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

被引：82

作者：

Vanhove, T. ^{[1
,2
]}

Bouwsma, H. ^{[3
]}

Hilbrands, L. ^{[4
]}

Swen, J. J. ^{[5
]}

Spriet, I. ^{[6
,7
]}

Annaert, P. ^{[8
]}

Vanaudenaerde, B. ^{[9
]}

Verleden, G. ^{[9
]}

Vos, R. ^{[9
]}

Kuypers, D. R. J. ^{[1
,2
]}

机构：

[1] KU Leuven Univ Leuven, Dept Microbiol & Immunol, Leuven, Belgium

[2] Univ Hosp Leuven, Dept Nephrol & Renal Transplantat, Leuven, Belgium

[3] Leiden Univ, Med Ctr, Dept Nephrol, Leiden, Netherlands

[4] St Radboud Univ, Med Ctr, Dept Internal Med Nephrol & Kidney Transplantat, Nijmegen, Netherlands

[5] Leiden Univ, Med Ctr, Dept Clin Pharm & Toxicol, Leiden, Netherlands

[6] Univ Hosp Leuven, Dept Pharm, Leuven, Belgium

[7] Univ Leuven, Dept Pharmaceut & Pharmacol Sci Clin Pharmacol &, Leuven, Belgium

[8] KU Leuven Univ Leuven, Dept Pharmaceut & Pharmacol Sci, Drug Delivery & Disposit, Leuven, Belgium

[9] KU Leuven Univ Leuven, Dept Clin & Expt Med, Div Resp Dis, Lung Transplant Unit, Leuven, Belgium

来源：

AMERICAN JOURNAL OF TRANSPLANTATION | 2017年 / 17卷 / 09期

关键词：

SINGLE NUCLEOTIDE POLYMORPHISMS; HUMAN LIVER-MICROSOMES; CYTOCHROME-P450; 2C19; POLYMORPHISMS; FLAVIN-CONTAINING MONOOXYGENASE; RENAL-TRANSPLANT PATIENTS; DRUG-INTERACTIONS; ANTIFUNGAL DRUGS; CYP2C19; GENOTYPE; VORICONAZOLE; PHARMACOKINETICS;

D O I：

10.1111/ajt.14232

中图分类号：

R61 [外科手术学];

学科分类号：

摘要：

Administration of azole antifungals to tacrolimustreated 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.

引用

页码：2372 / 2380

页数：9