with during the preinfusion period, the median (interquartile range) clearances of indoxyl sulfate and p-cresyl sulfate increased during ibuprofen infusion from 6.0 (6.5) to 20.2 (27.1) ml/min and from 4.4 (6.7) to 14.9 (27.1) ml/min (each P<0.001), respectively. Relative median (interquartile range) protein-bound uremic toxin dialysate outlet levels increased from preinfusion 1.0 (reference) to 2.4 (1.2) for indoxyl sulfate and to 2.4 (1.0) for p-cresyl sulfate (each P<0.001). Although median serum post- and predialyzer levels in the preinfusion period were similar, infusion led to a marked drop in serum postdialyzer levels for both indoxyl sulfate and p-cresyl sulfate (−1.0 and −0.3 mg/dl, respectively; each P<0.001). The removal of the nonprotein-bound solutes creatinine and urea was not increased by the ibuprofen infusion.ConclusionsInfusion of ibuprofen into the arterial bloodline during hemodialysis significantly increases the dialytic removal of indoxyl sulfate and p-cresyl sulfate and thereby, leads to greater reduction in their serum levels.

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Section: Discussionmentioning

confidence: 99%

Removal of Protein-Bound Uremic Toxins during Hemodialysis Using a Binding Competitor

Madero

Cano

Campos

et al. 2019

CJASN

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“…This model system was implemented in MATLAB 2019b. The model has previously been described in detail for PBUTs 6 . A fundamental difference between PBUTs and protein-bound drugs is that former are endogenous metabolic products continuously generated while latter are exogenous substances continuously metabolized.…”

Section: Methodsmentioning

confidence: 99%

A model-based analysis of phenytoin and carbamazepine toxicity treatment using binding-competition during hemodialysis

Maheshwari

Hoffman

Thijssen

et al. 2020

Sci Rep

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Hemodialysis (HD) has limited efficacy towards treatment of drug toxicity due to strong drugprotein binding. in this work, we propose to infuse a competitor drug into the extracorporeal circuit that increases the free fraction of a toxic drug and thereby increases its dialytic removal. We used a mechanistic model to assess the removal of phenytoin and carbamazepine during HD with or without binding-competition. We simulated dialytic removal of (1) phenytoin, initial concentration 70 mg/L, using 2000 mg aspirin, (2) carbamazepine, initial concentration 35 mg/L, using 800 mg ibuprofen, in a 70 kg patient. The competitor drug was infused at constant rate. For phenytoin (~ 13% free at t = 0), HD brings the patient to therapeutic concentration in 460 min while aspirin infusion reduces that time to 330 min. For carbamazepine (~ 27% free at t = 0), the ibuprofen infusion reduces the HD time to reach therapeutic concentration from 265 to 220 min. Competitor drugs with longer half-life further reduce the HD time. Binding-competition during HD is a potential treatment for drug toxicities for which current recommendations exclude HD due to strong drug-protein binding. We show clinically meaningful reductions in the treatment time necessary to achieve non-toxic concentrations in patients poisoned with these two prescription drugs.

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“…Depending on the drug, modeling the kinetics of protein plasma binding can, therefore, be crucial [21]. As, furthermore, nutritional components as well as other drugs administered at the same time can be bound by the same transport proteins, other drugs as well as nutrition can affect free drug concentration and thus efficacy [22].…”

Section: Binding Kinetics To Plasma Proteinsmentioning

confidence: 99%

“…For drugs that slowly dissociate from their targets, the free drug and drug-target will not be in rapid equilibrium. In this case, the traditional PK/PD model may underpredict the drug effect [22], whereas models with time-dependent drug-target binding will be more mechanistic and suitable for analyzing the relationship between drug concentration and efficacy [21]. However, it is challenging to estimate the relationship (i.e., define the function effect E = f(AT), see "Pharmacokinetics and pharmacodynamics") between target occupancy and drug effects.…”

Section: Linking Target Occupancy To Drug Efficacymentioning

confidence: 99%

Multi-scale modeling of drug binding kinetics to predict drug efficacy

Clarelli

Liang

Martinecz

et al. 2019

Cell. Mol. Life Sci.

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Optimizing drug therapies for any disease requires a solid understanding of pharmacokinetics (the drug concentration at a given time point in different body compartments) and pharmacodynamics (the effect a drug has at a given concentration). Mathematical models are frequently used to infer drug concentrations over time based on infrequent sampling and/or in inaccessible body compartments. Models are also used to translate drug action from in vitro to in vivo conditions or from animal models to human patients. Recently, mathematical models that incorporate drug-target binding and subsequent downstream responses have been shown to advance our understanding and increase predictive power of drug efficacy predictions. We here discuss current approaches of modeling drug binding kinetics that aim at improving model-based drug development in the future. This in turn might aid in reducing the large number of failed clinical trials.

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In silico comparison of protein-bound uremic toxin removal by hemodialysis, hemodiafiltration, membrane adsorption, and binding competition

Cited by 28 publications

References 41 publications

Removal of Protein-Bound Uremic Toxins during Hemodialysis Using a Binding Competitor

Removal of Protein-Bound Uremic Toxins during Hemodialysis Using a Binding Competitor

A model-based analysis of phenytoin and carbamazepine toxicity treatment using binding-competition during hemodialysis

Multi-scale modeling of drug binding kinetics to predict drug efficacy

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