Measuring and Using Free Drug Concentrations: Has There Been ‘Real’ Progress?

Musteata, Florin Marcel

doi:10.4155/bio-2017-0053

Cited by 14 publications

(11 citation statements)

References 14 publications

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“…Although it has been repeatedly shown that free drug concentrations correlate better with therapeutic effects than total concentrations, measurement of free drug concentrations has not been adopted more widely. 5 Indeed, concerns are comprehensible considering the variable fu, as reported for beta-lactams with low protein binding (fu CAZ about 90%, fu MEM 98%, and fu PIP 70% as provided by the manufacturers), where altered albumin concentrations in special populations should not have a significant influence. In an early review on the PK of CAZ an fu of 77.5%-95%, and in a more recent publication, an fu of 77.5%-98% has been reported.…”

Section: Discussionmentioning

confidence: 99%

“…4 Although additional pharmacokinetic modeling-based research has been suggested to enable the design of robust dosing regimens for drugs affected by altered protein binding, measurement of free concentrations has not been adopted more widely as the methods are considered to have low precision and accuracy. 5 Equilibrium dialysis (ED) is considered as the gold standard for the determination of free drug, but ultrafiltration is more commonly used in the clinical setting because of its simplicity and speed, requiring ,0.5 versus 4-24 hours [5][6][7] Although in ED plasma is usually dialyzed against isotonic phosphate-buffered saline (pH 7.4) at 378C, there is no consensus about a standard protocol for ultrafiltration. Ultrafiltration of antibiotics has been performed at 5-68C (because of stability concerns) or at room temperature (for convenience) or using a high relative centrifugal force $10,000 g (for time-saving) and normally without pH control.…”

Section: Introductionmentioning

confidence: 99%

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Measurement of Free Plasma Concentrations of Beta-Lactam Antibiotics: An Applicability Study in Intensive Care Unit Patients

Schießer

Hitzenbichler

Kees

et al. 2021

Therapeutic Drug Monitoring

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Background:The antibacterial effect of antibiotics is linked to the free drug concentration. This study investigated the applicability of an ultrafiltration method to determine free plasma concentrations of beta-lactam antibiotics in ICU patients.Methods: Eligible patients included adult ICU patients treated with ceftazidime (CAZ), meropenem (MEM), piperacillin (PIP)/ tazobactam (TAZ), or flucloxacillin (FXN) by continuous infusion. Up to 2 arterial blood samples were drawn at steady state. Patients could be included more than once if they received another antibiotic. Free drug concentrations were determined by high-performance liquid chromatography with ultraviolet detection after ultrafiltration, using a method that maintained physiological conditions (pH 7.4/ 378C). Total drug concentrations were determined to calculate the unbound fraction. In a post-hoc analysis, free concentrations were compared with the target value of 4• the epidemiological cut-off value (ECOFF) for Pseudomonas aeruginosa as a worst-case scenario for empirical therapy with CAZ, MEM or PIP/tazobactam and against methicillin-sensitive Staphylococcus aureus for targeted therapy with FXN.Results: Fifty different antibiotic treatment periods in 38 patients were evaluated. The concentrations of the antibiotics showed a wide range because of the fixed dosing regimen in a mixed population with variable kidney function. The mean unbound fractions (fu) of CAZ, MEM, and PIP were 102.5%, 98.4%, and 95.7%, with interpatient variability of ,6%. The mean fu of FXN was 11.6%, with interpatient variability of 39%. It was observed that 2 of 12 free concentrations of CAZ, 1 of 40 concentrations of MEM, and 11 of 23 concentrations of PIP were below the applied target concentration of 4 • ECOFF for P. aeruginosa. All concentrations of FXN (9 samples from 6 patients) were .8 • ECOFF for methicillinsensitive Staphylococcus aureus. Conclusions:For therapeutic drug monitoring purposes, measuring total or free concentrations of CAZ, MEM, or PIP is seemingly adequate. For highly protein-bound beta-lactams such as FXN, free concentrations should be favored in ICU patients with prevalent hypoalbuminemia.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Measurement of Free Plasma Concentrations of Beta-Lactam Antibiotics: An Applicability Study in Intensive Care Unit Patients

Schießer

Hitzenbichler

Kees

et al. 2021

Therapeutic Drug Monitoring

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“…From an analytical point of view, methods for measuring total drug concentrations require less time and resources than those aimed at quantifying the free drug, which often involves complex sample preparation procedures and more sensitive analytical tools [ 37 , 38 ].…”

