A meta-analysis of protein binding of flucloxacillin in healthy volunteers and hospitalized patients

Wallenburg, Eveline; Brüggemann, Roger J. M.; Roberts, Jason A.; Jager, Nynke G L; Ulldemolins, Marta; Wilkes, Sarah; Schouten, Jeroen; Chin, Paul; Heine, Rob ter

doi:10.1016/j.cmi.2021.06.039

Cited by 14 publications

(8 citation statements)

References 31 publications

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“…This correction is often based on PPB values from healthy volunteers, which poorly reflects the variability reported among critically ill patients. [5][6][7][8] Because of the central role of unbound fractions, several methods for the selective determination of unbound plasma concentrations have been proposed for different clinically important beta-lactam compounds. 5,9,10 Yet, the absence of a "gold standard" reference method complicates the interpretation of findings reported by different investigators and impedes further development.…”

Section: Introductionmentioning

confidence: 99%

Reproducible Quantification of Unbound Fractions of Four Beta-Lactam Antibiotics: Ultrafiltration Versus Microdialysis of Spiked Healthy Donor Plasma

Beijer

Clarin

Östervall

et al. 2023

Therapeutic Drug Monitoring

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Background: Ultrafiltration (UF) is a conventional method for isolating the protein-unbound plasma fractions of therapeutic drugs. However, the ideal UF conditions for specific compounds remain largely unexplored. By comparing UF-derived unbound concentrations with the corresponding results obtained using a reference method, the authors sought to identify appropriate UF conditions for cefotaxime, cloxacillin, flucloxacillin, and piperacillin. Methods:In vitro microdialysis (MD) with a no-net-flux approach was used as a reference method for plasma protein separation, for which UF performance was assessed. Four levels of relative centrifugal force (2500-11,290g) and 2 levels of temperature (37 vs. 228C) during 10 minutes of UF centrifugation were evaluated. Ultrafiltrates and reference microdialysates were analyzed using liquid chromatography-tandem mass spectrometry to obtain unbound concentrations. After identifying the appropriate UF conditions in the spiked plasma samples, exploratory analyses of clinical samples (n = 10 per analyte) were performed.Results: Of the evaluated UF alternatives, the best overall agreement with the MD-derived reference concentrations was obtained with 11,290 g UF performed at 228C. For cloxacillin specifically, 378C UF yielded better agreement than 228C UF at 11,290 g. Clinical sample analyses indicated minimal differences between 228C and 378C at 11,290 g UF for cefotaxime and piperacillin. However, consistently lower levels of unbound cloxacillin (median: 223%, IQR: 219% to 224%) and flucloxacillin (median: 227%, IQR: 221 to 234%) were observed after UF at 228C versus 378C. Conclusions:For the evaluated UF device, 10 minutes of 11,290 g UF at 228C is appropriate for flucloxacillin, cefotaxime, and piper-acillin, and can arguably be justified for cloxacillin as well for laboratory practice purposes. Maintenance of 378C during highcentrifugal UF may lead to overestimation, particularly for unbound flucloxacillin.

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Section: Introductionmentioning

confidence: 99%

Reproducible Quantification of Unbound Fractions of Four Beta-Lactam Antibiotics: Ultrafiltration Versus Microdialysis of Spiked Healthy Donor Plasma

Beijer

Clarin

Östervall

et al. 2023

Therapeutic Drug Monitoring

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“…For the medicines using dose titration method to achieve a target response or target concentration, a fixed dose adjustment method might not be necessary. Therapeutic drug monitoring based on unbound concentration offer more therapeutic advantages even when the unbound concentration cannot be accurately estimated from the total concentration 74,75 . This is reflected in our case examples within the categories of “no dose adjustment even though there was some degree of PB change” or “no dose adjustment consistently with no PB change,” where most therapies are administered in titration fashion.…”

Section: Discussionmentioning

confidence: 83%

“…Penetration into the extravascular space is highly important for antimicrobial therapy, as the majority of bacterial and fungal infections occur in the interstitial fluid of tissue 72 . The efficacy of flucloxacillin, for example, is dependent on the unbound concentration above the MIC 74,75 . For antibacterials with efficacy driven by unbound C max , higher dosing, rather than more frequent dosing, would be appropriate.…”

