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Jason A Roberts - One of the best experts on this subject based on the ideXlab platform.
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population pharmacokinetics of continuous infusion of piperacillin in critically ill patients
International Journal of Antimicrobial Agents, 2017Co-Authors: Sofie Dhaese, Jason A Roberts, Mieke Carlier, Alain Verstraete, Veronique Stove, Jan J De WaeleAbstract:Abstract Dosing recommendations for continuous infusion of piperacillin, a broad-spectrum beta-lactam antibiotic, are mainly guided by outputs from population pharmacokinetic models constructed with intermittent infusion data. However, the probability of target attainment in patients receiving piperacillin by continuous infusion may be overestimated when Drug Clearance estimates from population pharmacokinetic models based on intermittent infusion data are used, especially when higher doses (e.g. 16 g/24 h or more) are simulated. Therefore, the purpose of this study was to describe the population pharmacokinetics of piperacillin when infused continuously in critically ill patients. For this analysis, 270 plasma samples from 110 critically ill patients receiving piperacillin were available for population pharmacokinetic model building. A one-compartment model with linear Clearance best described the concentration–time data. The mean ± standard deviation parameter estimates were 8.38 ± 9.91 L/h for Drug Clearance and 25.54 ± 3.65 L for volume of distribution. Creatinine Clearance improved the model fit and was supported for inclusion as a covariate. In critically ill patients with renal Clearance higher than 90 mL/min/1.73 m2, a high-dose continuous infusion of 24 g/24 h is insufficient to achieve adequate exposure (pharmacokinetic/pharmacodynamic target of 100% fT>4 x MIC) against susceptible Pseudomonas aerginosa isolates (MIC ≤16 mg/L). These findings suggest that merely increasing the dose of piperacillin, even with continuous infusion, may not always result in adequate piperacillin exposure. This should be confirmed by evaluating piperacillin target attainment rates in critically ill patients exhibiting high renal Clearance.
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determining the mechanisms underlying augmented renal Drug Clearance in the critically ill use of exogenous marker compounds
Critical Care, 2014Co-Authors: Andrew A Udy, Jason A Roberts, Paul Jarrett, Janine Stuart, Melissa Lassigsmith, Therese Starr, Rachel Dunlop, Steven C Wallis, Jeffrey LipmanAbstract:Introduction The aim of this study was to explore changes in glomerular filtration (GFR) and renal tubular function in critically ill patients at risk of augmented renal Clearance (ARC), using exogenous marker compounds.
J F Bugge - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetics and Drug dosing adjustments during continuous venovenous hemofiltration or hemodiafiltration in critically ill patients
Acta Anaesthesiologica Scandinavica, 2001Co-Authors: J F BuggeAbstract:Continuous renal replacement therapy (CRRT) in critically ill patients with renal failure may significantly increase Drug Clearance, requiring Drug dosing adjustments. Drugs significantly eliminated by the kidney often undergo substantial removal during CRRT, and a supplemental dose corresponding to the amount of Drug removed by CRRT should be administered. Clearance by CRRT can either be measured or estimated. The high-flux membranes used in CRRT make no filtration barrier to most Drugs, and the filtrate concentration can be estimated by the unbound fraction of the Drug in plasma. When adding dialysis to filtration, this approach overestimates Drug Clearance, and a correcting factor should be used. A method for estimating Drug Clearance as a function of creatinine Clearance is also sug
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pharmacokinetics and Drug dosing adjustments during continuous venovenous hemofiltration or hemodiafiltration in critically ill patients
Acta Anaesthesiologica Scandinavica, 2001Co-Authors: J F BuggeAbstract:Continuous renal replacement therapy (CRRT) in critically ill patients with renal failure may significantly increase Drug Clearance, requiring Drug dosing adjustments. Drugs significantly eliminated by the kidney often undergo substantial removal during CRRT, and a supplemental dose corresponding to the amount of Drug removed by CRRT should be administered. Clearance by CRRT can either be measured or estimated. The high-flux membranes used in CRRT make no filtration barrier to most Drugs, and the filtrate concentration can be estimated by the unbound fraction of the Drug in plasma. When adding dialysis to filtration, this approach overestimates Drug Clearance, and a correcting factor should be used. A method for estimating Drug Clearance as a function of creatinine Clearance is also suggested, but it has the same limitations in overestimating Drug Clearance when dialysis is combined with filtration. For non-toxic Drugs, doses can safely be increased 30% above actual estimates to ensure adequate dosing. For Drugs with a narrow therapeutical margin, monitoring plasma concentrations are mandatory. When appropriate, the use of a readily available reference for Drug dosing is recommended.
