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

Abstract

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.

Keywords

Ascites Aquaretic effect Diuretic Liver cirrhosis Pharmacokinetics;Pharmacodynamics Tolvaptan

Introduction

Hepatic function plays a central role in the metabolism kinetics of most drugs, with the result that patients with hepatic dysfunction are more sensitive to drug effects compared with those with no hepatic dysfunction. Dose adjustment in patients with hepatic dysfunction may be essential to avoid excessive drug accumulation and serious adverse reactions.¹ Ascites is the most common complication of liver cirrhosis,² but ascites management in patients with liver cirrhosis is complicated by their poor response to conventional diuretics.³ High-dose loop diuretic treatment may have undesirable adverse effects, including activation of the renin–angiotensin and sympathetic nervous systems, electrolyte disturbances, and worsening of renal function.^{4 – 7} making it difficult to perform dose-escalating adjustments (for optimal diuretic effects) in patients with hepatic dysfunction.^{8 – 10}

Renal vasopressin V₂ receptor antagonists increase solute-free water excretion and serum sodium concentrations.^11,12 Tolvaptan (developed by Otsuka Pharmaceutical, Osaka, Japan) is an oral nonpeptide selective vasopressin V₂ receptor antagonist for the treatment of clinically significant hypervolaemic or euvolaemic hyponatraemia (serum sodium < 125 mEq/l) or less-marked hyponatraemia, in patients with heart failure, cirrhosis or syndrome of inappropriate antidiuretic hormone (SIADH).¹³ Tolvaptan selectively binds the vasopressin V₂ receptor and inhibits vasopressin-mediated reabsorption of water in renal collecting ducts, resulting in excretion of electrolyte-free water without increasing electrolyte excretion.^{14 – 17}

Tolvaptan at ≥ 15 mg/day, administered orally, has been shown to improve serum sodium levels effectively in patients with SIADH, cardiac failure or cirrhosis.^18,19 In addition, tolvaptan treatment resulted in decreased body weight and abdominal circumference, and improvements in ascites and oedema, in cirrhotic patients with persistent ascites and/or lower limb oedema.²⁰ A multiple-dose study to assess the pharmacokinetics, pharmacodynamics and safety of tolvaptan in healthy Japanese subjects found dose-dependent aquaretic effects and good tolerability at all doses (≥ 15 mg/day).²¹ Tolvaptan in combination with furosemide exerted diuretic effects and decreased body weight in Japanese patients with heart failure, with 15 mg/day tolvaptan providing better results than 7.5 mg/day.²²

Patients with cirrhosis have impaired liver function, therefore there is an urgent need to evaluate the pharmacokinetics and pharmacodynamics of tolvaptan at lower doses, such as 7.5 mg/day, in these patients.

The present study investigated the pharmacokinetics and pharmacodynamics of 3.75 or 7.5 mg/day tolvaptan, administered orally for 7 days, and verified treatment efficacy and safety in patients with ascites associated with liver cirrhosis.

Patients and methods

Study Population

This multicentre, double-blind, parallel-group, phase III study was conducted between February 2010 and August 2011, at 33 study sites in Japan. Male or female inpatients with liver cirrhosis who fulfilled the following criteria were eligible for inclusion in the study: (i) aged 20 – 80 years; (ii) persistent ascites despite conventional diuretic treatment; (iii) previous imaging diagnosis of liver cirrhosis; (iv) patients whose dose of conventional diuretics could not be increased due to adverse drug reactions or risk of adverse drug reactions, or where efficacy was insufficient; (v) patients who had been receiving one of the following combination therapies (loop diuretic and oral antialdosterone agent): (a) loop diuretic dose equivalent to ≥ 40 mg/day furosemide and ≥ 25 mg/day spironolactone or (b) loop diuretic dose equivalent to ≥ 20 mg/day furosemide and ≥ 50 mg/day spironolactone; (vi) inpatients or patients who could be admitted to the study site; (vii) adequate contraception.

