Cytochrome P450 time-dependent inhibition and induction: advances in assays, risk analysis and modelling

Abstract

Introduction: It is widely accepted that current practice of polypharmacy inevitably increases the incidence of drug–drug interactions (DDIs). Serious DDIs are a major liability for new molecular entities entering the pharmaceutical market. Various strategies are employed to avoid problematic compounds for clinical development. Progress made with reversible CYP DDIs has prompted a switch to study and model time-dependent inhibition and induction interactions.

Areas covered: An overview of popular experimental practices is presented with discussion of techniques and algorithms used to analyse the clinical DDI risk. Emphasis is placed on the transition from early, simple static equations, via more complex net mechanistic, static models to dynamic approaches involving multiple perpetrators and metabolites, simultaneous inhibition and induction.

Expert opinion: Inclusion of the more conservative terms for parameters required for DDI evaluation may eliminate promising chemical space, encourages poor practice and hampers innovation. Breakthroughs have originated from understanding of ‘outliers’ from such analyses where CYP enzyme–transporter interplay may be involved. The role of key transporters in drug disposition is firmly established as the chemistry required to address new targets deviates from traditional ‘drug-like’ space. Attempts to model more complex interactions for substrates of both CYP enzymes and drug transporters are still in their infancy and will benefit from dynamic modelling.

Keywords:

• cytochrome P450
• drug interactions
• induction
• inhibition
• time-dependent

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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