The Pharmacokinetics and Pharmacodynamics of Tolvaptan in Patients with Liver Cirrhosis with Insufficient Response to Conventional Diuretics: a Multicentre, Double-blind, Parallel-group, Phase III Study

• Published in: Journal of international medical research 2012-12, Vol.40 (6), p.2381-2393
• Main Authors: Sakaida, I, Yanase, M, Kobayashi, Y, Yasutake, T, Okada, M, Okita, K, Kageyama, Fujito, Miyaoka, Hiroaki, Nakamura, Hiroki, Sakaeda, Hiroshi, Kariyama, Kazuya, Takaishi, Kenji, Joukou, Kouji, Nakamuta, Makoto, Oshita, Masahide, Arai, Masahiro, Mita, Masaki, Omoto, Masaki, Shibatouge, Mitsushige, Tajiri, Nobuyoshi, Tanaka, Nobuyoshi, Mochida, Satoshi, Sakisaka, Syotaro, Ichida, Takafumi, Inokuma, Tetsuro, Takayanagi, Toshiaki, Saibara, Toshiji, Kimura, Toshiyuki, Aihara, Tsukasa, Tokumoto, Yoshio
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Antidiuretic Hormone Receptor Antagonists; Ascites - drug therapy; Benzazepines - pharmacokinetics; Benzazepines - pharmacology; Benzazepines - therapeutic use; Diuretics - therapeutic use; Double-Blind Method; Electrolytes - blood; Electrolytes - urine; Female; Humans; Liver Cirrhosis - drug therapy; Male; Middle Aged
• ISSN: 0300-0605; 1473-2300
• DOI: 10.1177/030006051204000637

OBJECTIVES: This study investigated the pharmacokinetic and pharmaco -dynamic profile of tolvaptan, and verified its efficacy and safety in patients with liver cirrhosis-associated ascites, with insufficient response to conventional diuretic treatment. Methods: This multicentre, doubleblind, parallel-group study allocated patients with cirrhosis to receive either 3.75 or 7.5 mg/day tolvaptan orally, once daily, for 7 days. Pharmacokinetic, pharmacodynamic and efficacy variables were measured. Results: Tolvaptan was shown to have high plasma concentrations, and prolonged duration of maximum concentration and half life, in these patients with impaired hepatic function. Tolvaptan resulted in dose-dependent decreases in body weight and ascites volume, and increases in urine output. There were no effects on urinary or serum electrolytes. Tolvaptan was well tolerated, with a good safety profile. Conclusions: Tolvaptan at 3.75 mg/day exerts some effects due to the pharmacokinetic profile in patients with liver cirrhosis. Tolvaptan at 7.5 mg/day is a clinically useful option for treating patients who do not respond well to conventional diuretics.