Exclusion criteria were: (i) hepatic encephalopathy (Inuyama classification²³ ≥ grade II), vascular invasive hepatocellular carcinoma, oesophageal or gastric varices requiring new therapy, repeated haemorrhoidal bleeding due to rectal varicose veins, heart failure, anuria or impaired urination; (ii) history of cerebrovascular disorder; (iii) history of hypersensitivity or idiosyncratic reaction to benzazepine derivatives; (iv) body mass index > 35; (v) systolic blood pressure < 90 mmHg; (vi) haemoglobin < 8.0 g/dl, total bilirubin > 4.0 mg/dl, serum creatinine > 2.0 mg/dl, serum sodium > 147 mEq/l or serum potassium > 5.5 mEq/l; (vii) inability to take oral medication; (viii) pregnancy; (ix) history of treatment with albumin products or blood products containing albumins; (x) previous investigational drug treatment; (xi) previous tolvaptan treatment; (xii) patients otherwise judged by the investigator to be inappropriate for inclusion in the study.

All patients provided written informed consent to participate in the study, and the study was approved by the institutional review board at each study site. The study was conducted in compliance with the Declaration of Helsinki according to Good Clinical Practice.²⁴

Treatment Design

The study comprised a screening period, a 3-day pretreatment observation period, a 7-day treatment period and a post-treatment observation period (Fig. 1). After providing informed consent, patients underwent screening tests and were enrolled in the 3-day pretreatment observation period. Patients with ascites ≥ 1000 ml (assessed via computed tomography) and increase or decrease in body weight of ≤ 1.0 kg between days 2 – 3 (or ≤ 2.0 kg between days 1 – 3) of the pretreatment observation period were eligible for treatment. Patients were allocated to receive either 3.75 or 7.5 mg/day tolvaptan in a double-blind manner, taken orally, once daily, after breakfast for 7 days. Concomitant conventional diuretic treatment was fixed from time of patient consent until final tolvaptan dose. Patients were hospitalized from the day before pretreatment observation until the completion of post-treatment observation. Final safety and efficacy evaluations were performed on day 7 following initiation of tolvaptan administration.

Figure 1:

Design of a study to evaluate the efficacy, safety, pharmacokinetics and pharmacodynamics of two different doses of tolvaptan in patients with liver cirrhosis-associated ascites, refractory to conventional diuretic treatment

Pharmacokinetics and Pharmacodynamics

Pharmacodynamic parameters were recorded using data from the pretreatment observation period as the baseline. Parameters included daily urine volume, urine sodium excretion, urine potassium excretion, serum sodium concentration and serum potassium concentration. Urine volume and urinary electrolytes were determined from samples collected at baseline and daily during the treatment period. Blood samples for serum sodium and potassium determination were collected at baseline, 4 – 8 and 22 – 24 h after dosing on day 1, 22 – 24 h after dosing on days 2, 3 or 4, and 22 – 24 h after dosing on day 7.

Pharmacokinetic variables of tolvaptan included maximum plasma concentration (Cmax), area under the curve at 24 h (AUC24h), maximum drug concentration time (tmax, h) and half-life (t½, h). Blood samples were collected in sterile tubes containing heparin sodium at 2, 4, 6, 8, 12 and 24 h postdose on days 1 and 7 of the treatment period. Plasma tolvaptan was quantified via liquid chromatography/mass spectrometry (API 3000; MDSSciex, Toronto, Canada), with a limit of detection of 2 ng/ml.

Efficacy Evaluation

Efficacy was evaluated using data from the pretreatment observation period as baseline. Criteria included changes in body weight, ascites volume and abdominal circumference, and were used as a reflection of overall volume status. Body weight was measured before breakfast and after urination at baseline and on days 1 – 7 of treatment. Ascites volume was measured via computed tomography at baseline and on day 7. Abdominal circumference was measured before breakfast at baseline and on day 7.

Safety Assessment

Safety evaluation was based on the assessment of physical signs and symptoms, laboratory tests (haematology, clinical chemistry and urinalysis), vital signs (blood pressure, pulse rate and body temperature), 12-lead electrocardiography, and pregnancy test (in women of childbearing age).

