Pharmacokinetics and Pharmacodynamics of Oral Tolvaptan Administered in 15- to 60-mg Single Doses To Healthy Korean Men

Abstract

Tolvaptan is a selective arginine vasopressin V2-receptor antagonist that is used as an aquaretic agent. This trial investigated the pharmacokinetics and pharmacodynamics of 15- to 60-mg single oral doses of tolvaptan in healthy Korean men. A dose block-randomized, placebo-controlled, double-blind, single ascending dose trial was conducted with 46 subjects receiving tolvaptan (15, 30, or 60 mg) or placebo. To determine pharmacokinetics and pharmacodynamics, blood and urine samples were collected at baseline and up to 48 hours after drug administration. Urine volume and fluid intake were measured for 24 hours starting the day before dosing (day -1) as baseline, and on the day of drug administration (day 1). Tolvaptan showed dose-linear pharmacokinetic characteristics regarding area under the concentration-time curve. Changes from baseline in 24-hour urine volume and 24-hour fluid balance correlated significantly with area under the concentration-time curve from time 0 to the last measurable time. Dose-dependent increases were observed in serum osmolality, serum sodium concentration, and free water clearance in the 4- to 8-hour interval after dosing, and these increases were maintained for at least 24 hours. Single 15- to 60-mg doses of tolvaptan exhibited linear pharmacokinetics and resulted in substantial, dose-dependent aquaresis in healthy Korean men.

Randomized, double blinded, placebo‐controlled trial to evaluate the efficacy and safety of tolvaptan in Chinese patients with hyponatremia caused by SIADH

“…Clinical trials with convincing results have shown that tolvaptan was an effective drug in correcting hyponatremia . Furthermore, there have been several studies that assessed the pharmacokinetic properties of tolvaptan in Asian populations . However, the efficacy of tolvaptan in Asian SIADH patients with non‐hypovolemic non‐acute hyponatremia has not been fully elucidated.…”

Analysis of tolvaptan and its metabolites in sports drug testing by high‐performance liquid chromatography coupled to tandem mass spectrometry

“… Published methods for the determination of tolvaptan in plasma involve the use of liquid‐liquid extraction (LLE), solid‐phase extraction (SPE), or protein precipitation for sample preparation. Sample analysis is performed by high‐performance liquid chromatography coupled to tandem mass spectrometry (HPLC‐MS/MS). An excretion of less than 1% of the unchanged drug in urine is described in literature .…”

Bioanalysis of tolvaptan, a novel AVP‐V2 receptor antagonist in human plasma by a novel LC‐ESI‐MS/MS method: a pharmacokinetic application in healthy South Indian male subjects

“…The reported procedures employed PP (Pei et al, 2013) and solid-phase extraction (Shoaf et al, 2007a(Shoaf et al, , 2007b(Shoaf et al, , 2012a(Shoaf et al, , 2012b(Shoaf et al, , 2012cKim et al, 2011;Yi et al, 2012) to extract tolvaptan from human plasma. Based on that, different sample pretreatment methods were investigated.…”

“…As per the literature, several studies (Shoaf et al, 2007a(Shoaf et al, , 2007b(Shoaf et al, , 2012a(Shoaf et al, , 2012b(Shoaf et al, , 2012cKim et al, 2011;Yi et al, 2012;Pei et al, 2013) have investigated the pharmacokinetics of tolvaptan in healthy subjects. Of these, only one report describes the chromatography, method development process and validation details.…”