Neuropathic Pain
Conditions
Brief summary
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.
Detailed description
The study hypothesis is that inhibition of Pgp efflux transporters will increase the CNS bio-distribution of the 5-HT3R antagonist ondansetron. Specifically: 1. Intravenous administration of ondansetron is expected to yield low CSF exposure. 2. Co-administration of ondansetron with intravenous tariquidar, an inhibitor of Pgp efflux transporters, will result in increased CSF exposure of ondansetron.
Interventions
DRUGOndansetron 8mg with Saline & Tariquidar
Each participant will receive two IV infusions of ondansetron, 24 hours apart. In the first and second sessions, respectively, placebo (D5W) or tariquidar (4mg/kg dose in D5W) 22 will be administered IV over 60 minutes. Ondansetron will be diluted in 50mL 0.9% normal saline, and tariquidar will be diluted in 250mL D5W.
DRUGOndansetron 16mg with Saline & Tariquidar
Each participant will receive two IV infusions of ondansetron, 24 hours apart. In the first and second sessions, respectively, placebo (D5W) or tariquidar (4mg/kg dose in D5W) 22 will be administered IV over 60 minutes. Ondansetron will be diluted in 50mL 0.9% normal saline, and tariquidar will be diluted in 250mL D5W.
Sponsors
Washington University School of Medicine
Study design
Allocation
NON_RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
1. Age 18-50; 2. Body mass index between 18.5 and 30; 3. Good general health with no remarkable medical conditions; 4. Able and willing to provide informed consent.
Exclusion criteria
1. Current pregnancy or lactation; 2. Known history of hepatic, renal, or cardiac disease, including Long QT Syndrome, cardiac arrhythmias or QTc interval \>450msec; 3. Known hypertension, endocrine disorders (such as diabetes mellitus), chronic pain, hematologic disorders, or psychiatric conditions requiring medications; 4. Abnormal vital signs at screening visit, including: * HR \<40 or \>100 * SBP \< 90mmHg or \>150mmHg * DBP \> 100mmHg 5. Abnormal troponin values at screening visit 6. 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. 7. Any contraindication for ondansetron administration; 8. Peri- or post-menopausal women experiencing symptoms such as hot flashes; 9. Contraindication to intrathecal catheter placement, such as known coagulopathy or history of clotting disorders, history of scoliosis or lumbar fusion, current infection or fever; 10. 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; 11. 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 3A4. * Other strong inhibitors or inducers of P-glycoprotein
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| CSF penetration of ondansetron with and without tariquidar - area under the curve (AUC) | 48 hours | CSF penetration of intravenous ondansetron will be determined as AUCCSF0-∞ of ondansetron, and compared between the two sessions, with and without tariquidar |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cmax CSF | 48 hours | Maximum CSF concentration (Cmax CSF) of ondansetron, compared between the sessions |
| CSF:plasma concentration ratio | 48 hours | CSF:plasma concentration ratio of ondansetron, compared between the two sessions |
| Plasma Cmax | 48 hours | Maximum plasma concentration (Cmax) of ondansetron, compared between the sessions |
Other
| Measure | Time frame | Description |
|---|---|---|
| Evaluation of analgesic effect of ondansetron in an experimental heat pain model | 48 hours | Comparison of analgesic effect of ondansetron in an experimental heat pain model: HPTT (as Δ°C from baseline) will be compared between the sessions at 30 min and 50 min after ondansetron infusion completion |
| Assessment of analgesic effect of ondansetron in an experimental cold pain model | 48 hours | Comparison of analgesic effect of ondansetron in an experimental cold pain model duration of tolerance and pain rating after 120 second (or maximum tolerable) hand submersion in 3-5°C water will be compared between the sessions at 40 minutes. |
Countries
United States
Outcome results
None listed