CIRRHOSIS INCREASES FREE DRUG LEVELS AFTER ORAL PROPRANOLOL

InPharma ◽  
1978 ◽  
Vol 165 (1) ◽  
pp. 15-15
Keyword(s):  
Free Drug ◽  
Drug Levels ◽  
Oral Propranolol

Intratumoral drug distribution of adavosertib in patients with glioblastoma: Interim results of phase I study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 2568-2568
Author(s):  
Carlos G Romo ◽  
Brian Michael Alexander ◽  
Nathalie Agar ◽  
Manmeet Singh Ahluwalia ◽  
Arati Suvas Desai ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Geometric Mean ◽  
Extracellular Fluid ◽  
Maximum Tolerated Dose ◽  
Brain Regions ◽  
Free Drug ◽  
Total Drug ◽  
Drug Levels ◽  
Drug Concentrations

2568 Background: Wee1 is a key regulator of the G2/M checkpoint and is frequently overexpressed in glioblastoma (GB). Adavosertib is a first-in-class oral, small molecule inhibitor of Wee1 that acts primarily as a DNA damage sensitizer. A phase I clinical trial was conducted to evaluate its safety and establish the recommended phase II dosing. Studies were undertaken to evaluate whether potentially therapeutic concentrations of the drug are achieved in recurrent tumor and adjacent non-enhancing brain regions with presumed intact blood-brain barrier (BBB). Methods: Twelve patients received five daily doses of adavosertib pre-operatively at either the maximum tolerated dose (MTD) for concurrent radiation or adjuvant temozolomide. Tissue from contrast enhancing (CE) and non-enhancing (NE) brain regions was obtained for analysis during surgical resection. A second stage is being conducted using microdialysis (MD) to facilitate continuous sampling of extracellular fluid (ECF) and measuring free drug concentrations in: normal-appearing brain, contrast enhancing tumor, and a peritumoral T2 hyperintense area. The concentration of total adavosertib in plasma and tissue homogenates and free drug in ECF were determined by validated LC/MS/MS methods. Results: Geometric mean concentrations of adavosertib after a 200 mg dose were 644 ng/mL and 119 ng/mL in CE and NE tissue specimens, respectively (6 patients). At the 425 mg dose, the mean concentrations were 3,576 ng/mL in CE tissue and 885 ng/mL in NE tissue (6 patients). MD was performed in 2 patients. Samples from functional MD catheters were collected from NE brain in patient no. 1 and from two NE areas and a FLAIR hyperintense region in patient no. 2, with the following results in the table. Conclusions: The total drug concentration in tissue samples was notably lower in regions of the brain with a relatively intact BBB as compared to contrast enhancing tissue. Concentrations of adavosertib measured by MD vary markedly depending on catheter location. Free drug levels in ECF within brain with a functional BBB, although considerably lower than total drug levels in tissue, were 2-10 times below the previously reported IC50 for antiproliferative activity against sensitive GB cell lines (127 ng/mL). Whether or not the target of the drug is effectively inhibited at these concentrations remains to be demonstrated. Clinical trial information: NCT01849146 . [Table: see text]

Combined Hemoperfusion and Continuous Veno-Venous Hemofiltration for Carbamazepine Intoxication

2021 ◽  
pp. 1-5
Author(s):  
Simon Baylis ◽  
Rahul Costa-Pinto ◽  
Sarah Hodgson ◽  
Rinaldo Bellomo ◽  
Ian Baldwin
Keyword(s):  
Combined Treatment ◽  
Drug Clearance ◽  
Free Drug ◽  
Low Molecular Weight ◽  
Serum Protein Binding ◽  
Drug Levels ◽  
Mass Removal ◽  
In Series ◽  
Extracorporeal Removal ◽  
Massive Overdose

<b><i>Introduction:</i></b> Carbamazepine (CBZ) is a widely used anticonvulsant with a low molecular weight that allows for extracorporeal removal of free drug by both dialytic and hemoperfusion techniques, particularly in a massive overdose where serum protein binding is saturated. This report presents a case of CBZ intoxication where we were able to compare the mass removal of CBZ using hemoperfusion, with the mass removal of CBZ achieved with continuous renal replacement therapy (CRRT) during combined treatment. <b><i>Methods:</i></b> The Jafron HA230 resin hemoperfusion cartridge was applied in series with the continuous veno-venous hemofiltration (CVVH) circuit. Baseline and ongoing serum drug levels along with further samples from pre- and post-hemoperfusion cartridges and from CVVH effluent were collected. <b><i>Results:</i></b> Combined CVVH and resin hemoperfusion therapy in series was associated with a 50% reduction in the CBZ level from 16 mg/L to 8 mg/L over 3 h, far more rapid than that observed with CVVH alone or in the absence of extracorporeal drug clearance in the preceding hours. The combination therapy removed close to 35 mg/h of CBZ. <b><i>Conclusion:</i></b> The combination of CRRT and hemoperfusion can be easily deployed, appears safe, and is able to combine the CBZ mass removal achieved with each technique, thus to maximize CBZ extraction.

