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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Summary

Background

RWJ-351647 is a selective V2 receptor antagonist that inhibits vasopressin-induced water reabsorption in the kidney.

Aim

To investigate the safety and tolerability of RWJ-351647 compared with placebo after single oral dose administration to patients with cirrhosis and ascites, on a stable treatment with furosemide and spironolactone.

Methods

Single oral doses of 1, 2 and 5 mg of RWJ-351647 were administered to 24 patients with ascites on stable concomitant diuretic treatment.

Results

RWJ-351647 had a tmax of 1 to 1.1 h and mean half-life of 10.4–17.4 h. There was no affect on the pharmacokinetics of concomitant diuretics. Increases in cumulative urine volume and free water excretion, and a decrease in urine osmolality were noted in a dose-dependent manner reaching the statistical significance at the 5-mg dose. Four patients exhibited a decrease of >2 kg in weight in the 24 h after dosing. RWJ-351647 was well tolerated, with no evidence of a dose-related increase in adverse events when compared with placebo. No changes in either serum chemistry or plasma AVP (arginine vasopressin) and renin levels were observed despite the observed aquaresis.

Conclusion

RWJ-351647 is an effective aquaretic causing dose-dependent increases in urine output and free water clearance, when co-administered with conventional diuretics in patients with cirrhosis and ascites.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

The development of ascites in patients with cirrhosis is associated with up-regulation of the renin-angiotensin system, which results in avid sodium retention along with a reduction in glomerular filtration rate. As the disease progresses, splanchnic vascular bed undergoes profound vasodilatation, and this results in further underfilling of systemic vascular compartment. This leads to non-osmotic secretion of antidiuretic hormone (ADH) or vasopressin, which results in the development of dilutional hyponatremia.1 Hyponatremia is a late complication of cirrhosis.

The standard treatment of patients with cirrhosis and ascites includes restriction of sodium intake to <2000 mg/day, and concomitant administration of a loop diuretic in combination with a potassium sparing diuretic (spironolactone or amiloride). However, as liver disease progresses, these diuretics become less effective, and moreover diuretics may induce or worsen hyponatremia. The conventional therapy for hyponatremia includes fluid restriction and discontinuation of diuretics. However, fluid restriction alone is frequently inefficacious. This has stimulated research in the development of drugs that could antagonize the action of ADH (vasopressin), which is a peptide hormone synthesized in the hypothalamus and regulated by osmoreceptors in the hypothalamus and baroreceptors in the heart and large arteries. The biologic effects of ADH are mediated via specific receptors called V1a, V1b and V2 receptors. Activation of the V1a receptor induces vasoconstriction and enhanced prostaglandin release, while the antidiuretic properties of ADH are mediated primarily through the V2 receptors. The V1b (also known as V3) receptor is involved in ACTH (adrenocorticotrophic hormone) release from the pituitary gland. In the kidneys, ADH binds and activates the V2 receptors expressed on the basolateral membrane of the collecting duct. This activation promotes the insertion of aquaporin 2 channels into the luminal surface increasing the permeability of the collecting tubules and ducts. These receptors play a major role in regulating the urine excretion and plasma osmolality. Receptor selective V2 antagonists block the action of ADH in the collecting tubules and can induce selective water loss. These molecules could have therapeutic applications in several water retaining disorders such as SIADH (Syndrome of Inappropriate Antidiuretic Hormone Secretion), cirrhosis, heart failure and nephrotic syndrome in conjunction with traditional diuretic therapy.

RWJ-351647 is an orally active selective vasopressin V2 receptor antagonist that has been shown to inhibit vasopressin-induced water reabsorption from the collecting ducts of the kidney in experimental models including primates.2, 3 In functional cell-based assays, it was shown to be a potent and selective antagonist of the V2 receptor with 140-fold greater antagonist activity against the human V2 receptor than the V1a receptor. No agonistic activity was observed with the compound in V1a, V1b, V2 or oxytocin receptor assays. When given orally, RWJ-351647 showed significant dose-dependent aquaresis and decreases in urine osmolality in rats and monkeys,2, 3 and demonstrated an electrolyte sparing effect expected of a V2 antagonist. Studies in healthy subjects have demonstrated that RWJ-351647 is an effective aquaretic, causing dose-dependent increases in urine output and free water clearance.4 The drug was well tolerated without a dose-related increase in adverse events.

