Pharmacokinetic Model of Drug Interaction of Tacrolimus with Combined Administration of CYP3A4 Inhibitors Voriconazole and Clarithromycin After Bone Marrow Transplantation.

Background and objectives: A pharmacokinetic model has been developed to quantify the drug-drug interactions of tacrolimus with concentration-dependent inhibition of cytochrome P450 (CYP) 3A4 from voriconazole and clarithromycin based on the CYP3A5 and CYP2C19 genotypes.

Methods: This retrospective study recruited unrelated bone marrow transplant recipients receiving oral tacrolimus concomitantly with voriconazole and clarithromycin. The published population pharmacokinetic model that implemented genotypes of CYP3A5 (tacrolimus) and CYP2C19 (voriconazole) was integrated. The tested CYP3A4 inhibition models (Sigmoid efficacy maximum [E_max], E_max, log-linear, and linear) were a function of competitive inhibition of voriconazole and mechanism-based inhibition of clarithromycin in a virtual enzyme compartment.

Results: The total tacrolimus trough concentrations were 119 points, with a median of 4.3 (range: 2.0-9.9) ng/mL (n = 3). The final model comprised the Sigmoid E_max model for voriconazole and clarithromycin, which depicted time-course alterations in tacrolimus concentration and clearance when given voriconazole and clarithromycin.

Conclusions: These findings could facilitate the model-informed precision dosing of tacrolimus after unrelated bone marrow transplant.