Michael Mayersohn - One of the best experts on this subject based on the ideXlab platform.
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interspecies prediction of human Drug Clearance based on scaling data from one or two animal species
Drug Metabolism and Disposition, 2007Co-Authors: Huadong Tang, Michael Mayersohn, Azher Hussain, Mauricio Leal, Eric FluhlerAbstract:A data-driven approach was adopted to derive new one- and two-species-based methods for predicting human Drug Clearance (CL) using CL data from rat, dog, or monkey (n = 102). The new one-species methods were developed as CLhuman/kg = 0.152 · CLrat/kg, CLhuman/kg = 0.410 · CLdog/kg, and CLhuman/kg = 0.407 · CLmonkey/kg, referred to as the rat, dog, and monkey methods, respectively. The coefficient of the monkey method (0.407) was similar to that of the monkey liver blood flow (LBF) method (0.467), whereas the coefficients of the rat method (0.152) and dog method (0.410) were considerably different from those of the LBF methods (rat, 0.247; dog, 0.700). The new rat and dog methods appeared to perform better than the corresponding LBF methods, whereas the monkey method and the monkey LBF method showed improved predictability compared with the rat and dog one-species-based methods and the allometrically based “rule of exponents” (ROE). The new two-species methods were developed as CLhuman = arat-dog · W human0.628 (referred to as rat-dog method) and CLhuman = arat-monkey · W human0.650 (referred to as rat-monkey method), where arat-dog and arat-monkey are the coefficients obtained allometrically from the corresponding two species. The predictive performance of the two-species methods was comparable with that of the three-species-based ROE. Twenty-six Wyeth compounds having data from mouse, rat, dog, monkey, and human were used to test these methods. The results showed that the rat, dog, monkey, rat-dog, and rat-monkey methods provided improved predictions for the majority of the compounds compared with those for the ROE, suggesting that the use of three or more species in an allometrically based approach may not be necessary for the prediction of human exposure.
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a global examination of allometric scaling for predicting human Drug Clearance and the prediction of large vertical allometry
Journal of Pharmaceutical Sciences, 2006Co-Authors: Huadong Tang, Michael MayersohnAbstract:Abstract Allometrically scaled data sets (138 compounds) used for predicting human Clearance were obtained from the literature. Our analyses of these data have led to four observations. (1) The current data do not provide strong evidence that systemic Clearance (CL s ; n = 102) is more predictable than apparent oral Clearance (CL po ; n = 24), but caution needs to be applied because of potential CL po prediction error caused by differences in bioavailability across species. (2) CL s of proteins ( n = 10) can be more accurately predicted than that of non-protein chemicals ( n = 102). (3) CL s is more predictable for compounds eliminated by renal or biliary excretion ( n = 33) than by metabolism ( n = 57). (4) CL s predictability for hepatically eliminated compounds followed the order: high CL ( n = 11) > intermediate CL ( n = 17) > low CL ( n = 29). All examples of large vertical allometry (% error of prediction greater than 1000%) occurred only when predicting human CL s of Drugs having very low CL s . A qualitative analysis revealed the application of two potential rules for predicting the occurrence of large vertical allometry: (1) ratio of unbound fraction of Drug in plasma ( f u ) between rats and humans greater than 5; (2) C logP greater than 2. Metabolic elimination could also serve as an additional indicator for expecting large vertical allometry.
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a mathematical description of the functionality of correction factors used in allometry for predicting human Drug Clearance
Drug Metabolism and Disposition, 2005Co-Authors: Huadong Tang, Michael MayersohnAbstract:The functionality of the correction factors, maximum life-span potential (MLP), and brain weight (BrW) used in allometry is mathematically described. Correction by MLP or BrW is equivalent to a multiplication of some constants by the predicted values in humans from simple allometry, but they have no relationship to measured pharmacokinetic parameters in the animal species. The values of these constants ( F MLP or F BrW) were calculated for some commonly used combinations of animal species. For all combinations of animal species, the value of F BrW is always greater than that of F MLP with a fold-increase of about 1.3 to 1.9. Different combinations of species give different values of F BrW and F MLP. In addition, the role of correction factors (MLP and BrW) or the “rule of exponents” (ROE) was evaluated. An intrinsic defect in using correction factors or ROE was revealed; different study designs will produce significantly different prediction results. However, ROE may still serve as a useful practical approach in predicting human CL since it was derived from real observations and has been applied to many examples.
