4 years ago

Determinants of the Magnitude of Interaction Between Tacrolimus and Voriconazole/Posaconazole in Solid Organ Recipients

H. Bouwsma, P. Annaert, T. Vanhove, D. R. J. Kuypers, B. Vanaudenaerde, I. Spriet, G. Verleden, L. Hilbrands, R. Vos, J. J. Swen
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 CYP3A4, CYP3A5, MDR1, CYP2C19, POR, and UGT1A4. 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 CYP3A5 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, CYP3A5 genotype and several clinical variables were identified as modulators of the tacrolimus–azole interaction, but these did not permit accurate predictions in individual patients.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/ajt.14232

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