Low-dose tolvaptan PK/PD: comparison of patients with hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion to healthy adults

Eur J Clin Pharmacol. 2017 Nov;73(11):1399-1408. doi: 10.1007/s00228-017-2302-7. Epub 2017 Aug 12.


Purpose: Tolvaptan (TLV) is indicated to treat hyponatremia due to syndrome of inappropriate diuretic hormone (SIADH) in Europe. Treatment is to be initiated at 15 mg QD but post-approval reporting indicates increasing use of 7.5 mg as the starting dose. Physicians believe 7.5 mg is effective and has a lower incidence of overly rapid correction of serum sodium.

Methods: Single TLV doses of 3.75, 7.5, and 15 mg were administered to 14 healthy adults in a crossover design and to 29 subjects ≥18 years with SIADH and serum sodium between 120 and 133 mmol/L in a parallel-group design. Pharmacodynamics and TLV plasma concentrations were assessed for 24 h post-dose.

Results: In SIADH subjects, corrections of serum sodium (Δ of ≥8 mmol/L in the first 8 h or ≥12 mmol/L in the first 24 h) were observed in one, one, and two subjects in the 3.75-, 7.5-, and 15-mg dose groups. Fluid balance (FB) for 0-6 h post-dose was correlated (r 2 = 0.37) with maximum increases in serum sodium; subjects with large corrections had large (~1 L) negative FB. Compared to healthy adults, subjects with SIADH did not drink in response to their negative FB and had larger increases in serum sodium at 24 h. Median time of maximum increase in healthy adults was 6 h, with no rapid corrections, and FB was near 0 mL by 24 h.

Conclusion: Starting titration with 7.5 mg TLV will not eliminate the risk of rapid corrections in serum sodium. Monitoring FB may indicate that a subject is at risk for over correction.

Keywords: Healthy subjects; Pharmacodynamics; Pharmacokinetics; Syndrome of inappropriate diuretic hormone (SIADH); Tolvaptan.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antidiuretic Hormone Receptor Antagonists / administration & dosage*
  • Antidiuretic Hormone Receptor Antagonists / pharmacokinetics
  • Antidiuretic Hormone Receptor Antagonists / pharmacology
  • Benzazepines / administration & dosage*
  • Benzazepines / pharmacokinetics
  • Benzazepines / pharmacology
  • Creatinine / urine
  • Cross-Over Studies
  • Double-Blind Method
  • Female
  • Healthy Volunteers
  • Humans
  • Hyponatremia / blood
  • Hyponatremia / etiology
  • Hyponatremia / metabolism*
  • Hyponatremia / urine
  • Inappropriate ADH Syndrome / blood
  • Inappropriate ADH Syndrome / complications
  • Inappropriate ADH Syndrome / metabolism*
  • Inappropriate ADH Syndrome / urine
  • Male
  • Middle Aged
  • Potassium / urine
  • Sodium / blood
  • Sodium / urine
  • Tolvaptan


  • Antidiuretic Hormone Receptor Antagonists
  • Benzazepines
  • Tolvaptan
  • Sodium
  • Creatinine
  • Potassium