Pharmacogenetic Directed Dosing Leads to Optimized Voriconazole Levels in Pediatric Patients Receiving Hematopoietic Stem Cell Transplants

Background: Invasive fungal infections are a significant cause of morbidity and mortality in recipients of hematopoietic cell transplantation (HSCT), warranting antifungal prophylaxis as a standard of care in these patients. Due to its broad spectrum activity and multiple available dosage forms, voriconazole remains one of the commonly used agents in this setting. Voriconazole is known to have wide inter- and intra-patient variability in levels. Additionally these levels are affected by a common CYP450 polymorphism, CYP450-2C19. We have previously shown that voriconazole dosing of 5 mg/kg/dose every 12 hours is not sufficient to achieve target prophylactic goal levels in pediatric patients undergoing HSCT, leaving these patients susceptible to fungal infections during their vulnerable post HSCT period. The aim of this follow-up study was to determine if genotype directed initial voriconazole dosing and subsequent adjustment based on our new algorithm (Fig 1) will decrease time to desired target range for fungal prophylaxis. A secondary aim was to determine if the incidence of adverse effects will increase secondary to using higher initial doses and larger dose adjustments. Here we report our experience using genotype and new algorithm directed initial and subsequent dosing of voriconazole respectively to optimize antifungal prophylactic regimen for this high risk population.  Methods: All patients undergoing HSCT at Cincinnati Children's Hospital Medical Center who received voriconazole anti-fungal prophylaxis between June 2013 and September 2013 were followed prospectively. All patients were genotyped for CYP2C19 polymorphisms which are known to alter voriconazole metabolism (normal, fast or slow metabolizers). Initial voriconazole dose was decided based on the patient's genotype and changes in dose were made as shown in Fig 1 to achieve concentrations within the target range of 1 mcg/mL to 5 mcg/mL.  All patients were monitored for common voriconazole side effects. Results: A total of 20 patients, aged 10 months to 26 years received voriconazole prophylaxis based on their CYP450-2C19 genotype and according to the above algorithm. The median time to reach the target level was 8 days (range 2-47 days). This was significantly improved compared to time to target level in our pilot study (median 30 days range 3-67 days) (p < 0.001) (figure 2). There were no adverse effects attributed to voriconazole therapy. There was one breakthrough fungal infection, despite voriconazole levels within the target range, from Candida albicans resistant to voriconazole. Conclusions: Our results show that CYP450-2C19 genotype directed initial dosing and subsequent dose adjustments as per the above algorithm, can successfully achieve prophylactic voriconazole target levels in pediatric patients undergoing HSCT.

Figure 2