This is your brain on drugs

Neuroscience is a particularly challenging field in drug development. Complexities in molecular signaling and electrical circuitry make it difficult to understand disease and design treatment. And the blood-brain barrier stands in the way of therapies. Pfizer has developed special techniques to predict how the brain absorbs—and expels—chemical compounds. On Tuesday, December 6, Jennifer Liras, PhD, senior director for neuroscience pharmacokinetics, dynamics and metabolism at Pfizer, shared the details of some of the company’s tactics in a Quadrant industry speaker seminar.

The brain is arguably our most vital organ, and is extremely sensitive to chemicals in its environment. The blood-brain barrier protects the brain from damage by keeping many foreign and natural molecules from entering. It surrounds all blood vessels that feed the brain. It is composed of a single layer of cells, tightly bound together. Molecules in the blood cannot leak between cells, but can pass through the cells to reach the brain. This is called “permeability.” Pfizer, Liras said, uses permeability experiments in the laboratory to predict whether a drug will cross the blood-brain-barrier to reach its therapeutic target in the brain.

Pfizer also considers drug efflux, which is mediated by transporters located in cell membranes. These transporters actively pump foreign molecules out of the brain. Pfizer uses laboratory experiments and animal models to predict efflux.

Drug candidates with high permeability and low efflux are the most promising and predictable. These are ideal for carrying forward to human clinical trials. Drug candidates that do not meet these criteria require further analysis to predict complications. Mathematical modeling provides a powerful tool, Liras said.

Pfizer uses physiologically based pharmacokinetic (PBPK) modeling to further assess drug candidates that are actively transported out of the brain. This technique calculates a predicted drug distribution using mathematical equations that describe physiological and compound-specific parameters. Physiological parameters include surface area, volume and transporter abundance in various tissues. Compound-specific parameters include metabolism, protein binding, permeability, and extent of transporter interaction. Parameters are measured in laboratory assays and animal models and then applied to the mathematical model.

Thus far Pfizer is pleased with the accuracy of their initial attempts at PBPK modeling of blood-brain barrier penetration, Liras said. However, inconsistency between pre-clinical animal models and human systems is troubling. The predictive power of rat and dog models is similar but inferior to non-human primates. Liras wrestles with the issue of balancing accuracy with ethics, she said.

Pfizer continues to refine their PBPK model as a way to identify promising neuroscience drug candidates. In the future they hope to incorporate this algorithm as a computation tool to aid medicinal chemists in the initial stages of drug design.