CYP2C19 Genotype-Specific Dosing Plus TDM on Reaching Therapeutic Voriconazole Blood Levels
Status:
Completed
Trial end date:
2020-08-28
Target enrollment:
Participant gender:
Summary
Invasive aspergillosis is a fungal infection which left untreated, is a significant cause of
morbidity and mortality. Immunocompromised patient populations such as solid organ transplant
and malignant hematology patients are especially susceptible to invasive fungal infections.
Voriconazole is an anti-fungal agent that is frontline therapy for invasive aspergillosis.
Treatment success is highly dependent on maintaining therapeutic voriconazole concentrations.
The current published literature has established that treatment failure is associated with
sub- and supra-therapeutic voriconazole concentrations.
Maintaining therapeutic voriconazole concentrations however, is challenging due to the high
inter and intra-patient variability in voriconazole pharmacokinetics. The complex kinetics of
voriconazole renders current manufacturers' dosing guidelines ineffective. Much of this
complexity has been linked to genetic polymorphisms in the cytochrome P450 2C19 gene, and it
has been found that CYP2C19 genotype plays an important role in determining voriconazole
exposure levels. Therapeutic drug monitoring has been found to increase efficacy of
voriconazole treatment through the monitoring of patients' voriconazole levels, allowing for
dosage adjustments in response to supra- or sub-therapeutic levels.
There are few robust studies that have examined the effect of CYP2C19 genotype on
voriconazole treatment outcomes. They have been unable to determine relationships between
CYP2C19 genetic status, and clinical efficacy and safety. No studies to our knowledge have
made dosing adjustments based on CYP2C19 genetic status.
The study aim is to explore the utility of voriconazole dosing that is based on the genetic
status of the patient in conjunction with therapeutic drug monitoring. Over the course of one
year, solid organ transplant recipients at Toronto General Hospital and malignant hematology
patients at Princess Margaret Cancer Centre receiving voriconazole therapy will be randomized
into one of two trial arms: a control arm receiving therapeutic drug monitoring only, or a
treatment arm receiving genotype-specific dosing in conjunction with therapeutic drug
monitoring. The investigators will compare the proportion of patients that achieve
voriconazole therapeutic concentrations, the number of dose adjustments needed to achieve
therapeutic voriconazole levels, and clinical outcomes between trial arms.