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Intracerebral Microdialysis to study the pharmacokinetics of drugs in the brain

Scientists at Leiden University have developed and use a highly sensitive and selective technique to study the pharmacokinetics of drugs in the brain: Intracerebral Microdialysis.

Currently, they provide access to this method and their expertise to external parties, and they are looking for partnerships to improve the method for drug discovery/development settings.

Drug development for central nervous system (CNS) diseases has encountered serious problems with only 9% of compounds that entered Phase 1 studies surviving to launch. Compounds that worked effectively on cloned human proteins and in animal models have been found ineffective in human disease. Reasons for the failure of these CNS drug candidates can, at least in part, be found in inconclusive pharmacokinetic data. In order to have the right drug at the right place at the right time in the right concentrations, the drug properties and pharmacokinetic processes that govern drug concentrations at specific CNS sites must be known, ideally with measurements included on target engagement and on drug effects.

For a long time, monitoring approaches have been searched for that could be used to predict human target site kinetics and (therewith) CNS effects. The blood-brain barrier (BBB) is the main obstacle preventing drugs in the blood stream from entering the brain. Intracerebral microdialysis is the most sensitive method available for studying BBB transport of drugs in vivo. To date, no other technique has been able to obtain such quantitative and time-resolved information on the unbound drug of interest. The technique is based on the constant perfusion of a very small probe, with a tip that consists of a semipermeable membrane (Fig. 1).

Microdialysis in human brain can also be combined with neurosurgical procedures, for example before removal of epileptogenic brain tissue. In such settings microdialysis can also be used to measure brain penetration of drugs, and provides the possibility to determine brain pharmacokinetics in conjunction with resulting biochemical efficacy of therapeutic approaches. However, although it is sensitive, the method currently does have shortcomings that limit its use. The very detailed information obtained is time-consuming to gather and to analyse chemically. Microdialysis is, therefore, currently suitable for and very valuable in academic research but it is less suitable in drug discovery/development settings for studying drug concentrations, where more rapid information is needed. Also, while minimally invasive to the brain of rats, the technique is not widely applicable to human brain. Even the smallest injury to the human brain made by choice should be avoided, if it were not for substantial motifs in benefiting the patient otherwise. Thus, microdialysis has been applied frequently in trauma patients, but for the purpose of drug development, human cerebrospinal fluid (CSF) is still considered the best possible fluid to obtain from humans that approximates unbound drug concentrations in brain extracellular fluid (BrainECF).

Nonetheless, it is questionable how closely CSF concentrations reflect brainECF concentrations in different locations in the brain, in diseases, and for different drugs. In a recent study, the Leiden scientists used a multiple microdialysis probe design in the rat (Fig. 2). This model was able to describe the rat pharmacokinetic data in the different brain compartments adequately. Interestingly, after scaling the physiological parameters to the human values, this model was able to predict available literature data on human lumbar CSF.

Key benefits

  • Highly sensitive and selective method to study the pharmaco-kinetics of unbound drugs in the brain
  • Concentration vs. time monitoring
  • In vivo measuring/sampling, ex vivo analysis

Applications

  • Study BBB transport of drugs in vivo
  • Monitoring local concentrations of drugs and/or metabolites at defined brain loci
  • Lead compound validation

Development stage

  • Optimized for use in animal models
  • Optimization required for drug discovery and/or development

Luris reference number

INV-0806.0379

Patent status

Partnering Opportunities:

  • Outsourcing animal studies of pharmacokinetics of drugs in the brain
  • Co-development of an improved method for drug discovery and/or development settings

Data available on request

Non-confidential and confidential presentations

Further information

Frits Fallaux Senior Knowledge Broker +31-71-527 2517 f.j.fallaux@luris.nl Room number: 1.13