Phase I Clinical Trial. Study of the Impact of Pharmacogenetic Markers in Predicting the Appearance of Extrapyramidal Symptomatology After the Treatment With Typical vs. Atypical Antipsychotics, in Healthy Volunteers
试验速览
- 阶段
- 1 期
- 入组人数
- 24
- 试验地点
- 2
- 主要终点
- Changes among genotypes in 24 h monitored Haloperidol and Risperidone pharmacokinetics
研究概览
简要总结
The purpose of this study is to determine in healthy volunteers treated with typical or atypical antipsychotics -AP-, the relationship between genetic polymorphisms in cytochrome genes CYP2D6 (*3, *4, *5, *6 and Nxn) and CYP3A5 (*3) with antipsychotic pharmacokinetics, occupancy of striatal dopaminergic receptors and the appearance of extrapyramidal symptomatology -EPS-.
详细描述
Objective:
The preliminary results indicate that pharmacological factors (AP, dose and drug availability depending on cytochrome activity) are risk factors for AP-induced EPS.
In this clinical trial, the investigators will study, in healthy volunteers, the effects on pharmacokinetics, occupancy of striatal dopaminergic receptors and the appearance of EPS according to genetic polymorphisms in cytochrome genes CYP2D6 (*3, *4, *5, *6 and Nxn) and CYP3A5 (*3). The investigators will compare a typical AP (Haloperidol) with an atypical AP (Risperidone), both of which are metabolized by CYP2D6 and CYP3A5.
Specific objectives:
- Study the relationship between genetic polymorphisms in cytochrome genes CYP2D6 (*3, *4, *5, *6 and Nxn) and CYP3A5 (*3) and plasmatic levels of Haloperidol and Risperidone.
- Study the relationship between genetic polymorphisms in cytochrome genes CYP2D6 (*3, *4, *5, *6 and Nxn) and CYP3A5 (*3) and the grade of occupancy of striatal dopaminergic receptors with Haloperidol and Risperidone.
- Study the relationship between plasmatic levels of Haloperidol and Risperidone and the grade of occupancy of striatal dopaminergic receptors with these two drugs.
- Study the relationship between genetic polymorphisms in cytochrome genes CYP2D6 (*3, *4, *5, *6 and Nxn) and CYP3A5 (*3), plasmatic levels of Haloperidol and Risperidone, and the grade of occupancy of striatal dopaminergic receptors with these two drugs, with the appearance of AP-induced EPS.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 30 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Risperidone
干预措施: Risperidone (Drug)
Placebo
干预措施: Placebo (Drug)
Haloperidol
干预措施: Haloperidol (Drug)
结局指标
主要结局
Changes among genotypes in 24 h monitored Haloperidol and Risperidone pharmacokinetics
时间窗: + 0.5h, +1h, +2h, +4h, +6h, +8h, +12h and +24h post-treatment
Through a catheter, blood samples will be obtained at different time frames. Samples will be kept with anticoagulants and centrifuged immediately to separate the plasmatic fraction, which will be kept at -70ºC. In order to determine the concentration of Haloperidol (and reduced Haloperidol) and Risperidone (and 9-OH Risperidone), high performance liquid chromatography -HPLC- will be achieved. A poblation-pharmacokinetic model of the two AP drugs will be designed, and drug vs. placebo treatment results will be compared. Parameters determined: AUC, Cmax, Tmax, T(1/2), Vd, CL and MRT.
Changes from placebo in occupancy of striatal dopaminergic receptors by Haloperidol and Risperidone at 5h
时间窗: +3h post-treatment: tracer injection. +5h post-treatment: image acquisition
The tracer \[123I\]IBZM, a dopaminergic antagonist, will be administered by means of intravenous injection (at +3h post-treatment) at the opposite arm from which blood samples will be obtained. Neuroimaging will be done in SPECT gamma chambers and images will be quantified comparing drug vs. placebo treatment results. Parameters determined: Average Count Striatum and Count Occipital Cortex, Specific Uptake Ratio, D2 Occupational Receptor. 100% of volunteers will undergo SPECT after placebo treatment and, among them, 50% after Haloperidol treatment and 50% after Risperidone treatment.
Changes from baseline in Extrapyramidal Symptomatology (EPS) at 3h, measured by Simpson-Angus Rating Scale (SARS)and Barnes Akathisia Rating Scale (BARS), and during 24 h, measured by actimetry
时间窗: Heteroadministered scales will be measured at -1h pre-treatment (basal level) and at +3h. Actimetry will be measured continuosly since -1h pre-treatment until +24h
AP-induced EPS measured by: * Heteroadministered scales: * Simpson-Angus Rating Scale (SARS). Assesses drug-induced parkinsonism (tremor, hypokinesia, rigidity, and postural instability). * Barnes Akathisia Rating Scale (BARS). Assesses drug-induced akathisia (restlessness and inability to sit still). * Actimetry: Continuous recording of movement, in terms of count of movements per minute, by using a wrist actimeter (model AW4) fitted to the arm not used for writing. Differences observed by comparing EPS after drug vs. placebo treatment will be considered.
次要结局
- Changes from baseline in 24h prolactin kinetics(At -1h pre-treatment (basal level) and at +0.5h, +1h, +2h, +4h, +6h, +8h, +12h and +24h post-treatment)
- Changes from baseline in Positive and Negative Symptomatology at 3h, measured by Brief Psychiatric Rating Scale (BPRS) and Scale for the Assessment of Negative Symptoms (SANS), and at 24h, measured by Subjective Deficit Syndrome Scale (SDSS)(BPRS and SANS scales will be measured at -1h pre-treatment (basal level) and at +3h. SDSS scale will be measured at -1h pre-treatment (basal level) and at +24h)
- Changes from baseline in anticholinergic activity through Whole Saliva Test (WST) during 8h(At -1h pre-treatment (basal level) and at +1h, +2h, +4h, +6h and +8h post-treatment)
- Changes from baseline in cardiovascular effects through Orthostatism measurement during 8h(At -1h pre-treatment (basal level) and at +1h, +2h, +4h, +6h and +8h post-treatment)
- Changes from baseline in sedative effects during 8h(At -1h pre-treatment (basal level) and at +1h, +2h, +4h, +6h and +8h post-treatment)