Effects of Tolvaptan in Healthy Adults
Condition: Healthy
Study type: Interventional
Phase: Phase 4

Summary: 
      Tolvaptan is one of new class of medications approved for treatment of low blood sodium
      (hyponatremia). It works by interfering with the effect of the antidiuretic hormone,
      vasopressin, thereby increasing urine output and decreasing body water. However, the
      magnitude of these effects vary from person to person. Thus, the efficacy of tolvaptan is
      less reliable than an infusion of a concentrated salt solution for emergency, short term
      treatment of hyponatremia.

      This study is designed to test 3 hypotheses about the variable efficacy of tolvaptan.

        1. The variable effect on urine output is due to individual differences in blood
           vasopressin which counteracts the effects of tolvaptan.

        2. The differences in blood vasopressin are due to individual differences in the amount
           secreted in response to a rise in blood sodium.

        3. The variable effect on blood sodium is due mainly to the variable effect on urine output
           and can be corrected by maintaining water intake below urine output.

      The study has 2 parts and will be performed in 12 healthy adult males.

        1. Six subjects will receive tolvaptan at a dose of 60 mg by mouth and six subjects will
           receive tolvaptan at 30 mg by mouth. Blood and urine will be collected hourly for 6
           hours and water will be ingested in prescribed amounts. For the next 16 hours, subjects
           will drink at will and blood and urine will be collected 4 more times.

        2. One week later, the same subjects will receive a concentrated salt solution (3% saline)
           by vein for 6 hours. During this time, blood and urine will be collected hourly but
           drinking will not be permitted. For the next 4 hours, subjects will be allowed to drink
           at will while blood and urine are collected twice more.

      The volume, concentration and creatinine content of each urine will be determined. Blood will
      be analyzed for sodium, vasopressin and, in the first study, tolvaptan.
    

Detailed description: 
      Subjects:12 healthy adult males, age 21-55,will be recruited via posters in medical center.
      They must pass screening history & physical examination and abstain from ingestion of
      grapefruit products for 3 days prior to study and from all caffeinated beverage for 24 hours
      before study.

      Procedures: Each subject will receive two different treatments one week apart. Each time,they
      will fast overnight, present to the Northwestern University Clinical Research Unit at
      Northwestern Memorial Hospital at about 0700 hours and be given a light breakfast. At 0900
      hours, staff will collect a completely voided urine (U0)and venous blood sample of 20 mL
      (B0)then weigh subject to nearest 0.1 kg, record vital signs (pulse rate and blood pressure),
      obtain a thirst score (rating from 1 to 10)and begin the treatment.

        1. The treatment on the first admission will be tolvaptan. Six subjects will receive
           tolvaptan at a dose of 60 mg by mouth and six subjects will receive tolvaptan at 30 mg
           by mouth. Hourly for the next 6 hours (i.e. until 1500 hours), all the measurements and
           samples obtained at baseline will be repeated as before. In addition, the subject will
           drink a volume of water that is 5 mL/kg body weight lower than the volume of urine just
           voided. This is expected to raise plasma sodium by about 7 millimoles/L in 6 hours. For
           the next 16 hours, subjects will remain and be allowed to drink at will. In addition,
           they will be served dinner at approximately 1700 hours and all the measures obtained at
           baseline will be repeated again at 1700, 1900, 2300 and 0700 hours when subjects will be
           discharged.

        2. On the second admission one week later, the procedures will be identical to the first
           admission with following exceptions: (a) instead of tolvaptan, at 0900 hours, subjects
           will be started on an infusion of 3% saline at a rate of 0.033 mL/min/kg body weight.
           This infusion will continue for 6 hours (i.e. until 1500 hours) and is expected to raise
           plasma sodium about 7 millimoles/L), the same as the tolvaptan treatment;(b) the volume
           of blood removed each time will be smaller (10 mL) since they will not be assayed for
           tolvaptan; (c)subjects will not be permitted to drink during the infusion. In addition,
           subjects will remain in the unit for only 4 more hours (until 1900 hours). During this
           time, they will be permitted to drink at will, will be served dinner at about 1700 hours
           and will have all baseline measurements repeated at 1700 and 1900 hours.

