SFKBIF103U Drug Delivery to the Central Nervous System (CNS

Volume 2018/2019
Education

BSc Programme in Pharmacy - elective

Content

Initial lectures will give an overview of the history of brain drug delivery. This will be followed by lectures describing brain anatomy, blood-brain and blood CSF barriers. The physicochemical parameters necessary for brain permeation will be treated in great detail, along with a detailed description of the tissue barrier properties. Brain efflux transporters and their substrate profiles will be dealt with. This will be followed by a detailed treatise of brain uptake transporters, brain drug metabolism and the use of in vitro modeling in predicting CNS drug uptake. The pharmacokinetic concepts specific for brain delivery will be introduced, including the importance of estimating protein binding in plasma and brain tissue. Single dosing and steady-state concepts will be covered. The translational aspects of preclinical studies will discussed, with focus on the low predictability between animal models and human patients. The pathology of some common brain diseases (stroke, Alzheimer's disease and brain cancer) will be treated, and the implications for drug delivery for a given disease will be discussed.  Novel drug delivery systems for CNS treatment will be covered, i.e. antibody constructs and Fab fragment design, as well as designer peptide approaches and targeted liposomes. The course will be concluded with case stories describing both successful development of CNS drugs, as well as failures, to be used as integrative examples of the parameters which may make a new treatment fly or fail.

Learning Outcome

The main objective of the course is to introduce the basic concepts and methods in CNS drug delivery and provide an overview of the different approaches used by academia and industry in the field. The course consists of a number of lectures, discussion classes and a written assignment. The course is recommended for students who upon completion of their studies will be employed in academic or industrial research or regulatory environments where knowledge of CNS drug delivery is essential, however the course will also give a solid understanding of delivery and ADME processes which reach beyond CNS delivery.

At the end of the course the students are expected to be able to:

Knowledge

  • describe how physicochemical properties of a small molecule API relates to its likelihood to become a CNS drug compound
  • describe the methods available for estimating brain efflux properties
  • describe the molecular properties of the blood-brain barrier
  • define the rate limiting steps in brain drug delivery
  • demonstrate knowledge on how brain pathologies may alter brain drug disposition
  • explain how CNS drug candidates are tested in vitro.
  • identify the pharmacokinetics of drug compound disposition to the brain
  • reflect on the concept and importance of free-versus bound drug compound concentrations in brain and blood.

 

Skills

  • deduct if a drug compound is suited for CNS delivery according to its physicochemical properties.
  • use Michaelis-Menten kinetics to estimate transporter activity and inhibition (using Excel, Graph-Pad or similar)
  • interpret data from in-vitro test models for CNS barrier permeability and efflux, using permeability estimates and efflux ratio's (Excel/GraphPad)

 

Competencies

  • integrate knowledge from organic chemistry, formulation, physical chemistry, pharmacokinetics, tissue barrier biology and pharmacology in order to design rational formulations for brain drug delivery.
  • apply simple mathematical models for predicting and describing brain drug uptake and efflux from both in vivo and in vitro studies.
Literature

The course will be based on chapters from the following textbooks:

  • "Drug Delivery to the Brain - Physiological Concepts, Methodologies and Approaches" by Hammarlund-Udenaes, Margareta, de Lange, Elizabeth, Thorne, Robert G. (Eds.) AAPS Advances in the Pharmaceutical Sciences Series.
  • “Diseases of the Nervous System” by Harald Sontheimer (Academic Press).
  • “Molecular Biopharmaceutics - Aspects of Drug Characterisation, Drug Delivery and Dosage Form Evaluation” by Bente Steffansen, Birger Brodin and Carsten Uhd Nielsen(Eds.) (Pharmaceutical Press).
Teaching is based on the assumption that the students have acquired knowledge, skills and competences corresponding to those obtained by completion of the first five semesters of the BSc Programme in Pharmacy.
Lectures and discussion classes, where students present selected parts of the curriculum to each other.
  • Category
  • Hours
  • Exam
  • 2
  • Lectures
  • 20
  • Preparation
  • 140
  • Theory exercises
  • 44
  • Total
  • 206
Oral
Collective
Continuous feedback during the course of the semester
Peer feedback (Students give each other feedback)
Credit
7,5 ECTS
Type of assessment
Written examination, 2 hours under invigilation
The examination will deal with selected broad questions regarding brain drug delivery. Background material will be the curriculum (selected chapters from the course textbooks).
Aid
All aids allowed

There is access to the following at the exam on Peter Bangs Vej:

  • Office (Word, Excel, Onenote and Powerpoint)
  • IO2 – the digital pen
  • Panoramic Viewer
  • Paint
  • Calculator – Windows' own
  • R – Statistical programme
  • ITX MC – multiple choice programme
  • Adobe reader
  • USB access – for usb stick with notes etc.
  • Programmes for assisting with dyslexia
Marking scale
7-point grading scale
Censorship form
No external censorship
Criteria for exam assesment

To achieve the grade 12 the student must be able to:

Knowledge

  • describe how physicochemical properties of a small molecule API relates to its likelihood to become a CNS drug compound
  • describe the methods available for estimating brain efflux properties
  • describe the molecular properties of the blood-brain barrier
  • define the rate limiting steps in brain drug delivery
  • demonstrate knowledge on how brain pathologies may alter brain drug disposition
  • explain how CNS drug candidates are tested in vitro.
  • identify the pharmacokinetics of drug compound disposition to the brain
  • reflect on the concept and importance of free-versus bound drug compound concentrations in brain and blood.

 

Skills

  • deduct if a drug compound is suited for CNS delivery according to its physicochemical properties.
  • use Michaelis-Menten kinetics to estimate transporter activity and inhibition (using Excel, Graph-Pad or similar)
  • interpret data from in-vitro test models for CNS barrier permeability and efflux, using permeability estimates and efflux ratio's (Excell)

 

Competencies

  • integrate knowledge from organic chemistry, formulation, physical chemistry, pharmacokinetics, tissue barrier biology and pharmacology in order to design rational formulations for brain drug delivery.
  • apply simple mathematical models for predicting and describing brain drug uptake and efflux from both in vivo and in vitro studies.