Pgp Transporter and CNS Biodistribution of Ondansetron in Healthy Volunteers

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

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.

Study Overview

• Status: Terminated
• Conditions: Neuropathic Pain
• Intervention / Treatment: Drug: Ondansetron 8mg with Saline & Tariquidar; Drug: Ondansetron 16mg with Saline & Tariquidar

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.

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University in St. Louis

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / 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.

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluation of analgesic effect of ondansetron in an experimental heat pain model	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	48 hours
Assessment of analgesic effect of ondansetron in an experimental cold pain model	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.	48 hours

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Investigators: Principal Investigator: Simon Haroutounian, PhD, Washington University School of Medicine

Publications and helpful links

General Publications

• Smith BH, Torrance N. Epidemiology of neuropathic pain and its impact on quality of life. Curr Pain Headache Rep. 2012 Jun;16(3):191-8. doi: 10.1007/s11916-012-0256-0.
• Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH, Gilron I, Haanpaa M, Hansson P, Jensen TS, Kamerman PR, Lund K, Moore A, Raja SN, Rice AS, Rowbotham M, Sena E, Siddall P, Smith BH, Wallace M. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015 Feb;14(2):162-73. doi: 10.1016/S1474-4422(14)70251-0. Epub 2015 Jan 7.
• Yawn BP, Wollan PC, Weingarten TN, Watson JC, Hooten WM, Melton LJ 3rd. The prevalence of neuropathic pain: clinical evaluation compared with screening tools in a community population. Pain Med. 2009 Apr;10(3):586-93. doi: 10.1111/j.1526-4637.2009.00588.x. Epub 2009 Mar 17. Erratum In: Pain Med. 2011 Aug;12(8):1294.
• Dogrul A, Ossipov MH, Porreca F. Differential mediation of descending pain facilitation and inhibition by spinal 5HT-3 and 5HT-7 receptors. Brain Res. 2009 Jul 14;1280:52-9. doi: 10.1016/j.brainres.2009.05.001. Epub 2009 May 8.

Study record dates

Study Major Dates

• Study Start (Actual): May 20, 2019
• Primary Completion (Actual): November 30, 2020
• Study Completion (Actual): November 30, 2020

Study Registration Dates

• First Submitted: January 14, 2019
• First Submitted That Met QC Criteria: January 15, 2019
• First Posted (Actual): January 18, 2019

Study Record Updates

• Last Update Posted (Actual): April 7, 2022
• Last Update Submitted That Met QC Criteria: March 28, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Pain; Neurologic Manifestations; Neuromuscular Diseases; Peripheral Nervous System Diseases; Neuralgia; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Antiemetics; Gastrointestinal Agents; Dermatologic Agents; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Serotonin Agents; Serotonin Antagonists; Anti-Anxiety Agents; Antipruritics; Ondansetron
• Other Study ID Numbers: 201811167

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No