Effects of Pgp Transporter Inhibition on CNS Biodistribution of Ondansetron in Healthy Volunteers
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 14
- 试验地点
- 1
- 主要终点
- CSF penetration of ondansetron with and without tariquidar - area under the curve (AUC)
研究概览
简要总结
To determine the time-course of plasma and CSF concentrations of intravenous (IV) ondansetron in healthy subjects, with and without selective inhibition of Pgp efflux transporter.
详细描述
The study hypothesis is that inhibition of Pgp efflux transporters will increase the CNS bio-distribution of the 5-HT3R antagonist ondansetron.
Specifically:
- Intravenous administration of ondansetron is expected to yield low CSF exposure.
- Co-administration of ondansetron with intravenous tariquidar, an inhibitor of Pgp efflux transporters, will result in increased CSF exposure of ondansetron.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Crossover
- 主要目的
- Other
- 盲法
- Single (Participant)
入排标准
- 年龄范围
- 18 Years 至 50 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Body mass index between 18.5 and 30;
- •Good general health with no remarkable medical conditions;
- •Able and willing to provide informed consent.
排除标准
- •Current pregnancy or lactation;
- •Known history of hepatic, renal, or cardiac disease, including Long QT Syndrome, cardiac arrhythmias or QTc interval >450msec;
- •Known hypertension, endocrine disorders (such as diabetes mellitus), chronic pain, hematologic disorders, or psychiatric conditions requiring medications;
- •Abnormal vital signs at screening visit, including:
- •HR <40 or >100
- •SBP < 90mmHg or >150mmHg
- •DBP > 100mmHg
- •Abnormal troponin values at screening visit
- •Abnormal complete blood count (CBC) or comprehensive metabolic panel (CMP) values at screening visit that could affect drug pharmacokinetics, or suggest undiagnosed medical condition which would increase the risk of complications resulting from this study.
- •Any contraindication for ondansetron administration;
- •Peri- or post-menopausal women experiencing symptoms such as hot flashes;
- •Contraindication to intrathecal catheter placement, such as known coagulopathy or history of clotting disorders, history of scoliosis or lumbar fusion, current infection or fever;
- •Ongoing use of any of the following medications with known effects on Pgp function: carbamazepine, phenytoin, phenobarbital, cyclosporine, clarithromycin, erythromycin, ritonavir, verapamil, rifampicin, St. John's wort;
- •Current treatment (or treatment within < 5 half-lives) with any medication, including QT-prolonging drugs and drugs known to have a significant interaction with ondansetron or P-gp substrates (see below:)
- •Antiretrovirals of Protease inhibitor (e.g. Ritonavir, Saquinavir) or Non-nucleoside reverse transcriptase inhibitors (e.g. Efavirenz, Zidovudine) family.
- •Phenytoin, Carbamazepine, Oxcarbazepine, Rifampin
- •Amiodarone
- •Azole antifungals (e.g. Itraconazole, Fluconazole)
- •Macrolide antibiotics (Erythromycin, Clarithromycin)
- •Cimetidine
- •Non-DHP calcium channel blockers Verapamil and Diltiazem
- •First generation antipsychotic medications Thioridazine, Haloperidol, Chlorpromazine, and Pimozide
- •Second generation antipsychotic medications Ziprasidone and Quetiapine
- •Antihistamine Terfenadine
- •Antidepressants Trazodone, Bupropion, monoamine oxidase inhibitors, Mirtazapine
- •Antiarrhythmics Propafenone, Flecainide, and Procainamide
- •Fluoroquinolone antibiotics Norfloxacin, Ofloxacin, and Ciprofloxacin
- •Cisapride
- •Fentanyl, Lithium, Tramadol
- •Intravenous Methylene blue
- •Other strong inhibitors or inducers of Cytochromes P450 2D6 or 3A
- •Other strong inhibitors or inducers of P-glycoprotein
研究组 & 干预措施
Ondansetron with Tariquidar
The participants will receive an IV ondansetron infusion with tariquidar. Participants will receive either 8mg or 16 mg of iv ondansetron, with 4mg/kg tariguidar.
干预措施: Ondansetron 8mg with Saline & Tariquidar (Drug)
Ondansetron with Tariquidar
The participants will receive an IV ondansetron infusion with tariquidar. Participants will receive either 8mg or 16 mg of iv ondansetron, with 4mg/kg tariguidar.
干预措施: Ondansetron 16mg with Saline & Tariquidar (Drug)
Ondansetron with Placebo
The participants will receive an IV ondansetron infusion with D5W as placebo. Participants will receive either 8mg or 16 mg of iv ondansetron.
干预措施: Ondansetron 8mg with Saline & Tariquidar (Drug)
Ondansetron with Placebo
The participants will receive an IV ondansetron infusion with D5W as placebo. Participants will receive either 8mg or 16 mg of iv ondansetron.
干预措施: Ondansetron 16mg with Saline & Tariquidar (Drug)
结局指标
主要结局
CSF penetration of ondansetron with and without tariquidar - area under the curve (AUC)
时间窗: 48 hours
CSF penetration of intravenous ondansetron will be determined as AUCCSF0-∞ of ondansetron, and compared between the two sessions, with and without tariquidar
次要结局
- Plasma Cmax(48 hours)
- Cmax CSF(48 hours)
- CSF:plasma concentration ratio(48 hours)
研究者
simon.haroutounian
Assistant Professor of Anesthsiology
Washington University School of Medicine