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Trial record 1 of 3 for:    "Neuromuscular Disease" | "Ondansetron"
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Pgp Transporter and CNS Biodistribution of Ondansetron in Healthy Volunteers

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ClinicalTrials.gov Identifier: NCT03809234
Recruitment Status : Recruiting
First Posted : January 18, 2019
Last Update Posted : June 27, 2019
Sponsor:
Information provided by (Responsible Party):
simon.haroutounian, Washington University School of Medicine

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.

Condition or disease Intervention/treatment Phase
Neuropathic Pain Drug: Ondansetron 8mg with Saline & Tariquidar Drug: Ondansetron 16mg with Saline & Tariquidar Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: Single (Participant)
Primary Purpose: Other
Official Title: Effects of Pgp Transporter Inhibition on CNS Biodistribution of Ondansetron in Healthy Volunteers
Actual Study Start Date : May 20, 2019
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : June 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 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.
Drug: Ondansetron 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.

Drug: Ondansetron 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.

Placebo Comparator: 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.
Drug: Ondansetron 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.

Drug: Ondansetron 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.




Primary Outcome Measures :
  1. CSF penetration of ondansetron with and without tariquidar - area under the curve (AUC) [ Time Frame: 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 Outcome Measures :
  1. Cmax CSF [ Time Frame: 48 hours ]
    Maximum CSF concentration (Cmax CSF) of ondansetron, compared between the sessions

  2. CSF:plasma concentration ratio [ Time Frame: 48 hours ]
    CSF:plasma concentration ratio of ondansetron, compared between the two sessions

  3. Plasma Cmax [ Time Frame: 48 hours ]
    Maximum plasma concentration (Cmax) of ondansetron, compared between the sessions


Other Outcome Measures:
  1. Evaluation of analgesic effect of ondansetron in an experimental heat pain model [ Time Frame: 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

  2. Assessment of analgesic effect of ondansetron in an experimental cold pain model [ Time Frame: 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.



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Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03809234


Contacts
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Contact: Simon Haroutounian, PhD 314-286-1715 sharout@wustl.edu

Locations
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United States, Missouri
Washington University in St. Louis Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Karen Frey    314-454-5980    freyk@wustl.edu   
Sub-Investigator: Michael Bottros, MD         
Sub-Investigator: Robert A Swarm, MD         
Sub-Investigator: Katarine N Gurba, MD         
Principal Investigator: Simon Haroutounian, PhD         
Sponsors and Collaborators
Washington University School of Medicine
Investigators
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Principal Investigator: Simon Haroutounian, PhD Washington University School of Medicine

Publications:
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Responsible Party: simon.haroutounian, Assistant Professor of Anesthsiology, Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT03809234     History of Changes
Other Study ID Numbers: 201811167
First Posted: January 18, 2019    Key Record Dates
Last Update Posted: June 27, 2019
Last Verified: June 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Neuromuscular Diseases
Ondansetron
Neuralgia
Peripheral Nervous System Diseases
Nervous System Diseases
Pain
Neurologic Manifestations
Signs and Symptoms
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Antipruritics
Dermatologic Agents
Serotonin Antagonists
Serotonin Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Antipsychotic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
Anti-Anxiety Agents