Adverse Drug Reactions Clinical Trial
Official title:
The Influence of CYP2C19 Polymorphisms on the Safety and Efficacy of Voriconazole in Adult Patients With Hematologic Malignancy Receiving Voriconazole Treatment Due to an Invasive Fungal Infection
Voriconazole is a drug used to treat invasive fungal infections. The amount of voriconazole
in a person's blood helps to determine how effectively it treats an infection, and how safe
it is. Patients respond differently when receiving the same dose - some clearly benefit,
other patients experience side effects, and others see limited improvement in their
infection.
Voriconazole is broken down in the liver mainly by an enzyme called CYP2C19, before being
excreted from the body. The activity of CYP2C19 differs between people because of variation
in the DNA that encodes the body's instructions to make CYP2C19.
If CYP2C19 activity is very high, voriconazole blood levels may remain below the target range
when a patient receives a standard dose of voriconazole, which may be insufficient to treat
their infection. By contrast, decreased CYP2C19 activity due to genetic variation may result
in excessively high voriconazole blood levels, predisposing to serious side effects.
Therefore, knowing a patient's CYP2C19 genetic makeup is very important for predicting their
response to voriconazole. Thus, the investigators aim to determine the influence of genetic
variation in CYP2C19 on the frequency and severity of side effects related to voriconazole,
and on the effectiveness of voriconazole for treating serious fungal infections. The findings
from this study will contribute to determining the optimal dose of voriconazole that patients
with different genetic variants in CYP2C19 should be started on, and will take us one step
closer to both understanding the genetic structure of CYP2C19 in the Turkish population, and
to 'personalised medicine'.
Rationale for the study:
Although the incidence of invasive aspergillosis (IA) in patients with hematological
malignancies has decreased by half, its mortality rate still remains of substantial clinical
concern.
Voriconazole is the first line therapy for the treatment of IA. Since it has a narrow
therapeutic window, the high inter/intra-individual variability and nonlinear
pharmacokinetics, therapeutic drug monitoring (TDM) is recommended to optimize clinical
outcomes. Voriconazole is metabolized principally by CYP2C19 (cytochrome P450 enzyme) and, to
a lesser extent, by CYP3A4 and CYP2C9 enzymes. Among the various covariates, CYP2C19 genetic
variability is the major determinant that contributes to interindividual variability of
voriconazole. While the poor metabolizers are more susceptible to toxicity, the risk of
treatment failure in ultra-metabolizers are considered to be higher. TDM improve the safety
and efficacy of voriconazole treatment. The appropriate time for TDM is after the first few
days (2-5 days) of initiation of standard treatment. However some adverse drug reactions
(ADRs) and deviation from the therapeutic range may occur until the TDM is done. Starting
with pharmacogenetic-guided dose would ensure safer and more effective therapy until the TDM
is performed and would lead to less frequent TDM with decreased treatment costs. Furthermore,
pharmacogenetic test results can also be used when interpreting the optimal dose of other
drugs that is metabolized with the same enzyme. The individual pharmacogenetic data also
enables safer and cost-effective therapy adjustments in the future, too.
Therefore, primary objective of the study is to determine the influence of CYP2C19 genetic
polymorphisms on the frequency and severity of ADRs related to voriconazole during the study
period in a Turkish university hospital. The secondary objective is to determine the
influence of CYP2C19 genetic polymorphisms on the effectiveness of voriconazole in this
setting. Our study will fill this gap by assessing the influence of CYP2C19 polymorphisms on
the safety and efficacy of voriconazole that is being used in patients with a hematologic
malignancy to treat an IA.
1.Methods
The study population will be drawn from patients aged 18 and over that are hospitalized in
Dokuz Eylul University Hospital Hematology Service due to a hematological malignancy, and are
receiving voriconazole for the management of an IFI, which is diagnosed based on EORTC/MSG (
European Organisation for Research and Treatment of Cancer / Mycosis Study Group) criteria.
1.1.Data and sample collection
1.1.1.Data collection: At baseline, demographics and clinical information will be recorded
from all patients directly and complemented from their medical records. All patients will be
followed up by the research team daily for the first 7 days following voriconazole
initiation, and then on days 14, 30 and 60. All follow up will be initially via assessment of
medical records, with additional data input from the patient directly. The medical records
include: the electronic hospital record system (PROBEL), paper-based patient records and
other patient follow-up- documents.
During routine clinical care, ADRs are monitored daily by a hematology fellow and/or an
infectious disease specialist. On days one to seven following voriconazole initiation, the
investigators will record these clinical evaluations daily; they will also capture these data
on days 14 and 30.
For participants that had either started voriconazole active treatment before they were
recruited, or were recruited during the maintenance phase of their voriconazole regimen, the
research team will assess their medicals records retrospectively between the point of
recruitment and day one of their active voriconazole treatment to detect ADRs.
On days 30 and 60, patient survival will be recorded by review of patient records only.
Treatment response (efficacy) will be determined based on the EORTC/MSG consensus criteria
30. These data will be obtained at all follow up points (from day one to seven, and days 14,
30 and 60).
The follow-up scheme and the consort flow diagram regarding the protocol are attached in the
appendix.
1.1.2.Sample collection: 1.1.2.1.Samples fo PGx analysis: For PGx analysis, participants will
donate one 9 mL blood sample collected into an EDTA (Ethylenediaminetetraacetic Acid) tube on
day one whilst blood samples are being taken from the patient for daily routine clinical
purposes (without requiring any other needle insertion). Samples for PGx analysis will be
coded and stored securely in the Department of Medical Pharmacology at the DEUTF. The samples
will be stored -80 celsius degree until used up. PGx analysis will be performed in the
Department of Molecular and Clinical Pharmacology at the University of Liverpool at the end
of the study. Participants and physicians will not be informed of the participant's genotype
as this is an observational study. The participant's clinical care will not be affected in
any way by taking part in the study
1.1.2.2.Samples for voriconazole concentration determination The second 9 mL blood sample
will be collected into a red cap tube on the fifth day (9th dose) of treatment before the
morning voriconazole dose, again whilst blood is being collected as part of routine clinical
care (without requiring any other needle insertion) to determine the trough voriconazole
concentration at steady state. This blood sample will be centrifuged and the serum stored in
the Department of Medical Pharmacology at the Dokuz Eylul University Faculty of Medicine.
When follow up is completed for a given patient, this serum sample will be transferred to an
accredited laboratory in Istanbul, Turkey, with maintenance and assurance of the cold chain
during sample transportation to guarantee sample integrity.
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