Abstract
Aims :
Voriconazole is the mainstay for the treatment for invasive fungal
infections in heart transplant patients and significantly increase
tacrolimus exposure because of drug-drug interaction (DDI). However, the
magnitude of this DDI is highly variable and hard to predicted. The
purpose of this study was to present the characteristics of DDI between
tacrolimus and voriconazole, and further identify the predictors of
tacrolimus dose modification.
Methods : We retrospectively enrolled 69 heart transplant
recipients without using voriconazole as the control and 68 patients
received voriconazole treatment in voriconazole group. CYP3A4*1G ,CYP3A5 *3 and CYP2C19*2 or *3 were genotyped by Sanger
sequencing. The requirement of tacrolimus dose for therapeutic
concentrations and tacrolimus dose-corrected trough concentration
(C0/D) before and after VRC administration were
evaluated.
Results : The DDI between tacrolimus and voriconazole was in a
large inter-individual variability with more than ten-fold changes in
tacrolimus dose (range 1.28–13.00) and C0/D (range
1.43–13.75). Besides, the fold changes of tacrolimus dose were
associated with CYP2C19 genotype, which was significantly lower
in CYP2C19 extensive metabolizers than that in CYP2C19 intermediate
metabolizers or poor metabolizers (4.06±1.85 vs 5.49±2.47,p =0.0031). While no significant difference was found in bothCYP3A4 and CYP3A5 genotypes. Moreover, CYP2C19genotype and hematocrit were independent predicting factors for
tacrolimus dose modification after voriconazole co-therapy.
Conclusions : This study
provided
a potential basis for comprehensive factors to adjust tacrolimus dosage
when co-administrated with voriconazole in individual patients.CYP2C19 genotype and hematocrit should be considered in tailoring
tacrolimus dose.