Statistical Analyses

The study used separate analysis sets for pharmacodynamics, pharmacokinetics, efficacy and safety analyses. Demographic and other baseline characteristics were calculated by treatment group. Descriptive statistics of plasma concentrations and pharmacokinetic parameters of tolvaptan at each timepoint were calculated by group and treatment day. Pharmacokinetic parameters were calculated using pharmacokinetic analysis software (WinNonlin^®, version 5.3; Pharsight Corporation, Mountain View, CA, USA). Descriptive statistics were calculated for each treatment group, for measured values and changes from baseline in pharmacodynamic parameters, body weight, ascites volume and abdominal circumference.

Statistical analyses were performed using SAS^® software, version 9.1.3 (SAS Institute, Cary, NC, USA). Paired Student's t-test was used to examine differences in variables on outcome measures at baseline and treatment assessments. A two-tailed P-value < 0.05 was considered statistically significant.

Results

In total, 65 patients were enrolled in the study, 40 of whom fulfilled inclusion and screening criteria, and underwent treatment. A flowchart indicating study recruitment, group allocation and treatment compliance is shown in Fig. 2. In the 3.75 mg/day group, three of 19 patients withdrew from the study (gastrointestinal haemorrhage n = 1, protocol violation n = 2), and four of 21 patients in the 7.5 mg/day group discontinued treatment (hepatic encephalopathy n = 1, withdrawal of consent n = 1, investigators' decisions n = 2). In total 33/40 (82.5%) patients completed treatment. Baseline demographic and clinical characteristics of the study groups are shown in Table 1.

Figure 2:

Flow chart indicating the recruitment and randomization of patients with liver cirrhosis-associated ascites refractory to conventional diuretic treatment, included in a study to evaluate the efficacy, safety, pharmacokinetics and pharmacodynamics of two different doses of tolvaptan

Table 1:

Baseline demographic and clinical characteristics of patients with liver cirrhosis-associated ascites refractory to conventional diuretic treatment, included in a study to evaluate the efficacy, safety, pharmacokinetics and pharmacodynamics of two different doses of oral tolvaptan (n = 40)

Characteristic	Tolvaptan daily dose
Characteristic	3.75 mg n = 19	7.5 mg n = 21
Age, years	67.3 ± 9.3	64.2 ± 10.4
Males	14 (73.7)	13 (61.9)
Body weight, kg	58.0 ± 10.3	59.3 ± 9.1
Abdominal circumference, cm	91.6 ± 8.7	91.3 ± 9.0
Ascites, ml	3313 ± 2051	3771 ± 2390
Albumin, g/dl	2.8 ± 0.5	2.8 ± 0.7
Creatinine, mg/dl	1.0 ± 0.3	1.1 ± 0.4
Cause of cirrhosis
Hepatitis B	1 (5.3)	0 (0.0)
Hepatitis C	11 (57.9)	9 (42.9)
Alcoholic cirrhosis	5 (26.3)	10 (47.6)
Primary biliary cirrhosis	0 (0.0)	0 (0.0)
Other	2 (10.5)	4 (19.1)
Child–Pugh classification (A/B/C)^25,26	0/9/10	0/11/10
Paracentesis ≤ 90 days before treatment	5 (26.3)	12 (57.1)
Hepatic encephalopathy	1 (5.3)	1 (4.8)
Liver cancer	4 (21.1)	6 (28.6)
Sodium restriction	8 (42.1)	13 (61.9)

Data presented as mean ± SD or n (%) of patients.

No statistically significant between-group differences (P ≥ 0.05; paired Student's t-test).

Pharmacodynamic and efficacy datasets included 16/19 patients in the 3.75 mg/day group (n = 3 exclusions for protocol violations) and 20/21 patients in the 7.5 mg/day group (n = 1 exclusion for deviation from inclusion criteria). Pharmacokinetic datasets included 17/19 patients in the 3.75 mg/day group (n = 2 exclusions for protocol violations) and 20/21 patients in the 7.5 mg/day group (n = 1 exclusion for deviation from inclusion criteria). In the 3.75 mg/day group, one patient was judged to be eligible for pharmacokinetic evaluation despite protocol violation. In the 7.5 mg/day group, four patients who withdrew during the treatment period were excluded from pharmacokinetic, pharmacodynamic and efficacy evaluations thereafter. Patients who received ≥ 1 dose of tolvaptan were included in the safety evaluation dataset.