Previous phase I studies with other forms of vasopression antagonists have shown an increase in urine excretion with an associated reduction in urine osmolality and an increase in serum sodium levels in patients with cirrhosis and hyponatremia.5 RWJ-351647 may have a synergistic effect when combined with diuretics in reducing the fluid retention as it works on a different site in the nephron.6 However, RWJ-351647 has not been previously administered to any patients. In this multicentre study, we determined the tolerability, safety, pharmacokinetics and pharmacodynamics of RWJ-351647 when it was added to a stable diuretic regimen of furosemide and spironolactone in patients with cirrhosis and ascites.

Patients and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Patients (age 30–65 years) with cirrhosis and ascites, on a stable diuretic regimen of furosemide (40 mg/day) and spironolactone (100 mg/day), and who failed to lose ≥2 kg weight in the week prior to the study, were included in the study. The diuretics doses for all subjects had been stable at furosemide 40 mg/day and spironolactone 100 mg/day for at least 5 days before randomization, and other treatments for ascites including paracentesis were not allowed within 2 weeks of the study drug. Only those subjects who failed to lose 2 kg in the week prior to study drug while on stable doses of diuretics were eligible for inclusion. Patients were maintained on a sodium-restricted diet (<2000 mg daily) throughout the study. Patients with renal impairment, recent infection, heart failure, head trauma, advanced liver disease (Child–Pugh Class C), prior history of transjugular intrahepatic porto-systemic shunting (TIPS) and those with significant electrolyte (sodium >145 mmol/L, potassium >5.0 mmol/L, serum osmolality >295 mOs/kg) or coagulation disorders (platelets <40 000/mm3, INR (International Normalized Ratio) >2.0) were excluded. Patients were prohibited from consuming the caffeine and other drugs that could impact sodium levels or platelet function for 2 weeks prior to participation in the study.

In this single-dose, sequential ascending dose design study, a single dose of RWJ-351647 1, 2, 5 mg or placebo was administered orally to patients who were hospitalized for the study purpose. At each dose level, six patients received RWJ-351647 and two patients received placebo in a double-blind fashion. Patients were started at 1 mg and the dose was increased to the next level in a different group of patients only after acceptable safety, tolerability, pharmacokinetics, and pharmacodynamics data were obtained.

Patients were screened 9–5 days prior to day 1 (the day of study drug administration). Patients were admitted to the clinical research unit (CRU) on day −2 and were discharged following the completion of assessments at 48 h postdose on day 3. Patients returned to the CRU for a follow-up visit 8–10 days after the dose of study drug. RWJ-351647 or placebo was administered as a single oral dose on day 1. Treatments were administered as an oral suspension in the morning with water after an overnight fast. All patients continued concomitant diuretic medications (40 mg furosemide and 100 mg spironolactone per day). Fluid intake was restricted to the equivalent volume of urine output from the preceding day.

Blood samples for assessment of RWJ-351647, its metabolites, furosemide and spironolactone were collected immediately before dosing and at 1, 2, 4, 6, 8, 10, 24 (day-2) and 48 (day-3) hours postdose. Urine volume (24 h) was measured on the day of the study drug administration (day 1) and the day prior to that (day −1). Urine samples were also collected over set time intervals up to 48 h after administration of RWJ-351647.

Plasma and urine samples were analysed to determine the concentrations of RWJ-351647 and RWJ-800015 (active metabolite) using the liquid chromatography coupled to mass spectrometry. Plasma samples were also analysed to determine the concentrations of spironolactone, furosemide and its metabolites. To ascertain the safety and tolerability of RWJ-351647, adverse events, clinical laboratory tests, vital signs, 12-lead EKG, physical examination and changes in body weight were assessed.

The primary objective of this study was to investigate the safety and tolerability of RWJ-351647 compared with placebo after single oral dose administration to patients with cirrhosis and ascites on a stable treatment with furosemide and spironolactone. The secondary objectives were to evaluate the pharmacokinetics and pharmacodynamics of RWJ-351647 with concomitant furosemide and spironolactone administration. We also evaluated the changes in serum and urine osmolality and electrolyte concentrations. As this was an early development study, no formal statistical calculations of sample size were made. The number of patients included was based upon clinical and statistical judgment and was considered adequate to address the study objectives.

The primary pharmacokinetic parameters analysed for RWJ-351647 and its metabolite RWJ-800015 were plasma AUC and Cmax. Prior to analysis, AUC and Cmax were dose-normalized and loge-transformed.