Clinical utility of monitoring free drug levels

2020 ◽  
pp. 27-42
Author(s):  
Amitava Dasgupta ◽  
Matthew D. Krasowski
Keyword(s):  
Clinical Utility ◽  
Free Drug ◽  
Drug Levels

The Effect of Sample Handling on Free Valproic Acid Levels

2020 ◽  
Author(s):  
Dan Wang ◽  
Elizabeth Champion-Lyons ◽  
Ron Neyens ◽  
Nicole Bohm ◽  
Brittany Caddell ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Anticonvulsant Drug ◽  
Free Fraction ◽  
Free Drug ◽  
Reference Laboratory ◽  
Negative Bias ◽  
Sample Handling ◽  
Drug Levels ◽  
Parallel Testing ◽  
Significant Bias

Abstract Background Valproic acid (VPA) is a broad-spectrum anticonvulsant drug. Under normal conditions, this drug is highly protein bound. However, in patients with hypoalbuminemia, the free fraction can increase substantially while the total VPA levels remain in therapeutic range. The neurologic activity and toxicity of the drug are directly related to free drug levels. Methods Our in-house free VPA assay was validated using 20 patient samples obtained from a reference laboratory (RL1). It was further evaluated by parallel testing with RL1 using samples collected from our patients. Subsequently, sample handling effects were investigated by comparing free VPA levels measured in our laboratory to 3 selected RLs with different sample transportation conditions. Results No significant bias was observed between the in-house assay (y) and RL1 (x) assay in free VPA measurement (y = 1.12x + 0.072, r = 0.994). However, patient samples collected in our institution and sent to RL1 revealed significant negative bias (y = 0.776x − 3.861, r = 0.954). A large discrepancy in free VPA levels was further observed from identical aliquots of the same samples transported to 3 RLs in different conditions. Conclusions Our study demonstrated that sample handling has significant impact on free VPA levels. The observed magnitude of variation exceeds a clinically acceptable limit and could alter clinical decisions.

scholarly journals Cross-Species Differential Plasma Protein Binding of MBX-102/JNJ39659100: A Novel PPAR- Agonist

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-10 ◽  
Author(s):  
Holly J. Clarke ◽  
Francine Gregoire ◽  
Fang Ma ◽  
Robert Martin ◽  
Spring Zhao ◽  
...  
Keyword(s):  
Protein Binding ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Species Differences ◽  
Free Drug ◽  
Drug Binding ◽  
Mouse Serum ◽  
Drug Levels ◽  
Ppar Agonist ◽  
Interspecies Differences

Drug binding to plasma proteins restricts their free and active concentrations, thereby affecting their pharmacokinetic properties. Species differences in plasma protein levels complicate the understanding of interspecies pharmacodynamic and toxicological effects. MBX-102 acid/JNJ39659100 is a novel PPAR- agonist in development for the treatment of type 2 diabetes. Studies were performed to evaluate plasma protein binding to MBX-102 acid and evaluate species differences in free drug levels. Equilibrium dialysis studies demonstrated that MBX-102 acid is highly bound (>98%) to human, rat and mouse albumin and that free MBX-102 acid levels are higher in rodent than in human plasma. Interspecies differences in free drug levels were further studied using PPAR- transactivation assays and a newly developed PPAR- corepressor displacement (biochemical) assay. PPAR- transactivation and corepressor displacement by MBX-102 acid was higher in rat and mouse serum than human serum. These results confirm the relevance of interspecies differences in free MBX-102 acid levels.

Micro-Scale Ultracentrifugation as an Alternative to Ultrafiltration for the Determination of the Unbound Fraction of Phenytoin in Human Serum

1986 ◽  
Vol 23 (5) ◽  
pp. 603-607 ◽  
Author(s):  
L Jack ◽  
C Cunningham ◽  
I D Watson ◽  
M J Stewart
Keyword(s):  
Human Serum ◽  
Simple Procedure ◽  
Free Fraction ◽  
Free Drug ◽  
Effect Of Temperature ◽  
Unbound Fraction ◽  
Drug Levels ◽  
Micro Scale ◽  
Great Utility

Free phenytoin has been determined using micro-scale ultracentrifugation followed by analysis by EMIT. The effect of temperature on the determined free fraction was investigated and the ultracentrifugation procedure validated against ultrafiltration. Ultracentrifugation gave free fractions which were on average 16% lower than those obtained using ultrafiltration, but correlation was good, as was the correlation with measurements of total phenytoin ( r=0·90). Micro-scale ultracentrifugation is a simple procedure which can be of great utility in the measurement and investigation of free drug levels.

Free Drug Levels Monitoring as a Detector of False Metabolic Refractory Epilepsy

1988 ◽  
Vol 28 (6) ◽  
pp. 349-353
Author(s):  
M. Gianelli ◽  
S. Gentile ◽  
L. Verzè ◽  
U. Dimanico ◽  
M. Baruchello ◽  
...  
Keyword(s):  
Refractory Epilepsy ◽  
Free Drug ◽  
Drug Levels
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