title: Determinants of the Magnitude of Interaction Between Tacrolimus and Voriconazole/Posaconazole in Solid Organ Recipients.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, KU Leuven-University of Leuven, Leuven, Belgium.|Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.
authors.forename: T
authors.identifier: http://orcid.org/0000-0001-5712-6294
authors.initials: T
authors.lastname: Vanhove
authors.affiliation: Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Bouwsma
authors.affiliation: Department of Internal Medicine: Nephrology and Kidney Transplantation, St Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: L
authors.initials: L
authors.lastname: Hilbrands
authors.affiliation: Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: J J
authors.initials: JJ
authors.lastname: Swen
authors.affiliation: Pharmacy Department, University Hospitals Leuven, Leuven, Belgium.|Department of Pharmaceutical and Pharmacological Sciences, Clinical Pharmacology and Pharmacotherapy, University of Leuven, Leuven, Belgium.
authors.forename: I
authors.initials: I
authors.lastname: Spriet
authors.affiliation: Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven-University of Leuven, Leuven, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Annaert
authors.affiliation: Lung Transplant Unit, Division of Respiratory Disease, Department of Clinical and Experimental Medicine, KU Leuven-University of Leuven, Leuven, Belgium.
authors.forename: B
authors.initials: B
authors.lastname: Vanaudenaerde
authors.affiliation: Lung Transplant Unit, Division of Respiratory Disease, Department of Clinical and Experimental Medicine, KU Leuven-University of Leuven, Leuven, Belgium.
authors.forename: G
authors.initials: G
authors.lastname: Verleden
authors.affiliation: Lung Transplant Unit, Division of Respiratory Disease, Department of Clinical and Experimental Medicine, KU Leuven-University of Leuven, Leuven, Belgium.
authors.forename: R
authors.initials: R
authors.lastname: Vos
authors.affiliation: Department of Microbiology and Immunology, KU Leuven-University of Leuven, Leuven, Belgium.|Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.
authors.forename: D R J
authors.initials: DRJ
authors.lastname: Kuypers
mesh_terms: D000935:Antifungal Agents / Q000627:therapeutic use; D015415:Biomarkers / Q000032:analysis*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D004347:Drug Interactions; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006084:Graft Rejection / Q000188:drug therapy* / Q000209:etiology; D006085:Graft Survival / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D016377:Organ Transplantation / Q000009:adverse effects*; D020641:Polymorphism, Single Nucleotide; D011183:Postoperative Complications; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors; D016559:Tacrolimus / Q000627:therapeutic use*; D014230:Triazoles / Q000627:therapeutic use*; D065819:Voriconazole / Q000627:therapeutic use*
chemical_list: D000935:Antifungal Agents; D015415:Biomarkers; D007166:Immunosuppressive Agents; D014230:Triazoles; C101425:posaconazole; D051544:Cytochrome P-450 CYP3A; D065819:Voriconazole; D016559:Tacrolimus
keywords: antibiotic: antifungal; calcineurin inhibitor: tacrolimus; clinical research/practice; complication: infectious; drug interaction; immunosuppressant; kidney transplantation/nephrology; pharmacology