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Project 3 - Modelling Tissue (lung) Target Exposure

 ESR - Elin Boger 

Aims

The design of drug compounds, formulations or dosage regimens are generally guided by an understanding of the pharmacokinetic-pharmacodynamic (PK/PD) relationships defining how efficacy and/or safety relate to the drug exposure in blood or in the target organs.

Simply put, pharmacokinetics is the study of the body's effect on drugs, whereas pharmacodynamics is the effect of drugs on the body.

Despite the historical success of inhalation based medicines, the understanding of the pharmacokinetic-pharmacodynamic releationships of inhaled drugs are currently hard to evaluate as there are no established methods for assessing the target site concentration of the drug in lung tissue. As such, my PhD project aims to evaluate this concentration by using different experimental methodologies and mathematical modelling.

Supervisor: Markus Fridén, AstraZeneca

Co-Supervisors: Pär Ewing (AstraZeneca), Margereta Hammarlund-Udenaes (UU), Mats Jirstrand (FCC), Mike Chappell (University of Warwick), Neil Evans (University of Warwick)

Project Objectives

  • To develop a mathematical systems pharmacology framework for non-linear processes such as the influence of transporters, protein and tissue binding on the distribution of the compound to the brain based on the specific physico-chemical properties of the drug.
  • Investigate and quantify brain and tissue distribution differences between young vs. old and between healthy vs. disease (Alzheimer's disease) using emerging MALDI imaging techniques combined with more traditional total and unbound concentration measurements in plasma and brain.

Project Update

Since target occupancy is driven by the unbound drug concentration at the target site, occupancy measurements would clarify the PK evaluation following topical administration. We have therefore developed a novel in vivo target occupancy methodology for the glucocorticoid receptor (GR) which allows occupancy to be assessed in the lung and in the spleen, these organs are used as a reference for systemic exposure. This methodology proved to be capable to show the dose-dependence after intravenous (IV) administration of a GR binder.

It has since also been used to study the time profile of target occupancy after both IV administration and dry powder inhalation of GR binders. Mathematical modelling is being applied for assessment of these data and for increasing the understanding of lung pharmacokinetics.

Publications

Conference Papers

  • 5th-7th September 2016: ‘A systems pharmacology approach for prediction of pulmonary and systemic pharmacokinetic and receptor occupancy of inhaled drugs’. QSP-UK, Surrey, UK.
  • 22nd April 2016: Warwick Postgraduate Symposium, Coventry, UK. Oral presentation.

Poster Presentations

  • 18th-20th November 2015: PKUK 2015, Chester, UK. Poster presented.
  • 9th March 2015: Warwick Postgraduate Symposium, Coventry, UK. Poster presented.
  • 17th-18th December 2014: Boger E, Ewing P, Lundqvist A, Chappell M, Evans N, Fridén M. Development of a PBPK model with lung disposition – towards an increased understanding of PK and PK/PD for inhaled drugs. Poster presented at AstraZeneca Modelling and Simulation Symposium; Mölndal, Sweden.
  • 5th-7th November 2014: PKUK 2014, Bath, UK. Poster presented.
  • 7th-9th May 2014: Spring Science Retreat, Mölndal, Sweden. Poster presented.
  • 30th October - 1st November 2013: Pharmacokinetics UK (PKUK), Harrogate, United Kingdom. Poster presented.


Other Presentations

  • 21st August 2015: ‘Target occupancy measurement in the lung: a novel tool to determine lung-selectivity and local target engagement of inhaled drugs.’ Presented at Inhalation Seminar, AstraZeneca, Mölndal, Sweden.
  • 13th August 2015: Chair at Summer Journal Club, Mölndal, Sweden.
  • 15th June 2015: ‘A systems pharmacology approach for quantitative prediction of lung targeting by inhalation.’ Presented at Inhalation Predictive Science, AstraZeneca, Mölndal, Sweden.
  • 12th June 2015: Hands-on lung PBPK modelling in MATLAB. Organized a work-shop for the M&S section at RIA DMPK AstraZeneca, Mölndal, Sweden.
  • 11th June 2015: ‘Thesis seminar: A systems pharmacology approach for quantitative prediction of lung targeting by inhalation’, presentation at AstraZeneca, Mölndal, Sweden.
  • 9th March 2015: Presented research results at School of Engineering Postgraduate Symposium.
  • 5th February 2015: Presentation on PK/PD modelling and inhalation pharmacokinetics for 1st year undergraduate students attending the module ES173: Biomedical Engineering at the University of Warwick.
  • 19th September 2014: ‘Evaluation of lung tissue target site exposure’, presentation at Uppsala University, pharmacometrics and translational PKPD.
  • 10th September 2014: ‘Science topic – Evaluation of lung tissue target site exposure’, presentation at AstraZeneca, RIA DMPK, Mölndal, Sweden.
  • 20th May 2014: ‘Evaluation of lung tissue target exposure to inhaled drugs using modeling of pharmacologic data’, presentation at AstraZeneca, Mölndal, Sweden.
  • 11th April 2014: ‘Pharmacokinetics of inhaled drugs’, presentation at Uppsala University.
  • 11th March 2014: ‘GR occupancy in the lung – time profile studies’, presentation at AstraZeneca, expert panel, Mölndal.
  • 3rd-4th December 2013: ‘Development of a novel pulmonary in vivo target occupancy methodology for the glucocorticoid receptor’, M&S symposium, AstraZeneca, Alderley Park.
  • 9th September 2013: ‘Time profile of target occupancy after inhalation and IV-administration of fluticasone propionate’, presentation at AstraZeneca, RIA DMPK, Mölndal.
  • 23rd August 2013: ‘Time profile of target occupancy after inhalation and IV-administration of fluticasone propionate’, presentation at AstraZeneca, RIA Bioscience, Mölndal.
  • 26th June 2013: ‘GR occupancy in the lung after IV versus DPI administration of fluticasone propionate’, presentation at AstraZeneca, RIA DMPK, Mölndal.


Conferences Attended

  • 5th November 2015: APS Modulating the Pharmacokinetics of Inhaled Drugs, Stevenage, UK.
  • 5th-8th May 2015: Respiratory Drug Delivery Europe 2015, Antibes, France.
  • 17th-18th December 2014: Modelling and Simulation Symposium AstraZeneca Molndal, Sweden.
  • 23rd-25th April 2014: 7th Noordwijkerhout Symposium on Pharmacokinetics, Pharmacodynamics and Systems Pharmacology.
  • 3rd-4th December 2013: AstraZeneca M&S Symposium, Alderley Park, UK.
  • 30th October – 1st November 2013: Pharmacokinetics UK (PKUK),

Awards

  • October 2016: PhD awarded to Elin Boger for her thesis entitled ‘Lung-Targeted Receptor Occupancy by Drug Inhalation: An Experimental and Computational Evaluation’.
  • 22nd April 2016: Best Oral Presentation' (Systems and Information) at the School of Engineering Postgraduate Symposium.
  • 2015: Breakthrough Scientist of the year in the AstraZeneca Science Awards 2015 for her work within the field of inhalation pharmacokinetics.
  • 3rd-4th December 2013: Poster prize for novelty of the work presented at the Astra Zenca Modelling and Simulation Workshop.