In vivo CYP3A4 activity does not predict the magnitude of interaction between itraconazole and tacrolimus from an...

The magnitude of interaction between the CYP3A4 substrate tacrolimus and various CYP3A4 inhibitors is highly unpredictable. We investigated whether an individual's baseline in vivo CYP3A4 activity, assessed using the oral midazolam (MDZ) probe, could be used to predict the magnitude of drug-drug interaction between tacrolimus and the potent CYP3A4 inhibitor itraconazole. In a prospective single-arm open-label study, 16 healthy volunteers were administered single doses of MDZ and tacrolimus before and after a 4-day course of itraconazole. Itraconazole treatment resulted in a 9.0-fold decrease in MDZ apparent oral clearance (CL/F) and a 3.3-fold decrease in tacrolimus CL/F (P < 0.001 for each). MDZ CL/F and tacrolimus CL/F were positively correlated both at baseline (r = 0.582, P = 0.018) and after itraconazole (r = 0.811, P < 0.001). Furthermore, baseline MDZ CL/F was positively correlated to the fold change in MDZ CL/F resulting from CYP3A4 inhibition (r = 0.759, P = 0.001). However, no predictors of change in tacrolimus CL/F resulting from CYP3A4 inhibition were identified, including baseline MDZ CL/F (P = 0.453), baseline tacrolimus CL/F (P = 0.759) and fold change in MDZ CL/F between both phases (P = 0.274). In conclusion, baseline oral MDZ clearance does not predict the magnitude of interaction between tacrolimus and itraconazole.