Prediction of Drug-drug Interactions

Predicting Drug-drug Interactions Using the Simcyp Simulator

Unmanageable drug-drug interactions have led to the withdrawal of numerous drugs from the market. Many of these interactions involve inhibition and, to a lesser extent, induction of drug metabolizing enzymes. Consequently, the ability to predict metabolically-based drug-drug interactions (mDDI) early in the drug development process is essential.

The sophisticated population-based PBPK models within the Simcyp® Simulator allow investigation of metabolic drug-drug interactions due to:

  • Competitive enzyme inhibition
  • Mechanism-based inhibition
  • Enzyme induction
  • Multiple drug-drug interactions

Interactions involving CYP suppression and drug transporters can also be simulated.

The Simcyp Simulator can accurately predict DDIs in relevant patient populations. This is done at two levels–the prediction of net change in exposure, and prediction of the change in the full plasma drug concentration–time profile.

The Simcyp Population-based Simulator allows users to identify individuals at greatest risk at a very early stage in drug development.

Competitive Enzyme Inhibition

The simplest form of enzyme inhibition is where the inhibitor drug occupies the active site of the enzyme, blocking the metabolism of the ‘victim’ drug. Drugs can also have an inhibitory effect on influx and efflux transporter proteins in the liver and intestine. These effects can be simulated within the Simcyp Simulator.

The ability to perform the simulation with different numbers of virtual subjects allows an assessment of the variability in the extent of the interaction and the number of subjects needed to power a clinical study.

It is also possible to model complex study designs (eg, involving dose-staggering of the interacting drugs) and to predict changes in the full plasma drug concentration–time profile. Furthermore, the Advanced Dissolution, Absorption and Metabolism (ADAM) model can be applied to the main inhibitor to predict metabolic drug-drug interactions in the intestine.

Mechanism-Based Enzyme Inhibition

Mechanism (or time) -based enzyme inhibition is associated with irreversible or quasi-irreversible loss of enzyme function, requiring synthesis of new enzyme before activity is restored.

The consequences of mechanism-based inhibition are:

  • Auto-inhibition of the clearance of the inactivator itself
  • Prolonged inhibition of the clearance of other drugs that share the same enzyme

There may also be serious immunotoxicological consequences if a reactive intermediate is covalently bound to the enzyme. Therefore, screening of new compounds for mechanism-based enzyme inhibition is now standard practice within the pharmaceutical industry.

Enzyme Induction

Many of the enzymes involved in drug metabolism may be up-regulated by exposure to drugs and environmental chemicals leading to increased rates of metabolism. This phenomenon is known as enzyme induction.

The Simcyp Simulator can predict the extent of in vivo induction from in vitro data using a concentration-dependent induction model. Accordingly, it can be used to assess the inducing potential of new chemical entities at clinically relevant concentrations within virtual populations.

The Simcyp induction model is highly flexible and can handle different in vitro experimental designs of varying complexity.

For compounds that both inhibit and induce CYPs, predicting the net effect in vivo is particularly challenging. Simcyp Simulator models allow this to be done in relevant virtual populations purely from in vitro data. An understanding of the change in the direction (net inhibition to net induction) of an interaction with time is essential for the design of multidose experimental studies needed to inform dosage recommendations when the extent of interaction is time-dependent.

Multiple Metabolic Drug-drug Interactions

Regulators have expressed concern about DDIs due to polypharmacy. For example, what would happen in a patient receiving five weak enzyme inhibitors concurrently?  The outcome is not necessarily additive and, clearly, the number of in vivo studies that would be necessary to evaluate all possible permutations of co-administered drugs is prohibitive.

However, simulations using the Simcyp Simulator can help to define ‘worst case’ combinations for further study.

“Before investigating the impact of multiple inhibitors on drug exposure, it is important to…estimate the combined effect of the inhibitors based on computer simulation”.  – FDA Guidance for Industry on Drug Interaction Studies (September 2006).

The current version of the Simcyp Simulator allows investigation of mutual interactions between up to four compounds (plus two metabolites).

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