Pgp Transporter and CNS Biodistribution of Ondansetron in Healthy Volunteers

NCT03809234 | Terminated Phase 1 DMC FDA Drug

• 1 other identifier: 201811167
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

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.

Conditions

Neuropathic Pain

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (3)

• Cmax CSF

  48 hours

• CSF:plasma concentration ratio

  48 hours

• Plasma Cmax

  48 hours

Other Outcomes (2)

• Evaluation of analgesic effect of ondansetron in an experimental heat pain model

  48 hours

• Assessment of analgesic effect of ondansetron in an experimental cold pain model

  48 hours

Study Arms (2)

Ondansetron with Tariquidar

EXPERIMENTAL

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; Drug: Ondansetron 16mg with Saline & Tariquidar

Ondansetron with Placebo

PLACEBO COMPARATOR

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; Drug: Ondansetron 16mg with Saline & Tariquidar

Interventions

Ondansetron 8mg with Saline & Tariquidar DRUG

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 with Placebo; Ondansetron with Tariquidar

Ondansetron 16mg with Saline & Tariquidar DRUG

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 with Placebo; Ondansetron with Tariquidar

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Age 18-50;
• Body mass index between 18.5 and 30;
• Good general health with no remarkable medical conditions;
• Able and willing to provide informed consent.

You may not qualify if:

• Current pregnancy or lactation;
• Known history of hepatic, renal, or cardiac disease, including Long QT Syndrome, cardiac arrhythmias or QTc interval \>450msec;
• Known hypertension, endocrine disorders (such as diabetes mellitus), chronic pain, hematologic disorders, or psychiatric conditions requiring medications;
• Abnormal vital signs at screening visit, including:
• HR \<40 or \>100
• SBP \< 90mmHg or \>150mmHg
• DBP \> 100mmHg
• Abnormal troponin values at screening visit
• 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.
• Any contraindication for ondansetron administration;
• Peri- or post-menopausal women experiencing symptoms such as hot flashes;
• Contraindication to intrathecal catheter placement, such as known coagulopathy or history of clotting disorders, history of scoliosis or lumbar fusion, current infection or fever;
• 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;
• 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.

Sponsors & Collaborators

• Washington University School of Medicine: lead

Study Sites (1)

Washington University in St. Louis

St Louis, Missouri, 63110, United States

Location

Related Publications (4)

• 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.

  PMID: 20849570 BACKGROUND

• 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.

  PMID: 22395856 BACKGROUND

• 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.

  PMID: 25575710 BACKGROUND

• 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.

  PMID: 19427839 BACKGROUND

MeSH Terms

Conditions

Neuralgia

Interventions

Ondansetron; Sodium Chloride; tariquidar

Condition Hierarchy (Ancestors)

Peripheral Nervous System Diseases; Neuromuscular Diseases; Nervous System Diseases; Pain; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Carbazoles; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds, 3-Ring; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• Simon Haroutounian, PhD

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Anesthsiology

Study Record Dates

• First Submitted: January 14, 2019
• First Posted: January 18, 2019
• Study Start: May 20, 2019
• Primary Completion: November 30, 2020
• Study Completion: November 30, 2020
• Last Updated: April 7, 2022

Record last verified: 2022-03

Locations

US (1)