Bioavailability Study Comparing Tolvaptan Administered Via Nasogastric Tube to Tolvaptan Tablets Swallowed Intact

• Area under the plasma drug concentration-time curve from time 0 to infinity (AUC) [ Time Frame: PK samples: from pre-dose to 36 hours ] [ Designated as safety issue: No ]
• Area under the plasma drug concentration-time curve from time 0 to the last quantifiable point (AUC(0-t)) [ Time Frame: PK samples: from pre-dose to 36 hours ] [ Designated as safety issue: No ]
• Maximum plasma concentration (Cmax) [ Time Frame: PK samples: from pre-dose to 36 hours ] [ Designated as safety issue: No ]
• Time to maximal concentration (Tmax) [ Time Frame: PK samples: pre-dose to 36 hours ] [ Designated as safety issue: No ]

The purpose of the study is to compare the relative bioavailability and pharmacokinetics of tolvaptan 15 mg tablets administered orally versus tolvaptan via nasogastric (NG) tube in healthy male and female subjects.

This study is an open 2-treatment, 2-period, 2-sequence crossover study to compare the relative bioavailability of tolvaptan tablets to tolvaptan given via nasogastric tube in 28 healthy adults. Subjects will be randomized to one of the two treatment sequences; either tolvaptan oral tablets swallowed intact followed by a tablet crushed and administered via nasogastric tube, or the reverse sequence. Serial pharmacokinetic samples will be collected following each tolvaptan administration and safety assessments will be performed. The relative bioavailability of tolvaptan administered via nasogastric tube will be compared to tolvaptan tablets swallowed intact.

This study is an open 2-treatment, 2-period, 2-sequence crossover study to compare the relative bioavailability of tolvaptan tablets to tolvaptan NG in 28 healthy adults. The study will be conducted at the University of North Carolina (UNC) Hospital in the Clinical Translational Research Center (CTRC). The study will consist of three phases (screening and two drug administration visits). Subjects will be randomized to one of the two treatment sequences; either tolvaptan oral tablets swallowed intact followed by a tablet crushed and administered via nasogastric (NG) tube, or the reverse sequence. Because enrollment will be staggered and males and females enrolled, the randomization will be blocked (groups of 4) to minimize imbalance in assignment to the two sequences during the enrollment period, and will be used in a bidirectional fashion to balance gender, with males entering with the lowest subject numbers (#1, #2, etc.), and females with the highest subject numbers (#32, #31, etc.) in the randomization schedule. The biomedical informatics core will generate the randomization schedule. During each inpatient phase, pharmacokinetic parameters will be monitored for 36 hours. Subjects will remain in the CTRC for 24 hours after each drug administration to allow for adequate pharmacokinetic sampling. Subjects will return to the clinic on study days 2 and 9 of the study schedule for 30 and 36 hour blood samples. Subjects will then undergo a one-week washout period and then will be crossed over to the alternative mode of administration. Subjects will be discharged from the study after vital signs are checked on study days 2 and 9 of the study schedule at 36 hours, assuming the subject is hemodynamically stable.

• Drug: Tolvaptan
  Tolvaptan 15 mg administered once orally as an intact tablet.
  Other Name: Samsca
• Drug: Tolvaptan
  Tolvaptan 15 mg administered once via nasogastric tube.
  Other Name: Samsca

• Experimental: Tolvaptan Intact Tablet Orally
  Intervention: Drug: Tolvaptan
• Experimental: Tolvaptan via Nasogastric Tube
  Intervention: Drug: Tolvaptan

Inclusion Criteria:

1. Healthy - defined as being free from significant cardiac, pulmonary, gastrointestinal, hepatic, biliary, renal, hematological, neurological and psychiatric disease as determined by history, physical examination and clinical laboratory test results.
2. Male or female between 18 and 40 years of age inclusive, at the time of signing the informed consent.

3. A female is eligible to enter and participate in this study if she is of:

   i. Non-child bearing potential (i.e. postmenopausal, surgically sterile, bilateral tubal ligation, or oophorectomy); or

   ii. Child bearing potential, has a negative serum pregnancy test at screening, a negative urine pregnancy test on each admission day, and certifies compliance with one of the following:

   • Complete abstinence from intercourse from 2 weeks prior to administration of the study drug, throughout the study, and 3 days after completion or premature discontinuation from the study to account for elimination of the study drug; or
   • Sterilization of monogamous male partner; or
   • Oral contraceptives if the subject has been taking them continuously for at least three months prior to the study; or
   • Any FDA approved non-hormonal intrauterine device (IUD); or
4. Within 20% of ideal body weight based on the subject's height (inches) and weight (kg).
5. Willing and able to give written informed consent prior to entering the study.

Exclusion Criteria:

1. Participated in another study within 30 days of the study period.
2. A serum sodium less than 135 mEq/L at screening or on study days 1 or 8 of the study schedule.
3. A positive urine or serum pregnancy test, or are currently breast-feeding.
4. A history of intestinal surgery or gastrointestinal disorder that may affect drug absorption.
5. Any clinically significant abnormal result on the screening blood tests, ECG, or physical exam.
6. Use of CYP3A4 inhibitors or inducers as medications, juices, or herbal supplements within 96 hours prior to the study period.
7. Use of oral or intravenous antibiotics within 14 days of the study period.
8. A current history of alcohol or drug abuse.
9. Any alcohol consumption within 24 h prior to study days 1 and 8 of the study schedule.