Pharmacokinetic parameters of tolvaptan are shown in Table 2. The C_max and AUC_24h were higher on day 7 than on day 1 in both treatment groups, and higher in the 7.5 mg/day group than the 3.75 mg/day group on both days 1 and 7, but none of these differences was statistically significant.

Table 2:

Pharmacokinetic parameters of oral tolvaptan in patients with liver cirrhosis-associated ascites refractory to conventional diuretic treatment

Parameter	Tolvaptan daily dose
	3.75 mg		7.5 mg
	Day 1	Day 7	Day 1	Day 7
C_max, ng/ml	66.2 ± 36.8	79.6 ± 41.7	100.5 ± 54.3	112.5 ± 60.4
	n = 17	n = 17	n = 20	n = 16
AUC_24h, ng/h per ml	753.6 ± 412.1	902.3 ± 566.7	1060.7 ± 732.3	1370.4 ± 1164.6
	n = 13	n = 12	n = 16	n = 15
t_max, h	6.0 ± 2.6	4.9 ± 2.9	5.6 ± 2.4	4.2 ± 1.7
	n = 17	n = 17	n = 20	n = 16
t_½, h	8.7 ± 4.2	14.5 ± 20.1	9.1 ± 5.4	8.5 ± 4.1
	n = 13	n = 12	n = 16	n = 15

Data presented as mean ± SD.

Cmax, maximum plasma concentration; AUC24h, area under the curve at 24 h; tmax, duration of maximum concentration; t½, half life.

No statistically significant differences (P ≥ 0.05; paired Student's t-test, within group comparisons; unpaired Student's t-test, between-group comparisons).

Figure 3 presents the 24-h timecourse of plasma tolvaptan concentrations on days 1 and 7 in both groups. Plasma tolvaptan concentrations remained at detectable levels at 24 h after administration on day 1 in both treatment groups. Tolvaptan concentrations before administration on day 7 were not higher than those 24 h after administration on day 1.

Figure 3:

Timecourse of plasma concentration of tolvaptan in the 24-h period following administration of (A) 3.75 or (B) 7.5 mg doses orally, in patients with persistent ascites associated with liver cirrhosis, on days 1 and 7 of treatment

Changes in daily urine volume from baseline and during the treatment period are shown in Table 3. Daily urine volumes were significantly higher than baseline in both treatment groups throughout the treatment period (P < 0.05 for all comparisons).

Table 3:

Daily urine volume and change from baseline in patients with liver cirrhosis-associated ascites refractory to conventional diuretic treatment, following daily oral administration of 3.75 or 7.5 mg tolvaptan

Timepoint	3.75 mg/day					7.5 mg/day
Timepoint	n	Urine ml	n	Change ml	Statistical significance^a	n	Urine ml	n	Change ml	Statistical significance^a
Baseline	15	1358 ± 630				19	1235 ±564
Day 1	16	1818 ± 762	15	486 ± 409	P = 0.0004	20	2081 ± 999	19	857 ±697	P < 0.0001
Day 2	16	1791 ± 682	15	429 ± 538	P = 0.0080	19	1878 ± 684	18	604 ± 506	P < 0.0001
Day 3	16	1667 ± 633	15	344 ± 472	P = 0.0136	18	1895 ± 807	17	584 ± 666	P = 0.0023
Day 4	16	1789 ± 762	15	475 ± 541	P = 0.0043	16	2024 ± 960	16	687 ± 882	P = 0.0071
Day 5	16	1715 ± 666	15	339 ± 583	P = 0.0406	16	1869 ± 754	16	532 ± 526	P = 0.0011
Day 6	16	1733 ± 827	15	382 ± 606	P = 0.0284	16	1864 ± 782	16	527 ± 518	P = 0.0010
Day 7	15	1748 ± 926	14	438 ± 657	P = 0.0268	16	2013 ± 813	16	676 ± 660	P = 0.0010

Data presented as mean ± SD.

