Pawel is an assoc prof (docent) within preclinical drug development at the Uppsala University, with over 20 years of post-graduate academic and industrial experience within the area of drug metabolism (DM), pharmacokinetics (PK) and physiologically based pharmacokinetics (PBPK).
Pawel gained his PhD degree in genetic toxicology at the University of Bremen, Germany in 1996. After a 2-year postdoctoral position at the Centre for Nutrition and Toxicology (CNT), Karolinska Institutet, Sweden Pawel continued his career within the department of DMPK at Pharmacia & Upjohn AB. In 2001 Pawel joined Biovitrum AB and worked as senior research scientist and DMPK project coordinator. In 2006 Pawel started at the AstraZeneca Clinical Pharmacology & DMPK department as a principal scientist working with DMPK and PBPK related items in development projects within the CNS therapeutic area.
Since 2014 Pawel is leading the Uppsala Drug Optimization and Pharmaceutical Profiling local platform at the Department of Pharmacy, Uppsala University, Sweden and the ADMEoT facility a national infrastructure within the SciLifeLab Drug Discovery and Development Platform DDD. Thus, Pawel provides strategic and scientific ADME/PK, PBPK simulations and PK/PD modelling support for Swedish academic preclinical drug development programmes within many different therapeutic areas e.g. infectious diseases, oncology and CNS related.
Currently, Pawel is project leader on behalf of DDD within ENABLE2, a national Swedish Gram Negative Antibacterial Engine. Pawel is also academic WP4 leader within IMI, Conception project. The WP4 is responsible for bioanalysis and popPK modelling of the human plasma and breast milk samples from clinical demonstration studies.
OpenTox Virtual Conference 2023
Metabolite identification studies and their role in the drug discovery and development process
Identification of metabolites may be one of the most time-consuming steps during the drug discovery and development process. Recent progress in analytical methods e.g. liquid chromatography (LC) and mass spectrometry (MS) enables such studies to be performed at an early stage and continues over the whole drug development process.
At the early drug discovery stage, the metabolite identification studies help to identify the metabolic “soft-spots” of molecules and thus guide the chemistry program in order to optimize high clearance compounds to more stable candidate drugs (CD). Additionally, such studies elucidate the individual variability in metabolism which often help to explain variations in candidate drug response.
The outcome of the metabolite identification studies is also detection of metabolites that could be pharmacologically active and contribute to the efficacy of the CD, for IP protection, but also detection of compounds that form reactive intermediates and/or toxic metabolites that could cause adverse effects. Such information is critical to have at an early stage for a successful drug discovery program.
The Metabolite in Safety Testing (MIST) guidance describes how the metabolites should be tested and compared between the species used in the toxicological studies and human. Thus, the metabolite identification studies are also important to select and justify animal species used in toxicological studies.
Finally, animal and human mass balance studies performed using the 14C-label should confirm and explain any items related to metabolism and elimination of the drug.
In this contribution, we would like to describe the principles and recent strategies used for metabolite identification studies in vitro, early in the drug discovery and development process.