Section: Discussionmentioning

confidence: 99%

“… 72 The efficacy of flucloxacillin, for example, is dependent on the unbound concentration above the MIC. 74 , 75 For antibacterials with efficacy driven by unbound C max , higher dosing, rather than more frequent dosing, would be appropriate. The pharmacological activity of anti‐viral drugs for HIV is dependent on unbound drug entering cells that harbor the human immunodeficiency virus.…”

Section: Discussionmentioning

confidence: 99%

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Re‐discover the value of protein binding assessments in hepatic and renal impairment studies and its contributions in drug labels and dose decisions

Courville,

Roupe,

Arold

2024

Clinical Translational Sci

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One of the key pharmacokinetic properties of most small molecule drugs is their ability to bind to serum proteins. Unbound or free drug is responsible for pharmacological activity while the balance between free and bound drug can impact drug distribution, elimination, and other safety parameters. In the hepatic impairment (HI) and renal impairment (RI) clinical studies, unbound drug concentration is often assessed; however, the relevance and impact of the protein binding (PB) results is largely limited. We analyzed published clinical safety and pharmacokinetic studies in subjects with HI or RI with PB assessment up to October 2022 and summarized the contribution of PB results on their label dose recommendations. Among drugs with HI publication, 32% (17/53) associated product labels include PB results in HI section. Of these, the majority (9/17, 53%) recommend dose adjustments consistent with observed PB change. Among drugs with RI publication, 27% (12/44) of associated product labels include PB results in RI section with the majority (7/12, 58%) recommending no dose adjustment, consistent with the reported absence of PB change. PB results were found to be consistent with a tailored dose recommendation in 53% and 58% of the approved labels for HI and RI section, respectively. We further discussed the interpretation challenges of PB results, explored treatment decision factors including total drug concentration, exposure–response relationships, and safety considerations in these case examples. Collectively, comprehending the alterations in free drug levels in HI and RI informs treatment decision through a risk‐based approach.

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“…TDM should be based on the unbound flucloxacillin concentration because the unbound concentration cannot be adequately estimated from the total concentration. 30 It must be noted that more information on an upper threshold associated between free drug concentration and neurotoxicity is urgently needed. Furthermore, TDM could assure optimal exposure for patients with augmented renal clearance and for those treated for infections caused by less susceptible pathogens.…”

Section: Discussionmentioning

confidence: 99%

High unbound flucloxacillin fraction in critically ill patients

Wallenburg¹,

Heine²,

Lange

et al. 2021

Journal of Antimicrobial Chemotherapy

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Objectives To describe the unbound and total flucloxacillin pharmacokinetics in critically ill patients and to define optimal dosing strategies. Patients and methods Observational multicentre study including a total of 33 adult ICU patients receiving flucloxacillin, given as intermittent or continuous infusion. Pharmacokinetic sampling was performed on two occasions on two different days. Total and unbound flucloxacillin concentrations were measured and analysed using non-linear mixed-effects modelling. Serum albumin was added as covariate on the maximum binding capacity and endogenous creatinine clearance (CLCR) as covariate for renal function. Monte Carlo simulations were performed to predict the unbound flucloxacillin concentrations for different dosing strategies and different categories of endogenous CLCR. Results The measured unbound concentrations ranged from 0.2 to 110 mg/L and the observed unbound fraction varied between 7.0% and 71.7%. An integral two-compartmental linear pharmacokinetic model based on total and unbound concentrations was developed. A dose of 12 g/24 h was sufficient for 99.9% of the population to achieve a concentration of >2.5 mg/L (100% fT>5×MIC, MIC = 0.5 mg/L). Conclusions Critically ill patients show higher unbound flucloxacillin fractions and concentrations than previously thought. Consequently, the risk of subtherapeutic exposure is low.

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A meta-analysis of protein binding of flucloxacillin in healthy volunteers and hospitalized patients

Cited by 14 publications

References 31 publications

Reproducible Quantification of Unbound Fractions of Four Beta-Lactam Antibiotics: Ultrafiltration Versus Microdialysis of Spiked Healthy Donor Plasma

Reproducible Quantification of Unbound Fractions of Four Beta-Lactam Antibiotics: Ultrafiltration Versus Microdialysis of Spiked Healthy Donor Plasma

Re‐discover the value of protein binding assessments in hepatic and renal impairment studies and its contributions in drug labels and dose decisions

High unbound flucloxacillin fraction in critically ill patients

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