Paired Student's t-test.

Table 4 presents data regarding total daily urinary sodium excretion. There were no significant changes from baseline in sodium excretion in either treatment group at day 1 or day 7. In addition, there were no significant changes from baseline in daily urinary potassium excretion in either group at day 1 or day 7 (data not shown).

Table 4:

Urinary sodium excretion and change from baseline in patients with liver cirrhosis-associated ascites refractory to conventional diuretic treatment, following daily oral administration of 3.75 or 7.5 mg tolvaptan

Dose	n	Timepoint	Sodium mEq/l	n	Change mEq/l
3.75 mg/day	15	Baseline	85.4 ± 44.6
	16	Day 1	80.3 ± 32.1	15	-4.0 ± 21.3
	14	Day 7	77.9 ± 36.4	13	-7.4 ± 29.5
7.5 mg/day	18	Baseline	79.1 ± 50.8
	20	Day 1	88.5 ± 55.3	18	8.6 ± 34.9
	16	Day 7	106.8 ± 58.5	15	17.6 ± 42.9

Data presented as mean ± SD.

No statistically significant differences (P ≥ 0.05; paired Student's t-test).

Treatment with 3.75 mg/day tolvaptan had no significant effect on serum sodium concentrations (Table 5). In the 7.5 mg/day group, however, serum sodium concentrations were significantly higher than baseline at 24 h, days 2 – 4 and day 7 (P < 0.05 for all comparisons; Table 5), although these values remained within normal limits (135 – 144 mEq/l).^27,28 There were no statistically significant changes in serum potassium concentrations at any timepoint in either group (data not shown).

Table 5:

Serum sodium concentration and change from baseline in patients with liver cirrhosis-associated ascites refractory to conventional diuretic treatment, following daily oral administration of 3.75 or 7.5 mg tolvaptan

Dose	n	Timepoint	n	Sodium mEq	Change mEq/l	Statistical significance^a
3.75 mg/day	16	Baseline		133.4 ± 4.5
	16	Day 1 (4 – 8 h)	16	133.4 ± 4.5	0.0 ± 2.5	NS
	16	Day 1 (24 h)	16	134.2 ± 4.4	0.8 ± 2.0	NS
	16	Day 2, 3 or 4	16	134.5 ± 5.3	1.1 ± 2.1	NS
	15	Day 7	15	133.2 ± 5.6	-0.1 ± 2.8	NS
7.5 mg/day	20	Baseline		133.9 ± 3.4
	20	Day 1 (4 – 8 h)	20	134.6 ± 4.4	0.8 ± 2.8	NS
	20	Day 1 (24 h)	20	135.7 ± 4.1	1.8 ± 1.8	P = 0.0003
	19	Day 2, 3 or 4	19	136.3 ± 3.9	2.5 ± 1.2	P < 0.0001
	16	Day 7	16	135.1 ± 3.1	1.3 ± 2.2	P = 0.0295

Data presented as mean ± SD.

Paired Student's t-test.

NS, not statistically significant (P ≥ 0.05).

Tolvaptan treatment induced significant decreases in body weight from baseline, starting from day 1, in both groups (P < 0.05 for all comparisons; Table 6). The decrease in body weight reached a plateau on day 4 in the 3.75 mg/day group, but patients in the 7.5 mg/day group continued to lose weight throughout the treatment period. Significant decreases in ascites volume on day 7 compared with baseline occurred in both treatment groups (P < 0.05 for both comparisons; Table 7). Abdominal circumference was smaller on day 7 than baseline in both groups, but this was only statistically significant in the 3.75 mg/day group (P = 0.028; Table 7).

