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.

Safety, Efficacy, and Exposure–Response of Voriconazole in Pediatric Patients With Invasive Aspergillosis, Invasive Candidiasis or Esophageal Candidiasis

“…24 A recently published article concluded that a CYP2C19 genotype-directed dosing algorithm (ie, 5, 6 or 7 mg/kg q12 h stratified by CYP2C19 status) allowed pediatric patients (n = 20) to reach target voriconazole concentration significantly sooner than pediatric patients with a standard dosing regimen (5 mg/kg q12 h, n = 25). 26 Of note, the doses evaluated in that publication are lower than those investigated in our studies. It is possible that the use of lower doses in these pediatric patients might be an important factor in the delay of reaching target concentration, in addition to the CYP2C19 polymorphism.…”

PharmGKB summary

“…Hence, more studies are needed to address this potential association. While one study did prospectively genotype CYP2C19 and showed a faster achievement of target voriconazole concentrations, this conclusion is limited due to the study’s small size, lack of PMs, and having only a single UM participant in the genotype-directed dosing arm [24]. These issues with the current body of literature warrant further research into this topic given the high morbidity and mortality rates of failed antifungal therapy in immunocompromised patients.…”

“…Literature evidence for the effect of variants in other genes involved in voriconazole metabolism or concentration, such as CYP3A4 and CYP2C9 , is very limited. One recent study found that dosing voriconazole based on CYP2C19 genotype leads to faster achievement of target concentrations, suggesting that preemptive CYP2C19 genotyping may be useful in the clinic [24]. …”

“…A recent study by Teusink et al . compared standard dosing of voriconazole to genotype-directed dosing [24]. A pilot study followed 25 individuals undergoing hematopoietic stem cell transplantation (HSCT) who received an initial dose of voriconazole of 5 mg/kg twice daily, regardless of genotype.…”

“…Doses were then adjusted, as in the pilot study, until they were within the target range. Comparison of the genotype-directed dosing arm to the standard dosing arm showed that patients in the genotype-directed dosing arm took a median of 6.5 days to reach the target therapeutic range, while patients in the standard dosing arm took a median of 29 days, a statistically significant difference [24]. …”