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出境医 / 临床实验 / Pgp Transporter and CNS Biodistribution of Ondansetron in Healthy Volunteers

Pgp Transporter and CNS Biodistribution of Ondansetron in Healthy Volunteers

Study Description
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.

Condition or disease Intervention/treatment Phase
Neuropathic Pain Drug: Ondansetron 8mg with Saline & Tariquidar Drug: Ondansetron 16mg with Saline & Tariquidar Phase 1

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 Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: Single (Participant)
Primary Purpose: Other
Official Title: Effects of Pgp Transporter Inhibition on CNS Biodistribution of Ondansetron in Healthy Volunteers
Actual Study Start Date : May 20, 2019
Actual Primary Completion Date : November 30, 2020
Estimated Study Completion Date : November 30, 2021
Arms and Interventions
Arm Intervention/treatment
Experimental: Ondansetron with 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.
 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.

Drug: 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.
Placebo Comparator: Ondansetron with Placebo
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
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.

Drug: 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.
Outcome Measures
Primary Outcome Measures :
  1. CSF penetration of ondansetron with and without tariquidar - area under the curve (AUC) [ Time Frame: 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 :
  1. Cmax CSF [ Time Frame: 48 hours ]
    Maximum CSF concentration (Cmax CSF) of ondansetron, compared between the sessions

  2. CSF:plasma concentration ratio [ Time Frame: 48 hours ]
    CSF:plasma concentration ratio of ondansetron, compared between the two sessions

  3. Plasma Cmax [ Time Frame: 48 hours ]
    Maximum plasma concentration (Cmax) of ondansetron, compared between the sessions


Other Outcome Measures:
  1. Evaluation of analgesic effect of ondansetron in an experimental heat pain model [ Time Frame: 48 hours ]
    Comparison of analgesic effect of ondansetron in an experimental heat pain model: HPTT (as Δ°C from baseline) will be compared between the sessions at 30 min and 50 min after ondansetron infusion completion

  2. Assessment of analgesic effect of ondansetron in an experimental cold pain model [ Time Frame: 48 hours ]
    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.


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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
Contacts and Locations

Locations
Layout table for location information
United States, Missouri
Washington University in St. Louis
Saint Louis, Missouri, United States, 63110
Sponsors and Collaborators
Washington University School of Medicine
Investigators
Layout table for investigator information
Principal Investigator: Simon Haroutounian, PhD Washington University School of Medicine
Tracking Information
First Submitted Date  ICMJE January 14, 2019
First Posted Date  ICMJE January 18, 2019
Last Update Posted Date January 6, 2021
Actual Study Start Date  ICMJE May 20, 2019
Actual Primary Completion Date November 30, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 17, 2019) 		CSF penetration of ondansetron with and without tariquidar - area under the curve (AUC) [ Time Frame: 48 hours ]
CSF penetration of intravenous ondansetron will be determined as AUCCSF0-∞ of ondansetron, and compared between the two sessions, with and without tariquidar
Original Primary Outcome Measures  ICMJE
 (submitted: January 15, 2019) 		CSF penetration of ondansetron with and without tariquidar [ Time Frame: 48 hours ]
CSF penetration of intravenous ondansetron will be determined as AUCCSF0-∞ of ondansetron, and compared between the two sessions, with and without tariquidar
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 15, 2019)
  • Cmax CSF [ Time Frame: 48 hours ]
    Maximum CSF concentration (Cmax CSF) of ondansetron, compared between the sessions
  • CSF:plasma concentration ratio [ Time Frame: 48 hours ]
    CSF:plasma concentration ratio of ondansetron, compared between the two sessions
  • Plasma Cmax [ Time Frame: 48 hours ]
    Maximum plasma concentration (Cmax) of ondansetron, compared between the sessions
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: January 15, 2019)
  • Evaluation of analgesic effect of ondansetron in an experimental heat pain model [ Time Frame: 48 hours ]
    Comparison of analgesic effect of ondansetron in an experimental heat pain model: HPTT (as Δ°C from baseline) will be compared between the sessions at 30 min and 50 min after ondansetron infusion completion
  • Assessment of analgesic effect of ondansetron in an experimental cold pain model [ Time Frame: 48 hours ]
    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.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Pgp Transporter and CNS Biodistribution of Ondansetron in Healthy Volunteers
Official Title  ICMJE Effects of Pgp Transporter Inhibition on CNS Biodistribution of Ondansetron in Healthy Volunteers
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: Single (Participant)
Primary Purpose: Other
Condition  ICMJE Neuropathic Pain
Intervention  ICMJE
  • 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.
  • Drug: 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.
Study Arms  ICMJE
  • Experimental: Ondansetron with 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.
    Interventions:
    • Drug: Ondansetron 8mg with Saline & Tariquidar
    • Drug: Ondansetron 16mg with Saline & Tariquidar
  • Placebo Comparator: Ondansetron with Placebo
    The participants will receive an IV ondansetron infusion with D5W as placebo. Participants will receive either 8mg or 16 mg of iv ondansetron.
    Interventions:
    • Drug: Ondansetron 8mg with Saline & Tariquidar
    • Drug: Ondansetron 16mg with Saline & Tariquidar
Publications *
  • 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.
  • 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.
  • 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.
  • 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: January 15, 2019) 		18
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE November 30, 2021
Actual Primary Completion Date November 30, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 50 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03809234
Other Study ID Numbers  ICMJE 201811167
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party simon.haroutounian, Washington University School of Medicine
Study Sponsor  ICMJE Washington University School of Medicine
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Simon Haroutounian, PhD Washington University School of Medicine
PRS Account Washington University School of Medicine
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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