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Determinants of the Magnitude of Interaction Between Tacrolimus and Voriconazole/Posaconazole in Solid Organ Recipients
Author(s) -
Vanhove T.,
Bouwsma H.,
Hilbrands L.,
Swen J. J.,
Spriet I.,
Annaert P.,
Vanaudenaerde B.,
Verleden G.,
Vos R.,
Kuypers D. R. J.
Publication year - 2017
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.14232
Subject(s) - tacrolimus , posaconazole , medicine , voriconazole , calcineurin , pharmacology , drug interaction , therapeutic drug monitoring , organ transplantation , gastroenterology , pharmacokinetics , transplantation , dermatology , antifungal
Administration of azole antifungals to tacrolimus‐treated solid organ recipients results in a major drug–drug interaction characterized by increased exposure to tacrolimus. The magnitude of this interaction is highly variable but cannot currently be predicted. We performed a retrospective analysis of 126 solid organ recipients (95 lung, 31 kidney) co‐treated with tacrolimus and voriconazole (n = 100) or posaconazole (n = 26). Predictors of the change in tacrolimus dose‐corrected trough concentrations (C/D) between baseline and tacrolimus–azole co‐therapy were assessed using linear mixed modeling. Patients were genotyped for relevant polymorphisms in CYP 3A4 , CYP 3A5 , MDR 1 , CYP 2C19 , POR , and UGT 1A4 . Tacrolimus C/D increased by a factor 5.0 ± 2.7 (range 1.0–20.2) for voriconazole and 4.4 ± 2.6 (range 0.9–18.0) for posaconazole, suggesting that a 66% dose reduction is insufficient for the majority of patients. Change in C/D was blunted in CYP 3A5 expressors (estimated effect: ‐43%, p = 0.017) and affected by hematocrit (+8% per %, p = 0.004), baseline C/D (‐14% per 100% increase, p < 0.001), and age (+1%, p = 0.008). However, the final model explained only 22% of interindividual variability in C/D change. In conclusion, CYP 3A5 genotype and several clinical variables were identified as modulators of the tacrolimus–azole interaction, but these did not permit accurate predictions in individual patients.