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Competitive enzyme inhibition
This is the simplest form of enzyme inhibition, 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 Simcyp. Quantitative prediction of the extent of inhibition depends on the inhibitor concentration at the active site [I] and the inhibition constant (ki) defining the interaction.
Within the Simcyp Simulator, the value of [I] is determined from the kinetic properties of the inhibitor and physiological parameters that modulate its input to both gut and liver. Values of ki for all relevant enzymes are obtained from in vitro data, either directly, or from IC50 values (where ki = IC50/2, when the IC50 is determined at a substrate concentration equal to its Km).
The facility to replicate the simulation with different numbers of virtual subjects allows an assessment of the variability in the extent of interaction and the power (number of subjects) needed for an actual in vivo study (Figure 10).
Figure 10. Outcome of simulating the inhibition of CYP2D6 mediated metabolism of dextromethorphan by quinidine. The study was simulated 20 times with 24 different virtual subjects in each run. The black line and blue area represent the median change predicted in a large population and its confidence limits. The squares and associated bars indicate the outcomes of the separate studies (median and confidence limits).
Using the 'PK Profile' option within the Simcyp Simulator, it is possible to model complex study designs (e.g. involving dose-staggering of the interacting drugs) and to predict changes in the full plasma drug concentration – time profile (Figure 11). Furthermore, the capabilities of the Advanced Dissolution, Absorption and Metabolism (ADAM) model can be applied to the main inhibitor providing mechanistic predictions of metabolic drug-drug interactions along the intestine.
Figure 11. Plasma midazolam (MDZ) concentration-time profiles after inhibition by ketoconazole (KTZ) when the relative timing of the administration of the two drugs is varied. The data points are experimental values (pink - control; blue - +KTZ); the solid lines are the profiles predicted by the Simcyp Simulator from in vitro data [Ozdemir et al., 2006, Manchester ISSX].
