SP740ASSESSMENT OF THE EFFECT OF DRUG FORMULATION ON THE EXTENT OF THE PHARMACOKINETIC INTERACTION BETWEEN VORICONAZOLE AND TACROLIMUS

Abstract

INTRODUCTION AND AIMS: To compare the change in tacrolimus pharmacokinetics during cytochrome P450 3A (CYP3A) inhibition with voriconazole after administration of an immediate-release (PrografVR ) and a prolonged-release formulation (EnvarsusVR ), liberating the drug throughout the gastrointestinal tract including the colon. As exploratory objectives we evaluated whether CYP3A activity (estimated with a midazolam microdose) correlates with the pharmacokinetic changes and assessed the potential impact of the CYP3A5 rs776746 polymorphism on the extent of the interaction. METHOD(S): In an open-label, single-centre, randomized, fixed-sequence, cross-over phase I clinical trial, eighteen healthy male volunteers received a single oral tacrolimus dose (PrografVR or EnvarsusVR , 3 mg each) alone or in combination with voriconazole (VFENDVR , 800 mg one day before tacrolimus administration followed by 400 mg per day for three days). Concentrations were quantified using sensitive validated high performance liquid chromatography methods combined with tandem mass spectrometry (UPLC/MS/MS) methods. Pharmacokinetics were analysed by non-compartmental methods. RESULT(S): The increase in tacrolimus exposure due to voriconazole was approximately 6-fold and was highly variable (1.8 to 19-fold) after PrografVR . The increase after administration of EnvarsusVR was significantly less pronounced (about 2.6-fold, P<0.01) with less variability (1.6 to 4.8-fold). Serious adverse events were not observed. CONCLUSION(S): Drug formulations affecting the site of absorption in the gastrointestinal tract can significantly affect the extent of drug-drug interactions. Prolongedrelease tacrolimus appears to be less susceptible to drug-drug interactions with CYP3A inhibitors. Because of the lower variability, dose recommendation for EnvarsusVR while taking a strong CYP3A inhibitor, such as voriconazole, might be feasible, but therapeutic drug monitoring will still be required.