Drug combinations and impact of experimental conditions on relative recovery in in vitro microdialysis investigations

Burau, Daniela; Petroff, David; Simon, Philipp; Ehmann, Lisa; Weiser, Christine; Dorn, Christoph; Kratzer, Alexander; Wrigge, Hermann; Kloft, Charlotte

doi:10.1016/j.ejps.2018.10.030

Cited by 14 publications

(11 citation statements)

References 17 publications

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“…After obtaining results of our in-vitro trials [ 11 ], microdialysis pump flow settings were optimized and changes of the retrodialysis protocol ( Table 2 ) were implemented. An amendment of the study protocol (version 3.0; November 2014) for group D is provided in additional files.…”

Section: Methodsmentioning

confidence: 99%

“…After a washing step, retrodialysis was started with the retroperfusate (RP), a perfusion solution containing a defined concentration of the respective study drug ( Table 2 ). Retrodialysate (RD) was collected as described in the retrodialysis protocol ( Table 3 ) [ 10 , 11 ]. Drug concentrations were determined in the retroperfusate (C RP ) and retrodialysate (C RD ) to determine the in vivo relative recovery as follows: relative recovery = (1 – C RD /C RP ) x 100%.…”

Section: Methodsmentioning

confidence: 99%

“…Study drug concentrations in microdialysates, plasma and plasma ultrafiltrate samples were analyzed at the Department of Pharmacology, University of Regensburg, Regensburg, Germany, using HPLC methods with photometric detection [ 11 ].…”

Section: Methodsmentioning

confidence: 99%

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Measurement of soft tissue drug concentrations in morbidly obese and non-obese patients – A prospective, parallel group, open-labeled, controlled, phase IV, single center clinical trial

Simon

Petroff

Dorn

et al. 2019

Contemporary Clinical Trials Communications

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Background Pharmacokinetic (PK) and pharmacodynamic (PD) data on perioperative antibiotic prophylaxis or antibiotic therapy are rare in patients suffering from morbid obesity. Furthermore, dosing regimens should be based on PK/PD models that ensure effective antibiotic exposure not in plasma, but primarily at the site of infection, mostly in the interstitial fluid (ISF). The aim of this trial is to investigate whether current dosing regimens of various antibiotics lead to effective concentrations in the ISF of morbidly obese patients. Methods We designed a prospective, parallel group, open-labeled, controlled single center trial to investigate the plasma and tissue pharmacokinetics of the antibiotics linezolid, meropenem, tigecycline, piperacillin/tazobactam, fosfomcyine, cefazolin, metronidazole and as secondary aim the analgesics metamizole and acetaminophen. Inclusion criteria comprise body mass index ≥35 kg/m 2 for obese or between 18.5 and 30 kg/m 2 for non-obese patients scheduled for elective abdominal surgery. For PK analysis, blood and microdialysate samples of subcutaneous tissue were collected 0–8 h after study drug administration. The primary endpoint is to investigate a possible dependency of the area-under-the-curve (AUC 0-8 ) in the interstitial fluid on body weight and obesity with population based pharmacokinetic analysis. Discussion Inadequate dosing regimes of antibiotics may be a relevant factor for morbidity and mortality of patients, as well as for the development of bacterial antibiotic resistance. The measurement of plasma and tissue concentrations will provide information necessary for PK/PD-modelling. These data about antibiotic PK/PDcharacteristics in soft tissue and their dependence on weight should help to develop weight-dependent models for calculation of patient's individual doses of different antibiotics. Trial registration EU clinical trials register (EudraCT-No. 2012-004383-22) and German Clinical trials Register (DRKS00004776);

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Measurement of soft tissue drug concentrations in morbidly obese and non-obese patients – A prospective, parallel group, open-labeled, controlled, phase IV, single center clinical trial

Simon

Petroff

Dorn

et al. 2019

Contemporary Clinical Trials Communications

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“…The concentration of the drug in the ISF was then given by C ISF = C µD × 100/relative recovery [24]. Due to the constant perfusate flow through the catheter and hence incomplete equilibrium at the membrane, only a fraction of the actual ISF drug concentration will be 'recovered' in the microdialysate, which is referred to as 'relative recovery' [26].…”

Section: Microdialysismentioning

confidence: 99%

“…Linezolid was determined by a validated HPLC-UV method, as described previously [26,27]. Sample treatment for the determination of total linezolid included the deproteinization of plasma with perchloric acid, and microdialysate was directly injected into the column.…”

Section: Drug Analysismentioning

confidence: 99%

Linezolid Concentrations in Plasma and Subcutaneous Tissue are Reduced in Obese Patients, Resulting in a Higher Risk of Underdosing in Critically Ill Patients: A Controlled Clinical Pharmacokinetic Study

Simon

Busse

Petroff

et al. 2020

JCM

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Background: Linezolid is used for the treatment of soft tissue infections in critically ill patients. However, data for characterizing the pharmacokinetics (PK) and assessing whether effective concentrations are reached at the target site are lacking. We hypothesized that current dosing regimens do not lead to effective concentrations in the plasma and interstitial fluid (ISF) of subcutaneous tissue in obese patients. Methods: As a controlled clinical model, critically ill obese and non-obese patients undergoing intra-abdominal surgery received 600 mg linezolid as a single infusion. Concentrations in the plasma and microdialysate from the ISF of subcutaneous tissue were determined up to 8 h after dosing. Pharmacokinetic analysis was performed by non-compartmental methods. As a therapeutic target, we used f AUC/MIC > 80. Results: Fifteen obese (BMI: 48.7 ± 11.2 kg/m 2 ) and 15 non-obese (23.9 ± 2.1 kg/m 2 ) patients were analyzed. AUC 0-8 in ISF decreased by −1.69 mg*h/L (95% CI: −2.59 to −0.79, p < 0.001) for every 10 kg increase in weight. PK in obese patients were characterized by lower maximal plasma concentrations (median 3.8 vs. 8.3 mg/L, p < 0.001) and a higher volume of distribution (41.0 vs. 30.8 L, p < 0.001), and the therapeutic target was not reached for MIC ≥ 1 mg/L in ISF and ≥ 2 mg/L in plasma. Conclusions: Increasing the weight led to a decrease of linezolid concentrations in the plasma and subcutaneous tissue. The current dosing regimen does not seem to produce sufficient concentrations to kill bacteria with MIC ≥ 2 mg/L, especially as empirical antimicrobial therapy in critically ill obese patients.

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Antiinfektive Therapie bei Adipositas – „einfach das Doppelte?“

Simon

2020

Anaesthesist

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Drug combinations and impact of experimental conditions on relative recovery in in vitro microdialysis investigations

Cited by 14 publications

References 17 publications

Measurement of soft tissue drug concentrations in morbidly obese and non-obese patients – A prospective, parallel group, open-labeled, controlled, phase IV, single center clinical trial

Measurement of soft tissue drug concentrations in morbidly obese and non-obese patients – A prospective, parallel group, open-labeled, controlled, phase IV, single center clinical trial

Linezolid Concentrations in Plasma and Subcutaneous Tissue are Reduced in Obese Patients, Resulting in a Higher Risk of Underdosing in Critically Ill Patients: A Controlled Clinical Pharmacokinetic Study

Antiinfektive Therapie bei Adipositas – „einfach das Doppelte?“

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