Pgp Transporter and CNS Biodistribution of Ondansetron in Healthy Volunteers

The Washington University

Status and phase: Terminated; Phase 1

Conditions: Neuropathic Pain

Treatments: Drug: Ondansetron 8mg with Saline & Tariquidar; Drug: Ondansetron 16mg with Saline & Tariquidar

Study type: Interventional

Funder types: Other

Identifiers

NCT03809234

201811167

Details and patient eligibility

About

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.

Full 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.

Enrollment: 14 patients

Sex: All

Ages: 18 to 50 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Other

Allocation: Non-Randomized

Interventional model: Crossover Assignment

Masking: Single Blind

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14 participants in 2 patient groups, including a placebo group

Ondansetron with Tariquidar

Experimental group

Description:

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.

Treatment:

Drug: Ondansetron 8mg with Saline & Tariquidar

Drug: Ondansetron 16mg with Saline & Tariquidar

Ondansetron with Placebo

Placebo Comparator group

Description:

The participants will receive an IV ondansetron infusion with D5W as placebo. Participants will receive either 8mg or 16 mg of iv ondansetron.

Treatment:

Drug: Ondansetron 8mg with Saline & Tariquidar

Drug: Ondansetron 16mg with Saline & Tariquidar