CYP2C19 QC

June 21, 2021 0 Comments

Invasive aspergillosis is a fungal infection that, if left untreated, is a major cause of morbidity and mortality. Immunosuppressed patient populations, such as solid organ transplant patients and malignant hematology, are especially susceptible to invasive fungal infections.

Voriconazole is an antifungal agent that is first-line therapy for invasive aspergillosis. Successful treatment is highly dependent on the maintenance of therapeutic voriconazole concentrations. The current published literature has established that treatment failure is associated with sub and supratherapeutic voriconazole concentrations.

However, maintaining therapeutic voriconazole concentrations is challenging due to the high inter-and intra-patient variability in the pharmacokinetics of voriconazole. The complex kinetics of voriconazole render current manufacturers’ dosage guidelines ineffective. Much of this complexity has been related to genetic polymorphisms in the cytochrome P450 2C19 gene, and the CYP2C19 genotype has been found to play an important role in determining levels of voriconazole exposure.

Therapeutic drug monitoring has been found to increase the efficacy of voriconazole treatment by monitoring patients’ voriconazole levels, allowing dose adjustments in response to supra or sub-therapeutic levels.

Few robust studies have examined the effect of the CYP2C19 genotype on the outcomes of voriconazole treatment. They have not been able to determine the relationships between CYP2C19 genetic status and clinical efficacy and safety. To our knowledge, no studies have made dose adjustments based on CYP2C19 genetic status.

The aim of the study 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 a year, solid organ transplant recipients at Toronto General Hospital and patients with malignant hematology at Princess Margaret Cancer Center receiving voriconazole therapy will be randomly assigned to one of two trial arms:

A control arm that receives only therapeutic drug monitoring, or a treatment arm that receives a genotype-specific dose in conjunction with therapeutic drug monitoring. Investigators will compare the proportion of patients achieving therapeutic voriconazole concentrations, the number of dose adjustments required to achieve therapeutic voriconazole levels, and clinical outcomes between the trial arms.

Detailed description:

Invasive aspergillosis (IA) is a fungal infection that, if left untreated, can cause dangerous complications and death. Transplant patients with weakened immune systems are at higher risk for AI. Voriconazole is a drug that is prescribed for AI. For voriconazole to work, it is important to keep the correct amount of medicine in your blood. Researchers check the correct amount of voriconazole in the blood by collecting blood samples.

This process is called therapeutic drug monitoring (TDM) and is usually done in transplant patients with weakened immune systems. However, maintaining the correct amount of drug in the blood remains difficult, as the body absorbs and excretes voriconazole differently for each person, depending on their genetic makeup. This study will try to understand if genetic testing from the beginning, in addition to MDD, will be able to provide us with tailored doses for each individual.

Study design:

Patients who consent to participate in this study and who are receiving voriconazole therapy for AI will be randomly divided into one of two groups. The control group will receive doses of voriconazole and then TDM according to the usual treatment for the patient’s condition. One treatment group will receive modified doses that are specific to their genetic makeup for the first four days of treatment and will then receive routine MDD.

This modified dosage for the treatment group is experimental and is not used routinely inpatient care. TDM will be performed on about the fourth day after starting voriconazole for all patients, and thereafter, normal treatment will resume for all patients.

Participation in the study will be for the entire time the patient is taking voriconazole. The study staff will meet with the patient once, as long as they meet the study criteria. This will be the only

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