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In vivo CYP 3A4 activity does not predict the magnitude of interaction between itraconazole and tacrolimus from an extended release formulation
Author(s) -
Vanhove Thomas,
Annaert Pieter,
Knops Noël,
Loor Henriëtte,
Hoon Jan,
Kuypers Dirk R J
Publication year - 2019
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/bcpt.13092
Subject(s) - tacrolimus , itraconazole , cyp3a4 , pharmacology , in vivo , pharmacokinetics , chemistry , drug interaction , calcineurin , oral administration , medicine , metabolism , cytochrome p450 , antifungal , transplantation , biochemistry , biology , microbiology and biotechnology , dermatology
The magnitude of interaction between the CYP 3A4 substrate tacrolimus and various CYP 3A4 inhibitors is highly unpredictable. We investigated whether an individual's baseline in vivo CYP 3A4 activity, assessed using the oral midazolam ( MDZ ) probe, could be used to predict the magnitude of drug–drug interaction between tacrolimus and the potent CYP 3A4 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 CYP 3A4 inhibition ( r = 0.759, P = 0.001). However, no predictors of change in tacrolimus CL /F resulting from CYP 3A4 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.