Decreased protein binding of moxifloxacin in patients with sepsis?

Dorn, Christoph; Nowak, Hartmuth; Weidemann, Caroline; Martini, Stefan; Zeitlinger, Markus; Adamzik, Michael; Kees, Frieder

doi:10.3205/id000029

Cited by 4 publications

(1 citation statement)

References 28 publications

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“…Deficiencies in fibrinolytic proteins, anticoagulant proteins, procoagulation factors, and protein synthesis, such as albumin, are often present in liver failure, in part due to failure of the synthesis and consumption. Hypoalbuminemia leads to alterations in PB, which may increase the unbound drug fraction in high-PB drugs [ 146 ] as described in Sect. 4.1.…”

Section: Host Factorsmentioning

confidence: 99%

Biomarkers Predicting Tissue Pharmacokinetics of Antimicrobials in Sepsis: A Review

Codina

Jorda

2022

Clin Pharmacokinet

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The pathophysiology of sepsis alters drug pharmacokinetics, resulting in inadequate drug exposure and target-site concentration. Suboptimal exposure leads to treatment failure and the development of antimicrobial resistance. Therefore, we seek to optimize antimicrobial therapy in sepsis by selecting the right drug and the correct dosage. A prerequisite for achieving this goal is characterization and understanding of the mechanisms of pharmacokinetic alterations. However, most infections take place not in blood but in different body compartments. Since tissue pharmacokinetic assessment is not feasible in daily practice, we need to tailor antibiotic treatment according to the specific patient's pathophysiological processes. The complex pathophysiology of sepsis and the ineffectiveness of current targeted therapies suggest that treatments guided by biomarkers predicting target-site concentration could provide a new therapeutic strategy. Inflammation, endothelial and coagulation activation markers, and blood flow parameters might be indicators of impaired tissue distribution. Moreover, hepatic and renal dysfunction biomarkers can predict not only drug metabolism and clearance but also drug distribution. Identification of the right biomarkers can direct drug dosing and provide timely feedback on its effectiveness. Therefore, this might decrease antibiotic resistance and the mortality of critically ill patients. This article fills the literature gap by characterizing patient biomarkers that might be used to predict unbound plasma-to-tissue drug distribution in critically ill patients. Although all biomarkers must be clinically evaluated with the ultimate goal of combining them in a clinically feasible scoring system, we support the concept that the appropriate biomarkers could be used to direct targeted antibiotic dosing.

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Section: Host Factorsmentioning

confidence: 99%

Biomarkers Predicting Tissue Pharmacokinetics of Antimicrobials in Sepsis: A Review

Codina

Jorda

2022

Clin Pharmacokinet

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Determination of free and total meropenem levels in human plasma and its application for the consistency evaluation of generic drugs

Yang

Zhang

Zhou

et al. 2023

Rapid Comm Mass Spectrometry

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Rationale The consistency evaluation of generic drugs is important for the overall reformation of drug registration in China. In this study, we used meropenem as a model drug to explore the key techniques for clinical consistency evaluation by studying the plasma protein binding (PPB) ratio of different preparations. Because the free portion of drug is the effective part in vivo, it is essential to measure the free drug concentration in the circulatory system. Therefore, in this study, a fast and accurate high‐performance liquid chromatography tandem mass spectrometry (HPLC–MS/MS) method was developed to determine the total and free concentrations of meropenem in human plasma. Methods Simple protein precipitation procedures were used for the sample processing assay, and ultrafiltration was implemented for the separation of free drugs. Liquid chromatography separation was performed using a hydrophilic interaction liquid chromatography (HILIC) silica column (2.1 × 50 mm, 3 μm). The mobile phase and sample preparation procedures were optimized. Factors affecting the measurement of free drug concentration were also determined. Nonspecific binding of the ultrafiltration membrane was negligible because the recovery rate for post‐ultrafiltration was greater than 96%. Results Under optimal conditions, the drug concentrations were linear from 0.5 to 50 μg/ml for both total and free drug concentrations. The PPB ratio was calculated based on the free and total drug concentrations. The PPB of meropenem varied from 1.4% to 24.2% in different subjects. The validated method was applied to evaluate PPB of four preparations, and the results varied from 6.57 ± 3.19% to 10.40 ± 8.31%. One‐way analysis of variance (ANOVA) showed no significant differences between the four preparations. Conclusions We established a rapid, robust, and reliable method for the determination of total and free meropenem concentrations using LC–MS/MS with ultrafiltration techniques. The method provided a new perspective for the clinical consistency evaluation of generic drugs.

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Clinical Ocular Exposure Extrapolation for Ophthalmic Solutions Using PBPK Modeling and Simulation

et al. 2022

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Background The development of generic ophthalmic drug products is challenging due to the complexity of the ocular system, and a lack of sensitive testing to evaluate the interplay of physiology with ophthalmic formulations. While measurements of drug concentration at the site of action in humans are typically sparse, these measurements are more easily obtained in rabbits. The purpose of this study is to demonstrate the utility of an ocular physiologically based pharmacokinetic (PBPK) model for translation of ocular exposure from rabbit to human. Method The Ocular Compartmental Absorption and Transit (OCAT™) model within GastroPlus® v9.8.2 was used to build PBPK models for levofloxacin (Lev), moxifloxacin (Mox), and gatifloxacin (Gat) ophthalmic solutions. in the rabbit eye. The models were subsequently used to predict Lev, Mox, and Gat exposure after ocular solution administrations in humans. Drug-specific parameters were used as fitted and validated in the rabbit OCAT model. The physiological parameters were scaled to match human ocular physiology. Results OCAT model simulations for rabbit well described the observed concentrations in the eye compartments following Lev, Mox, and Gat solution administrations of different doses and various administration schedules. The clinical ocular exposure following ocular administration of Lev, Mox, and Gat solutions at different doses and various administration schedules was well predicted. Conclusion Even though additional case studies for different types of active pharmaceutical ingredients (APIs) and formulations will be needed, the current study represents an important step in the validation of the extrapolation method to predict human ocular exposure for ophthalmic drug products using PBPK models.

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Decreased protein binding of moxifloxacin in patients with sepsis?

Cited by 4 publications

References 28 publications

Biomarkers Predicting Tissue Pharmacokinetics of Antimicrobials in Sepsis: A Review

Biomarkers Predicting Tissue Pharmacokinetics of Antimicrobials in Sepsis: A Review

Determination of free and total meropenem levels in human plasma and its application for the consistency evaluation of generic drugs

Clinical Ocular Exposure Extrapolation for Ophthalmic Solutions Using PBPK Modeling and Simulation

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