Designing pharmaceutical agents so that they pass the blood-brain barrier and are freely available to interact with receptors is one of the great challenges in CNS drug development. An easy-to-use toolkit has been developed to help overcome this hurdle.
CNS therapy is the second largest therapeutic area in pharmaceuticals. There are tremendous unmet medical needs for CNS disease therapies, however, the discovery of innovative CNS therapy is one of the most challenging tasks facing today’s industry.

CNS discrepancy

In drug development, CNS drug candidates have an 8% success rate and development times of 12-16 years, while non-CNS drugs have an 11% success rate and only ten to 12 years’ development time. This discrepancy is due to the greater complexity of the brain, side effects of centrally acting agents, low predictability of animal models for humans and the high selectivity of the blood-brain barrier, which prevents 98% of all CNS discovery compounds from reaching their targets in the brain. This greatly reduces the number of potential compounds that can become successful CNS agents.

The rate and extent of CNS uptake are key parameters that describe how compounds pass the blood-brain barrier. The rate of drug delivery to the brain is less relevant to drug action within the CNS than the extent of drug delivery, as most drugs are administered on a repeated basis. The efficacy of a CNS drug is mainly dependent on the extent of the uptake and, in particular, of the free concentration of the drug in the brain interstitial fluid. This concentration is determined by the drug’s brain penetration and by the fraction of unbound, pharmacologically active drug in the CNS.

While there are several in vitro methods for estimating the CNS uptake rates, in vitro methods for detecting the extent of the uptake, in particular the extent of the unbound drug, are scarce. As well as in situ dialysis, the only in vitro technique to determine the brain free fraction is microdialysis against brain homogenate. The TRANSIL Brain Absorption assay kit offers a ready-to-use fully quality controlled alternative. The assay determines both the brain/plasma distribution coefficient logBB and the brain free fraction.

Reducing animal trials

Established methods for quantifying the extent of CNS penetration and determination of the free concentration in the brain requires the analysis of the brain tissue and in situ dialysis of the drug with brain probes in live animals. Sovicell’s in vitro assay gives scientists access to the same data, however, in an experiment that lasts less than an hour and requires fewer resources.

Accuracy and ease of use

Studies have shown that the TRANSIL Brain Absorption Kits deliver consistent data for the brain-plasma distribution and the brain free fraction, which compare well with data from in vivo experiments. The average prediction error equals the in vivo measurement error. Sovicell’s kits are easy to handle and require only two minutes’ incubation time. Quantification can be done with all standard procedures including LC/MS, HPLC or UV detection.

Estimating the free concentration of candidate drugs in the brain is key to compound selection in lead optimisation. Sovicell’s assay system delivers accurate and rapid data for the freely available fraction of drugs in the brain and so is an ideal tool that delivers answers that matter in high throughput format. The benefits include:

  • highly predictive in vitro model for logBB and the brain free fraction
  • accurate, reproducible and rapid assay system
  • reduces permeability screening cost by at least 50%.

The TRANSIL Brain Absorption Kit offers a cost-effective solution to estimate the unbound drug concentration in the CNS.
Sovicell has a 15-year tradition supplying ADMET products and services, which enable its customers to rapidly obtain accurate and reproducible pharmacokinetic data about their drug candidates. The TRANSIL technology platform underpins the company’s reliable membrane permeability and protein binding assays.