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.