Statistical analysis

anova modelling, appropriate for a sequential panel design, was used to analyse the data. The estimated least square means and mean square errors from the anova model were used to construct the CI for the differences of the means of the log-transformed pharmacokinetic parameters. Urine volume, urine osmolality, serum osmolality and serum sodium data were analysed at each recorded time point after the RWJ-351647 dose to 24 h by anova with comparisons to investigate the dose–response effect. The study population was defined as all patients who received at least 1 dose of study treatment. sas version 8.2 was used for statistical analysis.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Twenty-four patients (18 male, age 38–61 years) from five centres were treated in this study and all patients completed the study. All treatment groups contained patients of both sexes, and most patients (79%) were white, but all treatment groups had at least one patient from another racial group. Mean serum sodium was in the normal range as shown in Table 1, but six patients had serum sodium between 130 and 135 mmol/L and one patient had sodium <130 mmol/L. All patients had cirrhosis and the cause of cirrhosis included hepatitis C (n = 13), hepatitis C and alcohol (n = 5), hepatitis B (n = 1), alcoholic cirrhosis (n = 3) and cryptogenic cirrhosis (n = 2). The mean Child–Pugh–Turcotte (CPT) score was 8.08 ± 1.4 (median 8, range: 6–11). There were no obvious differences between the treatment groups in all other recorded demographic and baseline measures (Table 1).

Table 1.   Baseline characteristics of study patients
 Placebo (n = 6)RWJ-351647
1 mg (n = 6)2 mg (n = 6)5 mg (n = 6)
  1. Data expressed as mean ± SD.

Age (years)50.5 ± 7.656.5 ± 5.251.5 ± 748.3 ± 1.2
Sex (male)4 (67%)4 (67%)5 (83%)5 (83%)
Race (white)5 (83%)5 (83%)4 (67%)5 (83%)
Body mass index (kg/m2)29.4 ± 10.223.9 ± 3.730.8 ± 6.329.9.7 ± 4.0.7
Serum osmolality (mOsm/kg)290 ± 7283 ± 5286 ± 5287 ± 8
Urine osmolality (mOsm/kg)371 ± 147451 ± 114374 ± 54362 ± 61
Sodium (mmol/L)137 ± 2136 ± 5137 ± 2136 ± 3
Creatinine (mg/dL)1.1 ± 0.40.7 ± 0.10.8 ± 0.20.7 ± 0.1
Albumin (mg/dL)3.1 ± 0.42.6 ± 0.353.2 ± 0.242.9 ± 0.74
Bilirubin (mg/dL)1.4 ± 0.71.7 ± 0.91.6 ± 0.72.0 ± 1
AST (aspartate aminotransferase) (IU/L)56 ± 3166 ± 37101 ± 4183 ± 61
ALT (alanine aminotransferase) (IU/L)35 ± 2243 ± 2564 ± 2547 ± 32
INR (International Normalized Ratio)1.26 ± 0.181.46 ± 0.351.3 ± 0.161.49 ± 0.15
MELD (Model for End-Stage Liver Disease) score11131114

The plasma concentration–time profiles of RWJ-351647 following the administration of 1-, 2- and 5-mg doses (linear and semi-logarithmic scales) are presented in Figure 1a,b. The absorption of RWJ-351647 was rapid, with a median tmax of 1.0–1.1 h. The terminal half-life of RWJ-351647 ranged from 4.6 to 26.4 h and was independent of dose (mean t1/2 values after 1-, 2- and 5-mg doses were 10.4, 17.4 and 12.2 h, respectively). Both Cmax and AUC of RWJ-351647 increased with dose. The variability of the pharmacokinetic parameters of RWJ-351647 (measured as coefficient of variation, CV%,) was high, as expected in this patient population, and ranged from approximately 40–70%. Urinary excretion of RWJ-351647 was negligible at all dose levels.

image

Figure 1.  (a) Mean plasma concentration–time profiles for RWJ-351647 (linear scale). (b) Plasma concentration–time profiles for RWJ-351647 (semi-logarithmic scale).

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The formation of the active metabolite RWJ-800015 was relatively rapid, with tmax values ranging from 1.1 to 4.2 h. As with the parent drug, the half-life was long and independent of dose (mean t1/2 values after 1-, 2- and 5-mg doses of RWJ-351647 were 19.4, 15.9, and 19.7 h, respectively). Both Cmax and AUC of RWJ-800015 increased with dose. Urinary excretion of RWJ-800015 was also negligible at all dose levels of RWJ-351647.

