Translational Pharmacokinetics and Pharmacodynamics

Our Research

Within the area of translational PKPD we address conversion of pharmacokinetic data from preclinical to the clinical settings. This is strongly needed for optimizing drug discovery processes and promoting efficient treatment of brain and spinal cord diseases as well as prevention of development various adverse events in central and peripheral nervous systems (CNS/PNS). In this regard, the role of biological barriers including blood-tissue (e.g., blood-brain barrier, BBB) and parenchymal cellular barriers. Our vision is to support development of effective CNS disease treatments and safer therapeutics by utilizing translational methods.

Principal investigator: Irena Loryan

Ongoing Projects

Investigation of Drug Transport Mechanisms Across Barriers of CNS for Successful Treatment of CNS Disorders

The blood-brain barrier (BBB) is a key functional and dynamic interface between blood and brain. BBB protects the brain but it is also the major hindrance for successful treatment of CNS disorders. Accumulating evidence indicates that the BBB and the whole neurovascular unit plays an important role in disease etiology and progression and may as such affect drug delivery to the brain. Other CNS barriers such as blood-CSF and blood-spinal cord barriers are sharing some similarities with BBB, yet have also unique characteristics in regard to drug transport. We are interested in brain drug delivery in relation to transport processes of both small and large molecules across the BBB and other CNS barriers. Using the concepts and methodologies developed in the group, we are exploring brain and spinal cord regional drug disposition, including the influence of diseases, with focus on the pharmacologically relevant unbound concentrations.

Unraveling the Pharmacokinetic Mechanisms in the Development and Prevention of Chemotherapy-Induced Peripheral Neuropathy (CIPN)

The overarching goal of a project is to

The overarching goal of a project is to systematically investigate drug-specific CIPN-site pharmacokinetics of several microtubule binding agents (MTAs) and antibody-drug conjugates, to establish the plasma and CIPN-site exposure relationship using data generated in preclinical studies by means of mathematical modeling approach. Specific focus will be on investigation of MTAs-specific innate membrane transport processes of distribution into the key CIPN-sites aiming to explore novel pharmacokinetic mechanisms for development and prevention of CIPN. Investigation of blood biomarkers for diagnostic and monitoring of CIPN are also explored.

Drug development

Our work also emphasizes the importance of bridging the expertise within academia and pharmaceutical industry in order to seek excellence in method development for better therapeutics treating CNS disorders.

Our team has supported drug discovery programs for several CNS and non-CNS targeting drug candidates developed by pharma companies and biotechs.
Our team has unique know-how in the field of brain drug disposition and has developed methods supporting the selection and validation of drug candidates.
We aim to bring our experience drug development programs and make our vision, to enhance the treatment of brain diseases and prevent the development of neurotoxicity, a reality.

Past Projects

1. IMI2 Project IM2PACT: Investigating Mechanisms and Models Predictive of Accessibility of Therapeutics into the brain

A new consortium of 27 international partners from academia, industry, and small and medium enterprises, aims to tackle the unmet challenge of discovery and characterisation of blood-brain barrier targets and transport mechanisms for brain delivery of therapeutics to treat neurodegenerative and metabolic diseases. The blood-brain barrier is a protective layer between the brain’s blood capillaries and the cells that make up brain tissue. This barrier provides a defence against the pathogens and toxins that may be in our blood, allowing very few molecules to pass through. It can also prevent many drugs from passing across into the brain, and this presents a major problem in treating neurological conditions and metabolic diseases, especially when using antibody therapies. On the other hand, several neurological diseases could originate from a dysfunctional blood-brain barrier. The funding from the Innovative Medicines Initiative (IMI) to the IM2PACT consortium will allow this public-private partnership, which includes leading international experts in the field, to facilitate the development of drugs to treat neurological disorders by:

discovering and developing innovative and effective brain transport mechanisms
establishing and characterising blood-brain barrier models with good predictability in health and disease
identifying translational read-outs closer to the pathogenesis of neurodegeneration and mimicking altered blood-brain barrier under disease conditions
in-depth understanding of the biology of the blood-brain barrier and characterisation of various pathophysiological mechanisms across the blood-brain barrier.

IM2PACT will foster the development of disease-modifying treatment in a setting of personalised medicine. For more details visit the web page: http://im2pact.org/about/about-im2pact/

1. IMI2 Project NeuroDeRisk: Neurotoxicity De-Risking in Preclinical Drug Discovery

Neurotoxicity, i.e., any adverse effect on the central nervous system or peripheral nervous system, is a major issue encountered in clinical phases of drug R&D that at the present stage of science and technology is still poorly predicted in the pre-clinical drug candidate assessment. As a part of the EU IMI2-RIA funded consortium NeuroDeRisk (Neurotoxicity De-Risking in Preclinical Drug Discovery) will provide novel validated and integrated tools for improving the preclinical prediction of adverse effects of pharmaceuticals on the nervous system, and thus help to de-risk drug candidates earlier in the R&D phases. Together with EFPIA members Sanofi, Novartis, MSD, Pfizer, UCB, Biopharma, AZ, Fujifilm Cellular Dynamics and a group of leading EU academic institutions, tPKPD will work evaluating pharmacokinetic aspects of the development of drug neurotoxicity.

For more details visit the web page: http://neuroderisk.eu/