Computational modeling approaches and regulatory pathways for drug combinations
Lucas Fillinger, Samuel Walter, Matthias Ley, Kinga Kęska, Leily Ghasemi Dehkordi, Klaus Kratochwill, Paul Perco · Drug Discovery Today · 2025
• Drug combinations offer therapeutic and economic advantages over monotherapies. • Computational modeling has become integral to the development of drug combinations. • Network models are powerful tools that can be used to identify mechanistically compatible drugs. • Drug combination approvals have been steadily increasing over the decades since 1943. • Regulatory harmonization across markets will reduce development time and costs. Drug combinations offer several advantages over monotherapies, but identifying effective drug combinations while avoiding adverse effects is a major challenge. Computational network models are particularly useful for identifying mechanistically compatible drug combinations and generating hypotheses about their mechanisms of action. Here, we discuss the advantages and challenges of in silico discovery approaches for drug combinations. Obtaining regulatory approval during later stages of product development can be more complex for drug combinations than for single drugs. The regulatory pathway is mainly determined by the approval status of the individual compounds included in a combination. We provide an overview of the regulatory guidelines for drug combination development and discuss trends from previous approvals.