Section: Analytical Tools For the Evaluation Of Asms’ Free Drug Fractionmentioning

confidence: 99%

“…Other methods, like UC and solid-phase micro-extraction (SPME), do not require membranes for the separation of the unbound fraction and seem not to be affected by the risk of artifacts [ 38 ]. Briefly, in the UC technique, a solution consisting of drug and proteins is placed in a centrifugal field and undergoes repeated centrifugations; this leads to the formation of a compact protein “pellet” at the bottom of the centrifugation tube that can be separated from the protein-free fraction supernatant.…”

Section: Analytical Tools For the Evaluation Of Asms’ Free Drug Fractionmentioning

confidence: 99%

The Effect of Plasma Protein Binding on the Therapeutic Monitoring of Antiseizure Medications

et al. 2021

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Epilepsy is a widely diffused neurological disorder including a heterogeneous range of syndromes with different aetiology, severity and prognosis. Pharmacological treatments are based on the use, either in mono- or in polytherapy, of antiseizure medications (ASMs), which act at different synaptic levels, generally modifying the excitatory and/or inhibitory response through different action mechanisms. To reduce the risk of adverse effects and drug interactions, ASMs levels should be closely evaluated in biological fluids performing an appropriate Therapeutic Drug Monitoring (TDM). However, many decisions in TDM are based on the determination of the total drug concentration although measurement of the free fraction, which is not bound to plasma proteins, is becoming of ever-increasing importance since it correlates better with pharmacological and toxicological effects. Aim of this work has been to review methodological aspects concerning the evaluation of the free plasmatic fraction of some ASMs, focusing on the effect and the clinical significance that drug-protein binding has in the case of widely used drugs such as valproic acid, phenytoin, perampanel and carbamazepine. Although several validated methodologies are currently available which are effective in separating and quantifying the different forms of a drug, prospective validation studies are undoubtedly needed to better correlate, in real-world clinical contexts, pharmacokinetic monitoring to clinical outcomes.

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“…Free drug concentrations can be measured by determining the concentration of drug in a plasma ultra-filtrate, through an appropriate filter or by equilibrium dialysis across a semi permeable membrane. Since, for most drugs, it is the unbound fraction that is pharmacologically active, measuring this fraction in our laboratories may be more useful [9].…”

Section: Blood (Serum/plasma)mentioning

confidence: 99%

What the lab can and cannot do: clinical interpretation of drug testing results

Kapur¹,

Aleksa²

2020

Critical Reviews in Clinical Laboratory Sciences

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Urine drug testing is one of the objective tools available to assess adherence. To monitor adherence, quantitative urinary results can assist in differentiating "new" drug use from "previous" (historical) drug use. "Spikes" in urinary concentration can assist in identifying patterns of drug use. Coupled chromatographic-mass spectrometric methods are capable of identifying very small amounts of analyte and can make clinical interpretation rather challenging, specifically for drugs that have a longer half-life. Polypharmacy is common in treatment and rehabilitation programs because of co-morbidities. Medications prescribed for comorbidities can cause drug-drug interaction and phenoconversion of genotypic extensive metabolizers into phenotypic poor metabolizers of the treatment drug. This can have significant impact on both pharmacokinetic (PK) and pharmacodynamic properties of the treatment drug. Therapeutic drug monitoring (TDM) coupled with PKs can assist in interpreting the effects of phenoconversion. TDM-PKs reflects the cumulative effects of pathophysiological changes in the patient as well as drug-drug interactions and should be considered for treatment medications/drugs used to manage pain and treat substance abuse. Since only a few enzyme immunoassays for TDM are available, this is a unique opportunity for clinical laboratory scientists to develop TDM-PK protocols that can have a significant impact on patient care and personalized medicine. Interpretation of drug screening results should be done with caution while considering pharmacological properties and the presence or absence of the parent drug and its metabolites. The objective of this manuscript is to review and address the variables that influence interpretation of different drugs analyzed from a rehabilitation and treatment programs perspective.

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Measuring and Using Free Drug Concentrations: Has There Been ‘Real’ Progress?

Cited by 14 publications

References 14 publications

Measurement of Free Plasma Concentrations of Beta-Lactam Antibiotics: An Applicability Study in Intensive Care Unit Patients

Measurement of Free Plasma Concentrations of Beta-Lactam Antibiotics: An Applicability Study in Intensive Care Unit Patients

The Effect of Plasma Protein Binding on the Therapeutic Monitoring of Antiseizure Medications

What the lab can and cannot do: clinical interpretation of drug testing results

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