Influence of CYP2C19 Genotype on Safety and Efficacy of Voriconazole in Pediatric Patients With Hematologic Malignancy
试验速览
- 阶段
- 不适用
- 入组人数
- 62
- 试验地点
- 1
- 主要终点
- Frequency and severity of voriconazole related adverse drug reactions
研究概览
简要总结
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 CY2C19 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. Besides, children tend to have faster voriconazole metabolism regardless of the genetic makeup, mainly because of higher liver mass/body proportion. That's why, younger patients needs higher doses and it is harder for them to reach target range. Having a high CYP2C19 activity and being young combined may cause to consider choosing an alternative drug. 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, we 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'.
详细描述
Invasive fungal infections are the leading cause of mortality and morbidity in immune compromised children. Aspergillus species are reported to be the most common molds that cause invasive infections among pediatric patients both in the United States and in Europe.
Voriconazole is recommended as the first line therapy for invasive Aspergillosis. The major proportion of the drug undergoes hepatic metabolism via cytochrome enzymes. The hepatic cytochrome enzyme that mainly involves in the metabolism of voriconazole is CYP2C19, which is known to be highly polymorphic. So far, more than 30 variant alleles have been defined in the gene that codes CYP2C19 enzyme.
Polymorphisms in CYP2C19 gene are associated with alterations in voriconazole metabolism. It is postulated that only 35-50% of the populations has normal metabolic activity for this drug. The carriers of defective alleles (*2/*2, *2/*3, *3/*3) in CYP2C19 gene have slower metabolic activity for voriconazole, while the carriers of *17 allele have increased enzyme activity and higher metabolic capacity for the drug.
Voriconazole has a narrow therapeutic window. When the therapy is initiated with standard doses, interpersonal differences in CYP2C19 activity make it difficult to remain in the optimal therapeutic range. Furthermore, it is reported that voriconazole concentrations in pediatric patients can exhibit up to 3-fold variation among individuals and it is extremely hard to reach and remain therapeutic concentration in younger children. As low serum concentrations cause decreased efficacy, supratherapeutic concentrations may cause voriconazole toxicity which also leads to significant morbidity, mortality and high treatment costs.
To ensure desired efficacy and safety of voriconazole treatment, therapeutic drug monitoring (TDM) is recommended, but unfortunately, it is not a part of routine clinical care in many hospitals, due to frequent blood sampling and analysis requirements and the high analysis costs. On the other hand, starting the therapy with standard doses and adjusting it with subsequent TDMs may cause delay in selecting optimal voriconazole dose and providing effective treatment.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 2 Years 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Aged between ≥2 years and <18 years
- •Receiving voriconazole for the treatment of an invasive fungal infection (IFI) and are within the first five days of the treatment course, OR are receiving voriconazole for the secondary prophylaxis against IFI during or after chemotherapy
- •Agree to give one additional blood sample twice during the study for the purposes of pharmacogenetic analysis and determination of the serum trough voriconazole concentration, whilst their blood is being collected during normal clinical follow up without the requirement for any additional intravenous intervention
- •Are willing and able to give informed consent and sign the informed consent form (by the patients and the parents OR the legal guardians)
排除标准
- •Have previously had CYP2C19 PGx testing performed
- •Pregnant/breastfeeding
- •Have cognitive impairment and/or psychiatric disorders and/or any other condition that will draw into question their capacity to provide informed consent
- •Have severe hepatic insufficiency (Child-Pugh Class C) and have renal failure (estimated GFR <15ml/min /1,73m2)
研究组 & 干预措施
Voriconazole
All eligible patients will be followed up for voriconazole related adverse drug events and efficacy
干预措施: Voriconazole (Drug)
结局指标
主要结局
Frequency and severity of voriconazole related adverse drug reactions
时间窗: Follow up period for primary outcome is 30 days for each participant
Voriconazole related adverse drug reactions of grade 3-5 systematically evaluated using Liverpool Causality Assessment Tool identified during study follow up. Severity of all adverse events will be graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0.
次要结局
- Non-response to voriconazole(Follow up period for this outcome is 60 days for each participant)
- Voriconazole trough concentration(30 minutes before the 9th dose of voriconazole)
- Survival(On days 30 and 60)
研究者
Mukaddes Gumustekin
Full Professor
Dokuz Eylul University