Translational aspects of blood–brain barrier transport and central nervous system effects of drugs: From discovery to patients

Abstract

The development of CNS drugs is associated with high failure rates. It is postulated that too much focus has been put on BBB permeability and too little on understanding BBB transport, which is the main limiting factor in drug delivery to the brain. An integrated approach to collecting, understanding, and handling pharmacokinetic-pharmacodynamic information from early discovery stages to the clinic is therefore recommended in order to improve translation to human drug treatment.

Lessons Learned from Alzheimer Disease: Clinical Trials with Negative Outcomes

“…Even if they are the appropriate size, they may be subject to transport out of the CNS, for example, by p‐glycoprotein transport mechanisms . The compound‐excluding mechanisms of the CNS differ in rodent models and in humans; thus, entry into the CNS in animal models does not adequately establish BBB penetration in humans . Tarenflurbil is an example of an AD treatment candidate that had effects on the animal model system of AD but likely did not cross the human BBB in sufficient amounts and failed in clinical trials .…”

“…The CSF levels are a reasonable surrogate of brain levels since brain levels are inaccessible in human studies. Brain accumulation, brain clearance mechanisms, and intracellular entry are not completely resolved by CSF measures and remain a source of uncertainty …”

Pharmacokinetic Properties of Anticancer Agents for the Treatment of Central Nervous System Tumors: Update of the Literature

“…In this manuscript we have highlighted limitations to the different methodologies used to assess the penetration of anticancer agents into the CNS, but due to the complexity of the different barriers, tumor types, and drugs used we cannot provide a recommendation on the “best” methods to assess CNS drug penetration. However, we point the reader to several recently published articles focusing on techniques to determine CNS drug penetration [6, 122–125]. Although each reported technique has different strengths and limitations, CSF sampling remains the most accessible method to estimate unbound drug concentrations in the tumor ECF.…”

“…Although each reported technique has different strengths and limitations, CSF sampling remains the most accessible method to estimate unbound drug concentrations in the tumor ECF. [122]. …”

Novel CNS drug discovery and development approach: model-based integration to predict neuro-pharmacokinetics and pharmacodynamics

“…' CNS drug discovery has been hampered by inadequate understanding or consideration of a number of factors. These include the complexity of brain anatomy and function; the neuro-PK with regard to blood-brain barrier (BBB) transport and intra-brain distribution as well as the measures to study these processes; adequate biomarkers of CNS drug effects (neuro-PD), and the complex nature of CNS diseases [1]. Also, the reductionist view and thereby lack of understanding of the interaction and interdependencies of all these factors have contributed to the high attrition rates of CNS drugs.…”