Table 6:

Body weight and change from baseline in patients with liver cirrhosis-associated ascites refractory to conventional diuretic treatment, following daily oral administration of 3.75 or 7.5 mg tolvaptan

Timepoint	3.75 mg/day					7.5 mg/day
Timepoint	n	Weight kg	n	Change kg	Statistical significance^a	n	Weight kg	n	Change kg	Statistical significance^a
Baseline	16	57.4 ± 10.6				20	58.9 ± 9.1
Day 1	16	57.0 ± 10.8	16	-0.4 ± 0.4	P = 0.0005	20	58.1 ± 8.9	20	-0.7 ± 0.9	P = 0.0019
Day 2	16	56.9 ± 10.7	16	-0.5 ± 0.6	P = 0.0044	19	58.5 ± 8.8	19	-0.8 ± 0.9	P = 0.0015
Day 3	16	56.7 ± 10.5	16	-0.8 ± 0.7	P = 0.0009	18	58.8 ± 8.8	18	-1.0 ± 1.3	P = 0.0039
Day 4	16	56.4 ± 10.6	16	-1.0 ± 0.7	P < 0.0001	16	58.4 ± 9.3	16	-1.1 ± 1.7	P = 0.0210
Day 5	16	56.3 ± 10.5	16	-1.1 ± 0.7	P < 0.0001	16	58.3 ± 9.3	16	-1.2 ± 2.0	P = 0.0340
Day 6	16	56.3 ± 10.5	16	-1.1 ± 0.8	P < 0.0001	16	58.1 ± 9.2	16	-1.4 ± 2.3	P = 0.0260
Day 7	15	56.4 ± 10.7	15	-1.1 ± 0.9	P = 0.0002	16	57.9 ± 9.1	16	-1.6 ± 2.2	P = 0.0130

Data presented as mean ± SD.

Paired Student's t-test.

Table 7:

Ascites volume and abdominal circumference at baseline and after treatment with 3.75 or 7.5 mg/day tolvaptan, administered orally, for 7 days in patients with liver cirrhosis-associated ascites refractory to conventional diuretic treatment

Dose	n	Timepoint	n	Ascites ml	Change ml	Statistical significance^a	Abdominal circumference cm	Change cm	Statistical significance^a
3.75 mg/day	16	Baseline		3244 ± 2233			91.3 ± 9.5
	15	Day 7	15	2864 ± 2515	-435 ± 554	P = 0.0088	90.5 ± 9.7	-1.3 ± 2.1	P = 0.0280
7.5 mg/day	20	Baseline		3881 ± 2396			90.8 ± 8.9
	16	Day 7	16	3444 ± 2807	-643 ± 1078	P = 0.0310	88.5 ± 11.4	-2.0 ± 4.0	NS

Data presented as mean ± SD.

Paired Student's t-test.

NS, not statistically significant (P ≥ 0.05).

There were no deaths in the present study. Table 8 lists adverse events experienced by patients included in the safety evaluation dataset. Serious adverse events included hepatic encephalopathy (one patient at 3.75 mg/day and three patients at 7.5 mg/day). Adverse events were reported in 13/19 patients (68.4%) in the 3.75 mg/day group and 15/21 (71.4%) patients in the 7.5 mg/day group.

Table 8:

Adverse events following daily oral administration of 3.75 or 7.5 mg tolvaptan for 7 days in patients with liver cirrhosis-associated ascites refractory to conventional diuretic treatment

Adverse event	Tolvaptan daily dose
Adverse event	3.75 mg n = 19^a	7.5 mg n = 21^a	Total n = 40^a
Hepatic encephalopathy	1 (5.3)	3 (14.3)	4 (10.0)
Dry mouth	1 (5.3)	0	1 (2.5)
Thirst	3 (15.8)	7 (33.3)	10 (25.0)
Pollakiuria	0	1 (4.8)	1 (2.5)
Dehydration	1 (5.3)	1 (4.8)	2 (5.0)
Blood potassium increase	2 (10.5)	1 (4.8)	3 (7.5)
Skin exfoliation	3 (15.8)	1 (4.8)	4 (10.0)
Blood pressure decrease	3 (15.8)	0	3 (7.5)

Data presented as n (%) of patients.

Adverse events observed with an incidence ≥ 10% or leading to discontinuation are presented; some patients experienced > 1 adverse event.

Patients who received at least one dose of tolvaptan were included in the safety evaluation.

Discussion

The present study investigated the pharmacokinetic and pharmacodynamic properties, and verified the efficacy and safety profiles of 3.75 and 7.5 mg/day tolvaptan, administered orally in patients with liver cirrhosis-associated ascites refractory to conventional diuretic treatment.

