Pgp Transporter and CNS Biodistribution of Ondansetron in Healthy Volunteers

Neuropathic Pain Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03809234
• Other study ID #: 201811167
• Status: Terminated
• Phase: Phase 1
• Start date: May 20, 2019
• Est. completion date: November 30, 2020

Study information

• Verified date: March 2022
• Source: Washington University School of Medicine
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 14
• Est. completion date: November 30, 2020
• Est. primary completion date: November 30, 2020
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 50 Years

Eligibility

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

Related Conditions & MeSH terms

• Neuralgia
• Neuropathic Pain

Intervention

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.
• 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.

Locations

Country	Name	City	State
United States	Washington University in St. Louis	Saint Louis	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
Washington University School of Medicine

Country where clinical trial is conducted

United States, 

References & Publications (4)

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. — View Citation

Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH, Gilron I, Haanpää 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. Review. — View 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. Review. — View 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. Erratum in: Pain Med. 2011 Aug;12(8):1294. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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 ?°C from baseline) will be compared between the sessions at 30 min and 50 min after ondansetron infusion completion	48 hours
Other	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
Primary	CSF penetration of ondansetron with and without tariquidar - area under the curve (AUC)	CSF penetration of intravenous ondansetron will be determined as AUCCSF0-8 of ondansetron, and compared between the two sessions, with and without tariquidar	48 hours
Secondary	Cmax CSF	Maximum CSF concentration (Cmax CSF) of ondansetron, compared between the sessions	48 hours
Secondary	CSF:plasma concentration ratio	CSF:plasma concentration ratio of ondansetron, compared between the two sessions	48 hours
Secondary	Plasma Cmax	Maximum plasma concentration (Cmax) of ondansetron, compared between the sessions	48 hours