The mastermind approach to CNS drug therapy: translational prediction of human brain distribution, target site kinetics, and therapeutic effects

Abstract

Despite enormous advances in CNS research, CNS disorders remain the world’s leading cause of disability. This accounts for more hospitalizations and prolonged care than almost all other diseases combined, and indicates a high unmet need for good CNS drugs and drug therapies.Following dosing, not only the chemical properties of the drug and blood–brain barrier (BBB) transport, but also many other processes will ultimately determine brain target site kinetics and consequently the CNS effects. The rate and extent of all these processes are regulated dynamically, and thus condition dependent. Therefore, heterogenious conditions such as species, gender, genetic background, tissue, age, diet, disease, drug treatment etc., result in considerable inter-individual and intra-individual variation, often encountered in CNS drug therapy.For effective therapy, drugs should access the CNS “at the right place, at the right time, and at the right concentration”. To improve CNS therapies and drug development, details of inter-species and inter-condition variations are needed to enable target site pharmacokinetics and associated CNS effects to be translated between species and between disease states. Specifically, such studies need to include information about unbound drug concentrations which drive the effects. To date the only technique that can obtain unbound drug concentrations in brain is microdialysis. This (minimally) invasive technique cannot be readily applied to humans, and we need to rely on translational approaches to predict human brain distribution, target site kinetics, and therapeutic effects of CNS drugs.In this review the term “Mastermind approach” is introduced, for strategic and systematic CNS drug research using advanced preclinical experimental designs and mathematical modeling. In this way, knowledge can be obtained about the contributions and variability of individual processes on the causal path between drug dosing and CNS effect in animals that can be translated to the human situation. On the basis of a few advanced preclinical microdialysis based investigations it will be shown that the “Mastermind approach” has a high potential for the prediction of human CNS drug effects.

Effect of intranasal stem cell administration on the nigrostriatal system in a mouse model of Parkinson's disease

“…One approach for resolving this issue is targeted intranasal (IN) delivery, which is an applicable method used to circumvent BBB rather than attempting to cross it (13). The nasal passage is the only direct connection between the brain and the external environment.…”

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

“…The knowledge on heterogeneity (variability) in rate and extent of processes between drug dosing and CNS effects is needed to predict the impact of drug-induced and disease-induced perturbations in the biological system. To that end, the integrative 'Mastermind Research Approach' [36] is needed to decipher the interrelationships of processes that govern plasma PK, BBB transport, intra-brain distribution, as well as CNS effects in different conditions.…”

“…This model has been applied to nine compounds with highly different physicochemical properties and demonstrated excellent description of the rat data for all these compounds, and an adequate prediction of human CNS data that were available for acetaminophen and morphine [34]. Here, it should be noted that one microdialysis experiment in a single freely moving animal can provide lots of serial data points, obtained under the same experimental condition of the animal, and thereby revealing the interrelationships of neuro-PK processes [36,37], which in addition is important also for refinement, reduction, and replacement of animal experiments [38].…”

“…Actually, it would be of great added value if neuro-PK and associated PD would be obtained in a single experimental subject or at least single experimental context, as rate and extent of body processes are context dependent (according to the Mastermind Research Approach [36]). To link (neuro-)PK to the physiologic response, PK-PD modeling is often applied.…”

“…The better we will be able to develop predictive models in preclinical studies, the more the number of often extremely costly clinical studies can be reduced. The focus should therefore be on the design of quantitative in vivo animal studies such that translational pharmacology approaches can be applied [25,36,37,61,89], which will be discussed below. In refined animal models, the biomarkers of the effect that can be measured in both animals and human will be particularly useful.…”