Effect of High- and Low-sodium Intake on the Pharmacokinetics and Pharmacodynamic Effects of Fimasartan
Condition: Hypertension
MeSH terms: Hypertension
Study type: Interventional
Phase: Phase 4

Summary: 
      It has been known that the blood pressure lowering effect of angiotensin receptor antagonists
      (ARBs) and angiotensin converting enzyme (ACE) inhibitors is impaired in patients on high
      sodium intake. There was an enhanced blood pressure lowering effect of ACE inhibitor when
      sodium intake was restricted or diuretics were added.

      The reason is partially explained by sodium sensitivity or low rennin activity in high sodium
      intake. However, the exact mechanism of sodium intake dependency is not clearly understood.

      In a recent study, an ARB, candesartan was revealed to have sodium intake dependency, showing
      lower plasma concentration when subjects were on high sodium intake compared to on low sodium
      intake. However, plasma concentration of another ARB, valsartan and an ACE inhibitor ramipril
      was not changed depending on the sodium intake.

      The strongly suggested mechanism is the involvement of transporter P-glycoprotein (Pg-P). the
      function and expression of Pg-P are modified by genetic polymorphism of multidrug resistance
      1 gene.

      Although the transport mechanism of Fimasartan from gut is not fully understood, it has been
      known that the multidrug resistance 1 is not involved. Thus, the pharmacokinetic and
      pharmacodynamic property of fimasartan is expected not to be affected by the status of sodium
      intake.

      The present study is designed to investigate whether the pharmacokinetic and pharmacodynamic
      property of fimasartan is changed depending on the sodium intake.
    

Detailed description: 
      The study design is a two-diet, two-period, two-sequence, randomized, open label and
      cross-over with 1-week diet-washout and 2-weeks drug-washout interval. The participants
      (n=16) are randomly assigned to either of 7 days of low sodium (50 mmol/day) or high sodium
      diet (300 mol) after hospitalization. After completion of 7-days of first period, all
      participants are discharge and recommended to eat usual diet. After 1-week of diet washout,
      all participants are hospitalized for second period. The compliance of diet is determined by
      measurement of 24-hour urine sodium excretion. The 24-hour urine sodium excretion should be <
      100 mmol/24-hour in the low sodium diet period and > 200 mmol/24-hour in high sodium diet
      period.

      On the morning of 7th day of each period (high sodium or low sodium diet period), all
      participants receive 60 mg of fimasartan in the fasting state. Blood samples for
      pharmacokinetic and pharmacodynamic study are drawn for 24-hour.

      The detailed measures are as followings:

        1. High- and low-sodium intake

             1. One of high- or low sodium intake for 7 days during each period

             2. Low sodium intake : 50 mmol/day by diet

             3. High sodium intake: 50 mmol/day by diet + 250 mmol/day by salt tablets

        2. 24 hour excreted amount of sodium in urine to determine the compliance for the high- and
           low-sodium intake

             1. 24 hour excreted amount of sodium in urine for low sodium intake < 100 mmol

             2. 24 hour excreted amount of sodium in urine for high sodium intake > 200 mmol

        3. Vital signs

           a. Systolic and diastolic blood pressures and pulse rate in sitting position and body
           temperature

        4. Blood chemistry and complete blood count

             1. Measure at the morning of first day after overnight fasting

             2. white blood cell count, red blood count, hemoglobin, hematocrit, platelet, Calcium,
                sodium, potassium, glucose, blood urea nitrogen, creatinine, uric acid,
                cholesterol, albumin, total bilirubin, AST, ALT, blood urea nitrogen

        5. Urinalysis

           a. potential of hydrogen, protein, bilirubin, glucose, urobilinogen, ketone, nitrite,
           blood

        6. Pharmacokinetic blood sampling

           a. Plasma samples for fimasartan concentration

        7. Pharmacodynamic blood sampling

             1. Plasma samples for renin activity

             2. Serum samples for aldosterone concentration
    

Intervention name(s): High-sodium diet; low-sodium diet
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): One of high- or low sodium intake for 7 days during each period
High sodium intake: 50 mmol/day by diet + 250 mmol/day by salt tablets; One of high- or low sodium intake for 7 days during each period
Low sodium intake : 50 mmol/day by diet
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment