title: Genotype-Directed Dosing Leads to Optimized Voriconazole Levels in Pediatric Patients Receiving Hematopoietic Stem Cell Transplantation.
abstract: Invasive fungal infections are a significant cause of morbidity and mortality in recipients of hematopoietic stem cell transplantation (HSCT), warranting antifungal prophylaxis as a standard of care in these patients. Voriconazole is commonly used in this setting because of its broad-spectrum activity and available dosage forms. There is wide well-known inter- and intrapatient variability in voriconazole concentrations, in part because concentrations are affected by common CYP2C19 polymorphisms. In 2 successive studies we have optimized voriconazole dosing to achieve target voriconazole serum concentrations using a genotype-specific dosing algorithm for antifungal prophylaxis in the post-HSCT period. In our pilot study all patients undergoing HSCT who received voriconazole antifungal prophylaxis were prospectively followed. Voriconazole concentrations were monitored weekly and doses adjusted until concentrations reached between 1 and 5.5 μg/L. The most common CYP2C19 polymorphisms were determined and correlated with voriconazole dose and time required to reach the target concentration range. In the subsequent study patients receiving voriconazole prophylaxis were dosed based on their CYP2C19 genotype and followed prospectively. In the pilot study 25 patients received voriconazole as antifungal prophylaxis for a median of 49 days (range, 15 to 196 days). The median time to reach the target concentration was 34 days for extensive metabolizers and 11 days for poor metabolizers. Three patients were genotyped as intermediate metabolizers; they reached the target concentration in a median of 56 days. Similarly, 2 patients who were genotyped as ultrarapid metabolizers reached the target range in 18 and 25 days. The time and dose required to reach the adequate concentration showed a trend toward correlation with individual CYP2C19 genotype, although voriconazole concentrations showed large interpatient variability in wild-type patients (extensive metabolizers). In our follow-up study, 20 patients received voriconazole prophylaxis prospectively dosed based on their CYP2C19 genotype. The median times to reach the target concentration using genotype-guided dosing were 9, 6.5, and 4 days for ultrarapid, extensive, and intermediate metabolizers, respectively. Overall, the median time to reach the target concentration with genotype-guided dosing was 6.5 days compared with a median time of 29 days when all patients were started on the same dose regardless of CYP2C19 genotype (P < .001). Our data show that traditional voriconazole dosing does not lead to timely achievement of target levels for fungal prophylaxis. However, a genotype-directed dosing algorithm allows patients to reach the voriconazole target range significantly sooner, providing better prophylaxis against fungal infections in the immediate post-transplant period.
authors.affiliation: Division of Pharmacy, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio. Electronic address: ashleyteusink@gmail.com.
authors.forename: Ashley
authors.initials: A
authors.lastname: Teusink
authors.affiliation: Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Alexander
authors.initials: A
authors.lastname: Vinks
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Kejian
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Stella
authors.initials: S
authors.lastname: Davies
authors.affiliation: Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Fukuda
authors.affiliation: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Adam
authors.initials: A
authors.lastname: Lane
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Shannon
authors.initials: S
authors.lastname: Nortman
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Diane
authors.initials: D
authors.lastname: Kissell
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Sarah
authors.initials: S
authors.lastname: Dell
authors.affiliation: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Filipovich
authors.affiliation: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Parinda
authors.initials: P
authors.lastname: Mehta
mesh_terms: D000293:Adolescent; D000465:Algorithms; D064591:Allografts; D002648:Child; D002675:Child, Preschool; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D009181:Mycoses / Q000235:genetics / Q000517:prevention & control; D011110:Polymorphism, Genetic; D057285:Precision Medicine; D065819:Voriconazole / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D065819:Voriconazole
keywords: Hematopoietic stem cell transplant; Pharmacogenetics; Voriconazole