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Multiple metabolic drug-drug interactions
Since polypharmacy is common, regulators have expressed concern about the co-administration of more than two drugs with regard to drug interactions. For example, what would happen in a patient receiving 5 weak enzyme inhibitors at the same time? The outcome is not necessarily additive and, clearly, the number of actual in vivo studies that would be necessary to evaluate all possible permutations of co-administered drugs is prohibitive.
However, simulations using Simcyp can help to define ‘worst case’ combinations for further study (Figure 14) (Rostami-Hodjegan & Tucker, 2004).
“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 4 compounds (plus 2 metabolites).
Figure 14. Simulations of the impact of the combined effect of 2 weak enzyme inhibitors.