Pgp Transporter and CNS Biodistribution of Ondansetron in Healthy Volunteers

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.

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