Jeffrey Lipman - One of the best experts on this subject based on the ideXlab platform.
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determining the mechanisms underlying augmented renal Drug Clearance in the critically ill use of exogenous marker compounds
Critical Care, 2014Co-Authors: Andrew A Udy, Jason A Roberts, Paul Jarrett, Janine Stuart, Melissa Lassigsmith, Therese Starr, Rachel Dunlop, Steven C Wallis, Jeffrey LipmanAbstract:Introduction The aim of this study was to explore changes in glomerular filtration (GFR) and renal tubular function in critically ill patients at risk of augmented renal Clearance (ARC), using exogenous marker compounds.
Tetsuya Terasaki - One of the best experts on this subject based on the ideXlab platform.
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Drug Clearance from Cerebrospinal Fluid Mediated by Organic Anion Transporters 1 (Slc22a6) and 3 (Slc22a8) at Arachnoid Membrane of Rats.
Molecular pharmaceutics, 2018Co-Authors: Zhengyu Zhang, Masanori Tachikawa, Yasuo Uchida, Tetsuya TerasakiAbstract:Although arachnoid mater epithelial cells form the blood–arachnoid barrier (BAB), acting as a blood–CSF interface, it has been generally considered that the BAB is impermeable to water-soluble substances and plays a largely passive role. Here, we aimed to clarify the function of transporters at the BAB in regulating CSF Clearance of water-soluble organic anion Drugs based on quantitative targeted absolute proteomics (QTAP) and in vivo analyses. Protein expression levels of 61 molecules, including 19 ATP-binding-cassette (ABC) transporters and 32 solute-carrier (SLC) transporters, were measured in plasma membrane fraction of rat leptomeninges using QTAP. Thirty-three proteins were detected; others were under the quantification limits. Expression levels of multiDrug resistance protein 1 (Mdr1a/P-gp/Abcb1a) and breast cancer resistance protein (Bcrp/Abcg2) were 16.6 and 3.27 fmol/μg protein (51.9- and 9.82-fold greater than in choroid plexus, respectively). Among those organic anion transporters detected onl...
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Drug Clearance from Cerebrospinal Fluid Mediated by Organic Anion Transporters 1 (Slc22a6) and 3 (Slc22a8) at Arachnoid Membrane of Rats
2018Co-Authors: Zhengyu Zhang, Masanori Tachikawa, Yasuo Uchida, Tetsuya TerasakiAbstract:Although arachnoid mater epithelial cells form the blood–arachnoid barrier (BAB), acting as a blood–CSF interface, it has been generally considered that the BAB is impermeable to water-soluble substances and plays a largely passive role. Here, we aimed to clarify the function of transporters at the BAB in regulating CSF Clearance of water-soluble organic anion Drugs based on quantitative targeted absolute proteomics (QTAP) and in vivo analyses. Protein expression levels of 61 molecules, including 19 ATP-binding-cassette (ABC) transporters and 32 solute-carrier (SLC) transporters, were measured in plasma membrane fraction of rat leptomeninges using QTAP. Thirty-three proteins were detected; others were under the quantification limits. Expression levels of multiDrug resistance protein 1 (Mdr1a/P-gp/Abcb1a) and breast cancer resistance protein (Bcrp/Abcg2) were 16.6 and 3.27 fmol/μg protein (51.9- and 9.82-fold greater than in choroid plexus, respectively). Among those organic anion transporters detected only at leptomeninges, not choroid plexus, organic anion transporter 1 (oat1/Slc22a6) showed the greatest expression (2.73 fmol/μg protein). On the other hand, the protein expression level of oat3 at leptomeninges was 6.65 fmol/μg protein, and the difference from choroid plexus was within two-fold. To investigate oat1’s role, we injected para-aminohippuric acid (PAH) with or without oat1 inhibitors into cisterna magna (to minimize the contribution of choroid plexus function) of rats. A bulk flow marker, FITC-inulin, was not taken up from CSF up to 15 min, whereas uptake Clearance of PAH was 26.5 μL/min. PAH uptake was completely blocked by 3 mM cephalothin (inhibits both oat1 and oat3), while 17% of PAH uptake was inhibited by 0.2 mM cephalothin (selectively inhibits oat3). These results indicate that oat1 and oat3 at the BAB provide a distinct Clearance pathway of organic anion Drugs from CSF independently of choroid plexus
