Biomedical subjects

Nele Plock

Publications and source records attributed to Nele Plock.

5 recordsLinked to original sources

PubMed2006

Pharmacokinetics of unbound linezolid in plasma and tissue interstitium of critically ill patients after multiple dosing using microdialysis.

The antimicrobial agent linezolid is approved for the treatment of severe infections caused by, e.g., methicillin-resistant Staphylococcus strains. In order to evaluate the penetration of linezolid into the interstitial space fluid (ISF) of subcutaneous adipose tissue and skeletal muscle of the target population, a microdialysis study was performed with 12 patients with sepsis or septic shock after multiple intravenous infusions. Unbound linezolid concentrations were determined for plasma and microdialysates by use of a validated high-performance liquid chromatography method. Individual compartmental pharmacokinetic (PK) analysis was performed using WinNonlin. In vivo microdialysis was found to be feasible for the determination of unbound linezolid concentrations at steady state in the ISF of critically ill patients. On average, linezolid showed good distribution into ISF but with high interindividual variability. A two-compartment model was fitted to unbound concentrations in plasma with a geometric mean distribution volume of 62.9 liters and a mean clearance of 9.18 liters/h at steady state. However, disposition characteristics changed intraindividually within the time course. In addition, an integrated model for simultaneous prediction of concentrations in all matrices was developed and revealed similar results. Based on the model-predicted unbound concentrations in ISF, a scheme of more-frequent daily dosing of linezolid for some critically ill patients might be taken into consideration to avoid subinhibitory unbound concentrations in the infected tissue. The developed integrated model will be a valuable basis for further PK data analysis to explore refined dosing guidelines that achieve effective antimicrobial therapy in all patients by use of the population PK approach.

Acetamides↗

PubMed2006

Pharmacokinetics of enfuvirtide in patients treated in typical routine clinical settings.

Therapeutic drug monitoring (TDM) is gaining importance for improving the success of antiretroviral treatment in human immunodeficiency virus-infected patients. However, enfuvirtide (ENF) concentrations are not regularly determined. The objective of this work was to study the pharmacokinetics (PK) of ENF in patients treated in routine clinical settings, to develop a population PK model describing the concentration-time profile, and to establish PK reference values. A liquid chromatography-tandem mass spectrometry method was developed and applied to serum samples submitted for TDM. A two-compartment model with linear absorption and elimination was fitted to 329 concentrations from 131 patients. The PK model was used for simulations resulting in percentile curves for ENF levels for the full dosing interval. The model predicted that a median concentration of 1,968 ng/ml would be reached 12 h after administration of 90 mg of ENF, and 23% and 58% of patients are expected to have concentrations below 1,000 ng/ml and 2,200 ng/ml, respectively. Both values have been proposed as cutoffs for virological efficacy. The median maximum concentration of drug in serum (Cmax) of 3,943 ng/ml, predicted for 3 h after drug administration, is lower than the Cmax reported previously. We found an enormous interpatient variability at every time point, with concentration spectrums covering >1 log and 52% and 123% interindividual variabilities in the typical clearance and volume of distribution, respectively, in contrast to preexisting PK data. In summary, ENF levels are lower and more variable than expected. Many patients may achieve insufficient concentrations. Further covariate analysis in the population PK model might help to identify factors influencing the variability in ENF concentrations.

Adult↗

PubMed2005

Urea as an endogenous surrogate in human microdialysis to determine relative recovery of drugs: analytics and applications.

During in vivo microdialysis studies time-consuming and laborious bedside calibration methods, e.g. retrodialysis, have to be performed. To reduce the burden on the patient it would be desirable to establish a reliable, time-saving calibration technique to obtain the in vivo recovery describing the relative drug transfer across the membrane of the microdialysis probe. The performed study aimed to evaluate and validate the use of urea as an endogenous reference compound to determine relative in vivo recovery of anti-infectives, e.g. linezolid used herein as model drug. In order to meet the special requirements imposed by microdialysis to measure urea concentrations in very small sample volumes ( approximately 10 microL) a photometric assay in 96-well microtiter plates was established based on the method of Berthelot. Subsequently, concentration- and flow rate-dependence were evaluated in vitro to determine the relative recovery (RR) of urea. Finally, urea and linezolid concentrations in human microdialysis samples were measured. The developed assay was validated according to international guidelines and met all requirements. Relative in vitro recovery was found to be independent from concentration and dependent on flow rate. Subsequently, relative in vivo recovery of urea was correlated with relative in vivo recovery of linezolid obtained by the traditional retrodialysis method. In healthy volunteers, the mean ratio of the relative recovery of linezolid to the relative recovery of urea was 0.6 for the subcutaneous (s.c.: CV 33.4%, n = 48) and 0.7 for the intramuscular probe (i.m.: CV 18.8%, n = 40), respectively. In critically ill patients this ratio was 0.7 for both tissues (s.c.: CV 32.8%, n = 18; i.m.: CV 22.1%, n = 17). Successful calibration of the urea reference technique without the need to use in vitro data will further promote the application of microdialysis in clinical studies especially in critically ill patients, as it reduces the imposed burden to a minimum.

Acetamides↗

PubMed2005

Successful management of discovered pH dependence in vancomycin recovery studies: novel HPLC method for microdialysis and plasma samples.

Vancomycin is a glycopeptide antibiotic approved for the treatment of serious infections or patients allergic to beta-lactams. A rapid HPLC assay using UV detection for the determination in microdialysate and human plasma was developed. After sample preparation, using methanol and trichloroacetic acid for plasma and water for microdialysate, 20 microL were injected and separated on a RP(18) column. Overall, the assay exhibited good precision and accuracy. The diffusion properties of vancomycin investigated in in vitro microdialysis experiments revealed an unfavourable concentration dependence avertable by keeping a constant pH using phosphate buffer as perfusate. The mean relative recoveries were 27.8% [coefficient of variation (CV) 11.1%] and 33.2% (CV 8.3%) for retrodialysis and recovery experiments, respectively. Following characterization of vancomycin in in vitro microdialysis, the developed setting is suitable for application in (pre-)clinical studies.

Chromatography, High Pressure Liquid↗

PubMed2005

Microdialysis--theoretical background and recent implementation in applied life-sciences.

In the past decade microdialysis has become a method of choice in the study of unbound tissue concentrations of both endogenous and exogenous substances. Microdialysis has been shown to offer information about substances directly at the site of action while being well tolerable and safe. The large variety of its field of application has been demonstrated. However, a few challenges have to be met to make this method generally applicable in routine applications. This review will provide an overview over theoretical aspects that have to be considered during the implementation of microdialysis. Moreover, a comparison between microdialysis and other tissue sampling techniques will demonstrate advantages and limitations of the methods mentioned. Subsequently, it will present a critical synopsis of a variety of scientific/biomedical applications of this method with emphasis on the most recent literature, focussing on target tissues while giving examples of substances examined. It is concluded that microdialysis will be of great value in future investigations of pharmacokinetics, pharmacodynamics and in monitoring of disease status and progression.

Animals↗