In vivo microdialysis in pharmacological studies of antibacterial agents in the brain

Notkina, Natalia; Dahyot‐Fizelier, Claire; Gupta, Arun Kumar

doi:10.1093/bja/aes216

Cited by 17 publications

(9 citation statements)

References 36 publications

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“…Microdialysis can thus provide important evidence as to whether the antibiotic minimum inhibitory concentration (MIC) can be attained in the brain. Treatment of cerebral infections is still a challenge, and that some of the dosages of antibacterial drugs may be inadequate for more resistant bacteria despite seemingly 'effective' plasma concentrations (79). Cerebral microdialysis pharmacokinetics studies of antibiotics can thus form the basis of more accurate dosage for patients with CNS infections (79).…”

Section: Microdialysis To Monitor Drug Pharmacokinetics In the Cnsmentioning

confidence: 99%

Microdialysis Monitoring in Clinical Traumatic Brain Injury and Its Role in Neuroprotective Drug Development

Thelin

Carpenter

Hutchinson

et al. 2017

AAPS J

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Abstract.Injuries to the central nervous system continue to be vast contributors to morbidity and mortality; specifically, traumatic brain injury (TBI) is the most common cause of death during the first four decades of life. Several modalities are used to monitor patients suffering from TBI in order to prevent detrimental secondary injuries. The microdialysis (MD) technique, introduced during the 1990s, presents the treating physician with a robust monitoring tool for brain chemistry in addition to conventional intracranial pressure monitoring. Nevertheless, some limitations remain, such as limited spatial resolution. Moreover, while there have been several attempts to develop new potential pharmacological therapies in TBI, there are currently no available drugs which have shown clinical efficacy that targets the underlying pathophysiology, despite various trials investigating a plethora of pharmaceuticals. Specifically in the brain, MD is able to demonstrate penetration of the drug through the blood-brain barrier into the brain extracellular space at potential site of action. In addition, the downstream effects of drug action can be monitored directly. In the future, clinical MD, together with other monitoring modalities, can identify specific pathological substrates which require tailored treatment strategies for patients suffering from TBI.

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Section: Microdialysis To Monitor Drug Pharmacokinetics In the Cnsmentioning

confidence: 99%

Microdialysis Monitoring in Clinical Traumatic Brain Injury and Its Role in Neuroprotective Drug Development

Thelin

Carpenter

Hutchinson

et al. 2017

AAPS J

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“…Microdialysis can thus provide important evidence as to whether sufficient concentrations can be attained in brain to kill bacteria, although with the caveat that BBB permeability may vary considerably between patients. In their recent review, Notkina et al [28] have remarked that treatment of cerebral infections is still a challenge and that some of the dosages of antibacterial drugs may be inadequate for more resistant bacteria despite seemingly effective plasma concentrations. Cerebral microdialysis studies with pharmacokinetic/pharmacodynamic modelling allow prediction of effectiveness of altered drug regimens and can thus form the basis of more accurate dosage for patients with CNS infections [28].…”

Section: Cerebral Microdialysis In Clinical Studies Of Drugsmentioning

confidence: 99%

Cerebral microdialysis in clinical studies of drugs: pharmacokinetic applications

Shannon

Carpenter

Guilfoyle

et al. 2013

J Pharmacokinet Pharmacodyn

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The ability to deliver drug molecules effectively across the blood–brain barrier into the brain is important in the development of central nervous system (CNS) therapies. Cerebral microdialysis is the only existing technique for sampling molecules from the brain extracellular fluid (ECF; also termed interstitial fluid), the compartment to which the astrocytes and neurones are directly exposed. Plasma levels of drugs are often poor predictors of CNS activity. While cerebrospinal fluid (CSF) levels of drugs are often used as evidence of delivery of drug to brain, the CSF is a different compartment to the ECF. The continuous nature of microdialysis sampling of the ECF is ideal for pharmacokinetic (PK) studies, and can give valuable PK information of variations with time in drug concentrations of brain ECF versus plasma. The microdialysis technique needs careful calibration for relative recovery (extraction efficiency) of the drug if absolute quantification is required. Besides the drug, other molecules can be analysed in the microdialysates for information on downstream targets and/or energy metabolism in the brain. Cerebral microdialysis is an invasive technique, so is only useable in patients requiring neurocritical care, neurosurgery or brain biopsy. Application of results to wider patient populations, and to those with different pathologies or degrees of pathology, obviously demands caution. Nevertheless, microdialysis data can provide valuable guidelines for designing CNS therapies, and play an important role in small phase II clinical trials. In this review, we focus on the role of cerebral microdialysis in recent clinical studies of antimicrobial agents, drugs for tumour therapy, neuroprotective agents and anticonvulsants.

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“…A significant challenge is the evaluation of model predictions with the human PBPK model, since observed brain concentrations are rarely obtainable. There are few examples of brain microdialysis and CSF sampling to determine drug pharmacokinetics due to the invasive nature of these techniques, and as such, they are only carried out on patients in specific disease states such as brain tumours, or acute brain injury (124). The most common non-invasive technique to assess the brain distribution of drugs in human is by imaging of radio-labelled drug.…”

Section: Part 3: Translational Approaches For Human Predictionsmentioning

confidence: 99%

Physiologically Based Pharmacokinetic Modelling of Drug Penetration Across the Blood–Brain Barrier—Towards a Mechanistic IVIVE-Based Approach

Ball

Bouzom

Scherrmann

et al. 2013

AAPS J

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Predicting the penetration of drugs across the human blood-brain barrier (BBB) is a significant challenge during their development. A variety of in vitro systems representing the BBB have been described, but the optimal use of these data in terms of extrapolation to human unbound brain concentration profiles remains to be fully exploited. Physiologically based pharmacokinetic (PBPK) modelling of drug disposition in the central nervous system (CNS) currently consists of fitting preclinical in vivo data to compartmental models in order to estimate the permeability and efflux of drugs across the BBB. The increasingly popular approach of using in vitro-in vivo extrapolation (IVIVE) to generate PBPK model input parameters could provide a more mechanistic basis for the interspecies translation of preclinical models of the CNS. However, a major hurdle exists in verifying these predictions with observed data, since human brain concentrations can't be directly measured. Therefore a combination of IVIVE-based and empirical modelling approaches based on preclinical data are currently required. In this review, we summarise the existing PBPK models of the CNS in the literature, and we evaluate the current opportunities and limitations of potential IVIVE strategies for PBPK modelling of BBB penetration.

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In vivo microdialysis in pharmacological studies of antibacterial agents in the brain

Cited by 17 publications

References 36 publications

Microdialysis Monitoring in Clinical Traumatic Brain Injury and Its Role in Neuroprotective Drug Development

Microdialysis Monitoring in Clinical Traumatic Brain Injury and Its Role in Neuroprotective Drug Development

Cerebral microdialysis in clinical studies of drugs: pharmacokinetic applications

Physiologically Based Pharmacokinetic Modelling of Drug Penetration Across the Blood–Brain Barrier—Towards a Mechanistic IVIVE-Based Approach

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