Pharmacokinetics of spironolactone and furosemide

There were no significant differences in the pharmacokinetic profiles of spironolactone (Figure 2a) and furosemide (Figure 2b) on Day −1 compared with those on day 1 after the administration of RWJ-351647. In all analyses, there were no differences between the treatment groups (P > 0.2, all tests) suggesting that single oral doses of up to 5 mg RWJ-351647 did not affect the pharmacokinetics (Cmax, tmax, and AUC0−10 h) of furosemide and spironolactone in patients with cirrhosis and ascites.

image

Figure 2.  (a) Mean plasma concentration profiles of spironolactone following its administration on day −1 and day 1 (linear scale). (b) Mean plasma concentration profiles of furosemide following its administration on day −1 and day 1 (linear scale).

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Pharmacodynamic results

Serum osmolality and serum sodium did not show any consistent differences between the treatment groups, after adjusting for baseline, at any postdose time point (P > 0.1, all tests) (Table 2). No increases in mean serum creatinine concentrations were observed up to 24 h after any dose of RWJ-351647. Similarly no clinically significant changes were seen in other serum biochemistry, haematology, urinalysis, urine biochemistry, plasma renin, plasma arginine vasopressin (APV) levels or coagulation studies.

Table 2.   Serum electrolytes before and after study drug administration
DaySerum Na (mmol/L)Serum K (mmol/L)Serum osmolality (mosm/kg)
P1 mg2 mg5 mgP1 mg2 mg5 mgP1 mg2 mg5 mg
  1. All data are expressed as mean ± SD; all results were non-significant.

Day −2 (48 h predose)137 ± 1.9136 ± 4.7137 ± 2.5136 ± 3.14.4 ± 0.64.0 ± 0.34.0 ± 0.64.2 ± 0.4    
Day −1 (24 h predose)136 ± 2.6136 ± 3.5137 ± 1.5137 ± 2.24.4 ± 0.54.2 ± 0.54.3 ± 0.44.2 ± 0.2290 ± 7.2283 ± 4.9287 ± 5.3287 ± 8.1
Day 2 (24 h postdose)137 ± 2.7137 ± 5.3136 ± 3.8138 ± 3.64.3 ± 0.44.1 ± 0.24.2 ± 0.44.2 ± 0.2289 ± 6.8289 ± 8.1285 ± 4.1291 ± 14.6
Day 3 (48 h postdose)136 ± 2.7135 ± 4.1135 ± 4.1137 ± 4.14.9 ± 0.84.2 ± 0.44.6 ± 0.84.5 ± 0.2    

Urine volumes for individual time periods 0–2, 2–4, 4–6, 6–10 and 10–24 h were measured on day −1 and day 1 after diuretic administration. In addition, measurement of cumulative urine volumes, urine osmolality and free water excretion were also performed on day −1 and day 1. At no time was the 1 mg cohort different from placebo. There was a trend towards increased urine volume and free water excretion with reduction in urine osmolality for the 2 mg cohort but statistically significant values were noted for the 5 mg cohort only. The individual data for urine volumes, cumulative urine volume, urine osmolality and free water excretion for the 5 mg cohort show significantly higher urine output, free water excretion and reduction in urine osmolality after dose administration (Table 3). Cumulative urine volumes and urine osmolality for each dose cohort are shown in Figure 3a,b, respectively. These figures demonstrate a dose-dependent increase in urinary output and decrease in urine osmolality that reaches statistical significance in the 5-mg dose cohort.

Table 3.   Urine output and osmolality with placebo and different doses of RWJ-351647 (n-6 for each group)
Time periodDayUrine volume (mean ± SD)Cumulative urine volume (mean ± SD)Urine osmolality (mosm/kg)Free water excretion (mean ± SD)
P1 mg2 mg5 mgP1 mg2 mg5 mgP1 mg2 mg5 mgP1 mg2 mg5 mg
  1. P = Placebo, * = P < 0.05 when compared with corresponding value on day −1. Significant results in bold.

