Ibuprofen kinetics in patients with renal insufficiency who are receiving maintenance hemodialysis

Ochs, Hermann R.; Greenblatt, David J.; Verburg-Ochs, Birgitt

doi:10.1002/art.1780281218

Cited by 9 publications

(2 citation statements)

References 21 publications

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“…Tryptophan and ibuprofen, the competitor drugs considered in analysis, are continuously metabolized by liver. The reported half-life of tryptophan and ibuprofen is 2.83 hrs and 2 hrs, respectively 44,45 . The drug half-life, stated here, corresponds to total serum concentration, i.e.…”

Section: Methodsmentioning

confidence: 99%

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

Maheshwari

Thijssen

Tao

et al. 2019

Sci Rep

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Protein-bound uremic toxins (PBUTs) are poorly removed during hemodialysis (HD) due to their low free (dialyzable) plasma concentration. We compared PBUT removal between HD, hemodiafiltration (HDF), membrane adsorption, and PBUT displacement in HD. The latter involves infusing a binding competitor pre-dialyzer, which competes with PBUTs for their albumin binding sites and increases their free fraction. We used a mathematical model of PBUT/displacer kinetics in dialysis comprising a three-compartment patient model, an arterial/venous tube segment model, and a dialyzer model. Compared to HD, improvements in removal of prototypical PBUTs indoxyl sulfate (initial concentration 100 µM, 7% free) and p-cresyl sulfate (150 µM, 5% free) were: 5.5% and 6.4%, respectively, for pre-dilution HDF with 20 L replacement fluid; 8.1% and 9.1% for post-dilution HDF 20 L; 15.6% and 18.3% for pre-dilution HDF 60 L; 19.4% and 22.2% for complete membrane adsorption; 35.0% and 41.9% for displacement with tryptophan (2000 mg in 500 mL saline); 26.7% and 32.4% for displacement with ibuprofen (800 mg in 200 mL saline). Prolonged (one-month) use of tryptophan reduces the IS and pCS time-averaged concentration by 28.1% and 29.9%, respectively, compared to conventional HD. We conclude that competitive binding can be a pragmatic approach for improving PBUT removal.

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Section: Methodsmentioning

confidence: 99%

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

Maheshwari

Thijssen

Tao

et al. 2019

Sci Rep

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“…The following supporting information can be downloaded at: , Figure S1: Simulated versus observed concentration profiles for plasma and CNS in rats; Figure S2: Simulated versus observed concentration profiles in rats; Figure S3: Goodness-of-fit plots of predicted vs observed pharmacokinetic metrics (AUC & Cmax) in plasma and CSF/ECF in rats; Table S1: Physiological parameters-Rat PBPK model; Table S2: Physiological parameters-Human PBPK model; Table S3: Physicochemical and Drug Specific Parameters for Acetaminophen, Oxycodone, Lacosamide, Ibuprofen & Levetiracetam. References [ 8 , 28 , 34 , 40 , 42 , 44 , 46 , 52 , 53 , 56 , 57 , 59 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 ] are cited in the supplementary materials.…”

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confidence: 99%

Interspecies Brain PBPK Modeling Platform to Predict Passive Transport through the Blood–Brain Barrier and Assess Target Site Disposition

Mehta,

Soliman,

Rodriguez-Vera

et al. 2024

Pharmaceutics

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The high failure rate of central nervous system (CNS) drugs is partly associated with an insufficient understanding of target site exposure. Blood–brain barrier (BBB) permeability evaluation tools are needed to explore drugs’ ability to access the CNS. An outstanding aspect of physiologically based pharmacokinetic (PBPK) models is the integration of knowledge on drug-specific and system-specific characteristics, allowing the identification of the relevant factors involved in target site distribution. We aimed to qualify a PBPK platform model to be used as a tool to predict CNS concentrations when significant transporter activity is absent and human data are sparse or unavailable. Data from the literature on the plasma and CNS of rats and humans regarding acetaminophen, oxycodone, lacosamide, ibuprofen, and levetiracetam were collected. Human BBB permeability values were extrapolated from rats using inter-species differences in BBB surface area. The percentage of predicted AUC and Cmax within the 1.25-fold criterion was 85% and 100% for rats and humans, respectively, with an overall GMFE of <1.25 in all cases. This work demonstrated the successful application of the PBPK platform for predicting human CNS concentrations of drugs passively crossing the BBB. Future applications include the selection of promising CNS drug candidates and the evaluation of new posologies for existing drugs.

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Pharmacokinetic Comparison of Flurbiprofen in End‐Stage Renal Disease Subjects and Subjects with Normal Renal Function

Cefali

Poynor

Sica

et al. 1991

The Journal of Clinical Pharma

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This study compared the pharmacokinetics of flurbiprofen (F) and three major metabolites in patients with end-stage renal disease (ESRD) undergoing continuous ambulatory peritoneal dialysis (CAPD) with the pharmacokinetics of F in normal subjects. A single 100-mg dose of F was administered to each of nine normal subjects and eight ESRD subjects. Blood and urine samples were collected in both groups; serial and end of dwell dialysate samples were obtained from the ESRD subjects. Plasma was analyzed for both the R and S optical isomers of F and its major metabolite, 4'-hydroxy-flurbiprofen (HF). Urine and dialysate were analyzed for F and three known metabolites. Plasma concentrations of F in the ESRD subjects were approximately 50% of the values obtained from the normal subjects (P less than .05). Flurbiprofen half-life and Tmax were not different. Elimination of HF was reduced in ESRD subjects. Urinary data suggest that HF was the major metabolite excreted (36% of the dose) in normal subjects whereas 3',4'-dihydroxy-flurbiprofen was the major metabolite (9% of the dose) excreted in the ESRD group. Mean urinary recovery of the dose was 73% in the normal subjects, but only 16% in ESRD subjects. Neither F nor its metabolites were detected in dialysate. Small enantiomer differences were seen. This study suggests that ESRD subjects have lower plasma levels of F than normal subjects when administered equal size doses. Accumulation of metabolites may occur in ESRD subjects upon multiple dosing. Enantiomer differences are not clinically significant.

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Ibuprofen kinetics in patients with renal insufficiency who are receiving maintenance hemodialysis

Cited by 9 publications

References 21 publications

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

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

Interspecies Brain PBPK Modeling Platform to Predict Passive Transport through the Blood–Brain Barrier and Assess Target Site Disposition

Pharmacokinetic Comparison of Flurbiprofen in End‐Stage Renal Disease Subjects and Subjects with Normal Renal Function

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