Clinical trial NCT03809234: Pgp Transporter and CNS Biodistribution of Ondansetron in Healthy Volunteers
Official title: Effects of Pgp Transporter Inhibition on CNS Biodistribution of Ondansetron in Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Neuropathic Pain
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
First posted: 2019-01-18
Enrollment: 14
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: OTHER

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.

Eligibility 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

Primary outcomes:
measure: CSF penetration of ondansetron with and without tariquidar - area under the curve (AUC)
timeFrame: 48 hours
Secondary outcomes:
measure: Cmax CSF
timeFrame: 48 hours
measure: CSF:plasma concentration ratio
timeFrame: 48 hours
measure: Plasma Cmax
timeFrame: 48 hours
Other outcomes:
measure: Evaluation of analgesic effect of ondansetron in an experimental heat pain model
timeFrame: 48 hours
measure: Assessment of analgesic effect of ondansetron in an experimental cold pain model
timeFrame: 48 hours
Locations:
city: Saint Louis
country: United States
facility: Washington University in St. Louis
state: Missouri
Study officials:
affiliation: Washington University School of Medicine
name: Simon Haroutounian, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.