0–2 hDay −1273 ± 127240 ± 265411 ± 225458 ± 162273 ± 127240 ± 265411 ± 225458 ± 162371 ± 146451 ± 113373 ± 54362 ± 61−28 ± 51−43 ± 17−57 ± 5334 ± 49
Day 1341 ± 103391 ± 344523 ± 402808 ± 652341 ± 103391 ± 344523 ± 402808 ± 652301 ± 49364 ± 293335 ± 108246 ± 101*−23 ± 5631 ± 8536 ± 138125 ± 171*
2–4 hDay −1339 ± 348262 ± 232471 ± 222300 ± 176612 ± 439503 ± 285883 ± 364758 ± 251300 ± 48312 ± 78363 ± 68403 ± 56    
Day 1304 ± 147385 ± 293562 ± 672776 ± 485*645 ± 225776 ± 5621085 ± 5451585 ± 630*278 ± 55286 ± 73239 ± 32179 ± 38*    
4–6 hDay −1265 ± 163144 ± 89100 ± 94217 ± 212878 ± 515648 ± 273984 ± 366975 ± 350307 ± 65376 ± 96455 ± 129537 ± 5410 ± 45−26 ± 14−35 ± 176 ± 22
Day 1118 ± 43230 ± 96170 ± 111304 ± 205764 ± 2081006 ± 5401256 ± 4741889 ± 745*360 ± 116322 ± 91391 ± 135326 ± 117*−20 ± 44−8 ± 36−1 ± 2114 ± 36*
6–10 hDay −1243 ± 149265 ± 164368 ± 214462 ± 4051122 ± 516914 ± 2411352 ± 5061438 ± 618374 ± 59464 ± 181371 ± 88626 ± 48    
Day 1325 ± 272309 ± 279447 ± 306720 ± 4421090 ± 3921315 ± 6091704 ± 6832609 ± 931*390 ± 173481 ± 158364 ± 142407 ± 320    
10–24 hDay −1842 ± 444659 ± 467716 ± 415762 ± 4131964 ± 7681573 ± 6232069 ± 7622200 ± 703403 ± 290574 ± 249515 ± 273680 ± 165−26 ± 61ND−83 ± 108ND
Day 1773 ± 537801 ± 5601310 ± 12311361 ± 7611863 ± 5642117 ± 10473014 ± 13103970 ± 1399*332NDNDND−4NDNDND
image

Figure 3.  (a) Mean (±1 SD) cumulative urine volume. (b) Mean (±1 SD) urine osmolality.

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Urine concentrations of electrolytes (sodium, potassium and chloride) decreased slightly following the dosing with RWJ-351647, especially with the 5-mg dose (Table 4). This was expected with a decrease in urine osmolality and increase in free water clearance. These trends reflected the dose-related increase in urine volume and urinary excretion rate and the slightly reduced urinary concentrations of electrolytes.

Table 4.   Electrolyte excretion before and after study drug administration
Time periodDayUrine Na (mmol/L) mean ± SD)Urine K (mmol/L) mean ± SDUrine chloride (mmol/L) mean ± SD
P1 mg2 mg5 mgP1 mg2 mg5 mgP1 mg2 mg5 mg
  1. All data are expressed as mean ± SD. All results were non-significant.

0–2 hDay −187 ± 2577 ± 38106 ± 33104 ± 1926 ± 1631 ± 1028 ± 1529 ± 1397 ± 2480 ± 44119 ± 28124 ± 24
Day 180 ± 2860 ± 2944 ± 1261 ± 1721 ± 624 ± 1629 ± 1522 ± 1887 ± 3562 ± 2749 ± 1468 ± 14
2–4 hDay −185 ± 2783 ± 2385 ± 5887 ± 3017 ± 420 ± 625 ± 1434 ± 993 ± 2992 ± 3395 ± 61105 ± 49
Day 189 ± 1266 ± 1861 ± 2345 ± 2617 ± 819 ± 629 ± 1522 ± 1898 ± 2470 ± 2569 ± 2450 ± 32
4–6 hDay −167 ± 2272 ± 1663 ± 5468 ± 4018 ± 726 ± 1029 ± 1437 ± 870 ± 2988 ± 2774 ± 6573 ± 46
Day 174 ± 2959 ± 3354 ± 3653 ± 1826 ± 1120 ± 926 ± 721 ± 578 ± 2566 ± 3269 ± 4253 ± 24
6–10 hDay −158 ± 2739 ± 2641 ± 4165 ± 3928 ± 1141 ± 2234 ± 2058 ± 1763 ± 3546 ± 3738 ± 3949 ± 54
Day 160 ± 3162 ± 4742 ± 3134 ± 2632 ± 1440 ± 1732 ± 2132 ± 2260 ± 3549 ± 3235 ± 3422 ± 15
10–24 hDay −139 ± 2529 ± 1826 ± 1178 ± 936 ± 3339 ± 3432 ± 1629 ± 1543 ± 468 ± 312 ± 543 ± 23
Day 128 ± 2149 ± 2733 ± 2144 ± 3033 ± 3044 ± 2844 ± 1737 ± 2728 ± 2730 ± 1722 ± 2130 ± 25

Fluid balance was calculated as daily fluid intake minus daily cumulative urinary volume. Over the 24-h period of day 1, mean fluid balances of 11, −681, −1309 and −2377 ml were obtained in patients receiving placebo, 1, 2 and 5 RWJ-351647, respectively. On day 1, four patients had a negative fluid balance of >2000 mL (one patient on 2 mg, and three patients on 5-mg dose). Fluid balance on day −2, day −1 and day 2 were similar in all treatment groups. Although there were no significant changes in mean body weight in any single treatment group during the study period, three (50%) patients in the 5 mg group had a weight loss of >2 kg after 24 h postdose.

