Pgp Transporter and CNS Biodistribution of Ondansetron in Healthy Volunteers

Phase 1

Terminated

• Conditions: Neuropathic Pain
• Interventions: Drug: Ondansetron 8mg with Saline & Tariquidar; Drug: Ondansetron 16mg with Saline & Tariquidar

• Registration Number: NCT03809234
• Lead Sponsor: 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.

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 Timeline

• Study First Submitted: 2019-01-14
• Study First Submitted QC: 2019-01-15
• Study First Posted: 2019-01-18
• Study Start: 2019-05-20
• Primary Completion: 2020-11-30
• Study Completion: 2020-11-30
• Status Verified: 2022-03
• Last Update Submitted: 2022-03-28
• Last Update Posted: 2022-04-07

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 14

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.

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Ondansetron with Placebo	Ondansetron 8mg with Saline & Tariquidar	The participants will receive an IV ondansetron infusion with D5W as placebo. Participants will receive either 8mg or 16 mg of iv ondansetron.
Ondansetron with Placebo	Ondansetron 16mg with Saline & Tariquidar	The participants will receive an IV ondansetron infusion with D5W as placebo. Participants will receive either 8mg or 16 mg of iv ondansetron.
Ondansetron with Tariquidar	Ondansetron 8mg with Saline & 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.
Ondansetron with Tariquidar	Ondansetron 16mg with Saline & 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.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
Plasma Cmax	48 hours	Maximum plasma concentration (Cmax) of ondansetron, compared between the sessions
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

Trial Locations

Locations (1)

Washington University in St. Louis; 🇺🇸 Saint Louis, Missouri, United States