Research in patients with heart failure has reported pharmacokinetic parameters for the 7.5 mg/day tolvaptan that were considerably lower than those observed in the 7.5 mg/day group in the present study.²² In addition, tolvaptan was present at detectable levels in plasma 24 h after administration in the present study, in contrast to the findings in patients with heart failure.²² Tolvaptan plasma concentrations before administration on day 7 were not higher than those observed 24 h after administration on day 1 in the present study, suggesting no accumulation of plasma tolvaptan concentration. The findings of the present study are consistent with drug metabolism being dependent on hepatic function.¹ Tolvaptan is mainly metabolized by cytochrome P₄₅₀ 3A4 (CYP3A4), a member of the human hepatic microsomal cytochrome P₄₅₀ superfamily.²⁹ It is possible that the extended AUC_24h, tmax and t½ of tolvaptan in the present study are associated with diminished CYP3A4 activity, in patients with impaired hepatic function.

Administration of tolvaptan resulted in dose-dependent reductions in body weight, ascites volume and abdominal circumference, and an increase in urine volume, in the present study. There were no changes in urinary electrolyte (sodium and potassium) excretion after administration of 3.75 or 7.5 mg/day tolvaptan, demonstrating the aquaretic effect of this agent.³⁰ In addition, tolvaptan had minimal effects on serum electrolyte concentrations. The effects of 3.75 mg/day tolvaptan on body weight, urine volume, ascites volume and abdominal circumference may be explained by the high AUC_24h and prolonged tmax and t_1/2 in patients with impaired hepatic function due to cirrhosis.³¹ Tolvaptan dose adjustment may be necessary in patients with liver cirrhosis, to find the optimal treatment approach for each patient. Further studies are required to determine a definitive factor or marker for optimal dose adjustment. Although administration of 3.75 mg/day tolvaptan demonstrated significant effects in the present study, 7.5 mg/day may be more beneficial, based on the continuous and consistent decrease in body weight and marked improvement in ascites volume observed at this dose.

In conclusion, 7.5 mg/day tolvaptan is a clinically useful option for the treatment of patients with liver cirrhosis who do not respond well to conventional diuretics, without inducing serum electrolyte abnormalities.

Footnotes

Conflicts of interest: This study was funded by Otsuka Pharmaceutical, Osaka, Japan. Dr Isao Sakaida received research grants from Otsuka Pharmaceutical, MSD, Chugai Pharmaceutical, and Takeda Pharmaceutical, and served as a consultant for Otsuka Pharmaceutical with payment of consultancy fee to Yamaguchi University Graduate School of Medicine. Mitsuru Okada is an employee of Otsuka Pharmaceutical. No other author has any conflict of interest to declare in relation to this article.

References

Verbeeck

: Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction. Eur J Clin Pharmacol 2008; 64: 1147–1161.

Ginès

, Cárdenas

, Arroyo

: Management of cirrhosis and ascites. N Engl J Med 2004; 350: 1646–1654.

Runyon

, for the AASLD Practice Guidelines Committee: Management of adult patients with ascites due to cirrhosis: an update. Hepatology 2009; 49: 2087–2107.

Wong

: Management of ascites in cirrhosis. J Gastroenterol Hepatol 2012; 27: 11–20.

Felker

, Lee

, Bull

: Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med 2011; 364: 797–805.

Gross

: Treatment of hyponatremia. Intern Med 2008; 47: 885–891.

Butler

, Forman

, Abraham

: Relationship between heart failure treatment and development of worsening renal function among hospitalized patients. Am Heart J 2004; 147: 331–338.

Kuiper

, van Buuren

, de Man

: Ascites in cirrhosis: a review of management and complications. Neth J Med 2007; 65: 283–288.

Kuiper

, de Man

, van Buuren

: Review article: management of ascites and associated complications in patients with cirrhosis. Aliment Pharmacol Ther 2007; 26 (Suppl. 2): 183–193.

10.

Moore

, Wong

, Gines

: The management of ascites in cirrhosis: report on the consensus conference of the International Ascites Club. Hepatology 2003; 38: 258–266.

