Clinical Approaches to Decipher Complex Drug-Drug Interactions
Presented by: Janne Backman, Ph.D., M.D., University of Helsinki
Tuesday, May 5, 2020
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Drug-drug interactions (DDIs) can have adverse, even hazardous clinical consequences. To avoid market withdrawals or restrictions in the clinical usage of drugs, pharmaceutical companies are attempting to avoid harmful DDIs early in drug development and regulatory agencies have published recommendations to guide DDI studies. Simple DDIs based on a single pharmacokinetic mechanism can already be predicted with great confidence, but there are many challenges to predict DDIs involving multiple simultaneous mechanisms. Therefore, increasing attention is given to complex DDIs in the scientific community.
Although the term “complex DDI” is not clearly defined, and could include DDIs with both pharmacokinetic and pharmacodynamic mechanisms, it is most often used to describe pharmacokinetic DDIs with multiple simultaneous mechanisms and pathways (Varma et al. 2015). Such DDIs include, for example, those with simultaneous involvement of transporters and drug metabolizing enzymes, simultaneous inhibition and induction or even autoinhibition and autoinduction of metabolism, time-dependent inhibition and involvement of major drug metabolites. In addition, involvement of multiple perpetrator drugs gene-drug and disease-drug interactions can be regarded as a complex DDI. For instance, complex DDIs include those involving the antidiabetic repaglinide (Niemi et al. 2003), a substrate for CYP2C8, CYP3A4 and OATP1B1, and gemfibrozil and clopidogrel, whose glucuronide metabolites are mechanism-based inhibitors of CYP2C8 and direct inhibitors of OATP1B1 (Bergmann et al. 2015, Floyd et al. 2012, Itkonen et al. 2015, Ogilvie et al. 2006, Tornio et al. 2014). In this talk, different types of complex interactions will be reviewed, with examples of potentially hazardous complex DDIs and clinical study designs that can be used to decipher their mechanisms and clinical consequences.
About the Speaker:
||Janne T. Backman (born in 1968) studied medicine at the University of Helsinki in Finland, and graduated in 1994. He completed his PhD in 1996 at the University of Helsinki, after which he worked as a post-doctoral research fellow at the Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany, until end of 1997. After returning to Finland, he worked in various positions, including clinical practice, and received a specialist degree in clinical pharmacology in 2001. Since 2014, he has been Professor in Clinical Pharmacology and Individual Medicine at Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Finland.|
Apart from teaching clinical pharmacology to medical students, Dr. Backman is responsible for directing the training program for medical specialists in clinical pharmacology and he is vice director of the Doctoral Program for Drug Research at his university. He has supervised 14 PhD theses. He is the president of The Finnish Society of Clinical Pharmacology (FSCP), and has served 4 years as the treasurer of European Association for Clinical Pharmacology and Therapeutics (EACPT). In 2019, he was nominated as a member of the Finnish Academy of Science and Letters for his merits in his scientific discipline.
Dr. Backman's research interests have included drug–drug interactions, drug metabolism, pharmacogenetics, and other sources of individual variability in pharmacokinetics. Most recently, he has been particularly interested in the clinical significance of complex drug-drug interactions, the role of metabolites as inhibitors of drug metabolism, CYP2C8-mediated drug-drug interactions, and interactions involving kinase inhibitors. He has published more than 170 original articles in international peer-reviewed journals, and his H-index is 61 (Scopus, March 1, 2020). In 2015, he was listed as Thomson Reuters Highly Cited Researcher in “Pharmacology and Toxicology”.