Pgp Transporter and CNS Biodistribution of Ondansetron in Healthy Volunteers

Study Overview
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Brief Summary
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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
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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.

Official Title
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Effects of Pgp Transporter Inhibition on CNS Biodistribution of Ondansetron in Healthy Volunteers

Conditions
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Neuropathic Pain

Intervention / Treatment
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* Drug: Ondansetron 8mg with Saline & Tariquidar
* Drug: Ondansetron 16mg with Saline & Tariquidar


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-50; Body mass index between 18.5 and 30; Good general health with no remarkable medical conditions; Able and willing to provide informed consent. Exclusion Criteria: 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 3A4. Other strong inhibitors or inducers of P-glycoprotein

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ondansetron with Tariquidar<br>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. | Drug: Ondansetron 8mg with Saline & Tariquidar<br>* 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.<br>Drug: Ondansetron 16mg with Saline & Tariquidar<br>* 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.<br>|
| Placebo Comparator: Ondansetron with Placebo<br>The participants will receive an IV ondansetron infusion with D5W as placebo. Participants will receive either 8mg or 16 mg of iv ondansetron. | Drug: Ondansetron 8mg with Saline & Tariquidar<br>* 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.<br>Drug: Ondansetron 16mg with Saline & Tariquidar<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CSF penetration of ondansetron with and without tariquidar - area under the curve (AUC) | CSF penetration of intravenous ondansetron will be determined as AUCCSF0-∞ of ondansetron, and compared between the two sessions, with and without tariquidar | 48 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax CSF | Maximum CSF concentration (Cmax CSF) of ondansetron, compared between the sessions | 48 hours | 
| CSF:plasma concentration ratio | CSF:plasma concentration ratio of ondansetron, compared between the two sessions | 48 hours | 
| Plasma Cmax | Maximum plasma concentration (Cmax) of ondansetron, compared between the sessions | 48 hours |