      The data collected during these two tests will be obtained as follows:

        1. weight in kg to the nearest 0.1 kg

        2. thirst intensity as rated by the subject on a scale of 1 to 10.

        3. pulse and blood pressure recumbent

        4. urine volume to the nearest 5 mL

        5. urine osmolarity by freezing point depression in Clinical Research Unit Core Laboratory

        6. urine creatinine in clinical chemistry laboratory of Northwestern Memorial Hospital

        7. blood placed on ice, centrifuged immediately at 4 C, plasma removed for:

             1. osmolarity by freezing point depression in Clinical Research Unit Core Lab (STAT)

             2. sodium by ion specific electrode in Northwestern Memorial Hospital chemistry
                laboratory after sealed storage at 4 degrees C for 2-16 hours

             3. vasopressin by radioimmunoassay in Clinical Research Unit Core Laboratory after
                sealed storage at -4 C for approximately 6 months

             4. tolvaptan (first study only) by reverse phase, high performance liquid
                chromatography at ICON Labs (Dublin) after storage at -20 C for approximately 6
                months.

      DATA analysis and interpretation will be as follows:

        1. To test the hypothesis that the variable effect of tolvaptan on urine concentration and
           flow depends on the level of plasma vasopressin as well as plasma tolvaptan, the
           relationship between the osmolarity of the first 9 urine collections after treatment to
           the area under the curve (AUC) for plasma vasopressin, for plasma tolvaptan and for the
           ratio of plasma tolvaptan/plasma vasopressin during the concurrent time periods will be
           determined by regression analysis in each of the 12 subjects. The same analysis will be
           performed using urine volume instead of urine osmolarity. Hypothesis 1 predicts that in
           all subjects, the best correlation (r value)will be between urine osmolarity and the
           ratio of tolvaptan/vasopressin. It also predicts that the slopes of every individual
           regression line will be negative (i.e. the higher the ratio of tolvaptan to
           vasopressin)the lower the urine osmolarity). However, the slopes may differ between
           subjects owing to individual differences in the concentrating capacity of the kidneys.

        2. To test the hypothesis that the individual differences in plasma vasopressin during
           treatment are due to the inherent,genetically determined differences in the secretory
           response to osmotic (sodium) stimuli that are known to exist in humans, the relationship
           of plasma vasopressin to plasma sodium (or osmolarity)during the first 6 hours of
           treatment with tolvaptan or 3% saline will be determined separately by regression
           analysis and compared. Based on previous findings, the correlation of plasma vasopressin
           to plasma sodium (or osmolarity) should be very high (r>0.9) in every subject during 3%
           saline infusion but the slopes will vary markedly between subjects. The hypothesis
           predicts that these correlations and marked differences in slopes will not differ after
           tolvaptan treatment. This prediction will be tested by regressing the slope during
           tolvaptan against the slope in the same subject during 3% saline infusion in all 12
           subjects. If the hypothesis is correct, the correlation coefficient between the
           individual slopes will be greater than 0.8 and the line describing the relation will
           have a slope approximating 1 with an intercept near zero on both axes.

        3. To test the hypothesis that the variable effect of tolvaptan on plasma sodium can be
           reduced by continuously adjusting fluid intake to a level below urine output by a
           constant amount (5 mL/kg each hour), the relation of plasma sodium to elapsed time over
           the 6 hour period after tolvaptan and during saline infusion will be calculated
           separately for each subject by regression analysis and compared. If the hypothesis is
           correct, the correlation coefficients for the tolvaptan and saline treatments should be
           uniformly high e.g. greater than 0.9 in all subject even though the slopes of the lines
           describing these relationships may differ.
    

Intervention name(s): Tolvaptan; Hypertonic saline infusion
Intervention type(s): Drug; Drug
Intervention description(s): Adult male volunteers will be given a given a 60mg or a 30 mg dose of tolvaptan. Blood and urine samples will be collected at specified time points for the next 24 hours.; A week after the first intervention(tolvaptan), the subjects will undergo a hypertonic saline infusion for 6 hours. Blood and urine samples will be collected at specified time points until 4hour hours after the infusion.
Other intervention name(s): Samsca; 3% saline solution
Intervention MeSH terms: Tolvaptan
Intervention model: Single Group Assignment
Masking: None (Open Label)
Keywords: Tolvaptan; Aquaretic Efficacy