11.

Ireland

: Hyponatremia: prolonged use of the vasopressin antagonist tolvaptan is a safe and effective treatment for hyponatremia. Nat Rev Nephrol 2010; 6: 315.

12.

Decaux

, Soupart

, Vassart

: Non-peptide arginine-vasopressin antagonists: the vaptans. Lancet 2008; 371: 1624–1632.

13.

Yamamura

, Nakamura

, Itoh

: OPC-41061, a highly potent human vasopressin V2-receptor antagonist: pharmacological profile and aquaretic effect by single and multiple oral dosing in rats. J Pharmacol Exp Ther 1998; 287: 860–867.

14.

Veeraveedu

, Watanabe

, Ma

: Effects of nonpeptide vasopressin V₂ antagonist tolvaptan in rats with heart failure. Biochem Pharmacol 2007; 74: 1466–1475.

15.

Gheorghiade

, Konstam

, Burnett

Jr : Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Trials. JAMA 2007; 297: 1332–1343.

16.

Orlandi

, Zimmer

, Gheorghiade

: Tolvaptan for the treatment of hyponatremia and congestive heart failure. Future Cardiol 2006; 2: 627–634.

17.

Gheorghiade

, Orlandi

, Burnett

: Rationale and design of the multicenter, randomized, double-blind, placebo-controlled study to evaluate the Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan (EVEREST). J Card Fail 2005; 11: 260–269.

18.

Konstam

, Gheorghiade

, Burnett

Jr : Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA 2007; 297: 1319–1331.

19.

Schrier

, Gross

, Gheorghiade

: Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med 2006; 355: 2099–2112.

20.

Okita

, Sakaida

, Okada

: A multicenter, open-label, dose-ranging study to exploratively evaluate the efficacy, safety, and dose-response of tolvaptan in patients with decompensated liver cirrhosis. J Gastroenterol 2010; 45: 979–987.

21.

Kim

, Hasunuma

, Sato

: Pharmacokinetics, pharmacodynamics and safety of tolvaptan, a novel, oral, selective nonpeptide AVP V2-receptor antagonist: results of single- and multiple-dose studies in healthy Japanese male volunteers. Cardiovasc Drugs Ther 2011; 25 (Suppl. 1): S5–S17.

22.

Inomata

, Izumi

, Matsuzaki

: Phase III clinical pharmacology study of tolvaptan. Cardiovasc Drugs Ther 2011; 25 (Suppl. 1): S57–S65.

23.

Saito

, Tada

, Nakamoto

: Efficacy of non-invasive elastometry on staging of hepatic fibrosis. Hepatol Res 2004; 29: 97–103.

24.

Giordano

: The 2008 Declaration of Helsinki: some reflections. J Med Ethics 2010; 36: 598–603.

25.

Pugh

, Murray-Lyon

, Dawson

: Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973; 60: 646–649.

26.

del Olmo

, Flor-Lorente

, Flor-Civera

: Risk factors for nonhepatic surgery in patients with cirrhosis. World J Surg 2003; 27: 647–652.

27.

Flear

, Gill

, Burn

: Hyponatraemia: mechanisms and management. Lancet 1981; 318: 26–31.

28.

Miller

: Hyponatremia and arginine vasopressin dysregulation: mechanisms, clinical consequences, and management. J Am Geriatr Soc 2006; 54: 345–353.

29.

Dixon

, Lien

: Tolvaptan and its potential in the treatment of hyponatremia. Ther Clin Risk Manag 2008; 4: 1149–1155.

30.

Vaghasiya

, DeVita

, Michelis

: Serum and urine responses to the aquaretic agent tolvaptan in hospitalized hyponatremic patients. Int Urol Nephrol 2012; 44: 865–871.

31.

Gassanov

, Semmo

: Arginine vasopressin (AVP) and treatment with arginine vasopressin receptor antagonists (vaptans) in congestive heart failure, liver cirrhosis and syndrome of inappropriate antidiuretic hormone secretion (SIADH). Eur J Clin Pharmacol 2011; 67: 333–346.