Safety and tolerability

Overall, 13 (54%) of 24 patients experienced at least one adverse event at some time during the study including three (50%) of six patients in the placebo, 1 and 5 mg treatment groups, and four (67%) of six patients in the 2 mg treatment group. Adverse events were similar in patients on placebo (50% vs. 56%) group when compared with those on study drug. There were two serious adverse events: one patient died because of liver failure on day 46 and another developed Vibrio vulnificus sepsis on day 10. Both patients received 1 mg of study drug and both events were considered not related to study drug. There was no evidence of a dose-related increase in either the number of patients experiencing adverse events or the incidence or severity of adverse events across the dose range studied. The most common adverse event was headache in 3/24 (13%, one each with placebo, 2 and 5 mg). Other adverse events reported included dizziness in two (8%, one each with placebo and 2 mg), abdominal pain in two (8%, one each with 2 and 5 mg), abdominal distension in two (8%, one each with placebo and 1 mg), and peripheral edema in two (8%, one each with placebo and 2 mg). Other adverse events, experienced by one patient each, included thirst, postural dizziness, anxiety, constipation, diarrhoea, muscle cramps, encephalopathy and cold sensitivity. Only one adverse event (mild asthenia in a patient receiving 2 mg) was considered probably related to study the drug. Overall, the majority of adverse events (71%) in all treatment groups were mild, and no patients were withdrawn due to adverse events. There were no clinically significant changes or dose-related trends in any of the 12-lead EKG parameters following the administration of RWJ-351647.

Treatment-emergent increases in serum creatinine and/or blood urea nitrogen were observed in nine patients treated with RWJ-351647. In two patients (one with 1 mg, one with 2 mg), elevations were observed after day 3 and in seven patients (two with 1 mg, one with 2 mg and four with 5 mg) elevations were observed between day −1 and day 3. None of the above changes was noted as adverse events or considered to be clinically significant.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Our current study showed that a single oral dose of V2-receptor antagonist RWJ-351647 increased urine volume and excretion rate in patients with cirrhotic ascites in a dose-dependent fashion with the urine volumes and excretion rate achieving the statistical significance at the 5-mg dose level. Increases in free water clearance were also most pronounced with the 5-mg dose. Urine osmolality showed results consistent with the dose relationships observed with urine volume. Fluid balances over the 24-h period postdose showed a progressive negative net balance with increasing dose, being most significant at the 5-mg dose. A single oral dose of RWJ-351647 did not affect the pharmacokinetics of furosemide and spironolactone. The incidence and nature of adverse events after single oral doses of RWJ-351647 were similar to that observed with placebo.

V2 receptors are found exclusively in the renal collecting ducts and the activation of V2 receptors by ADH is responsible for water reabsorption. The development of V2 receptor antagonists is a logical step in the management of fluid overload and hyponatremia as V2 receptor antagonists could theoretically produce pure aquaresis without electrolyte losses. Many molecules have been tested in the past decade with mixed results. The single dose study of OPC 312607 in both cirrhotics and healthy controls found significant increase in urinary excretion and decreased urine osmolality at 2 h postdose. Although the drug was well tolerated, with repeated administration, the urinary excretion and osmolality returned to baseline suggesting a tachyphylactic response.8, 9 Similar effects were noted with the dual V1a/V2 receptor antagonist Conivaptan when used in combination with a loop diuretics (±spironolactone) in patients with heart failure where diuretic response lasted for about 5 days indicating the presence of unknown compensatory mechanisms.10, 11 Human phase 2 studies of the compound VPA-985 (Wyeth-Ayerst Inc., Collegeville, PA, USA) showed a dose-dependent increase in renal free water clearance without significant renal impairment in patients with hyponatremia.12 In this study, dose-dependent increase in renal water clearance along with improvement in serum sodium and osmolality was observed with VPA-985 over a study period of 7 days. The higher doses (500 mg/day) were associated with significant dehydration and marked increases in serum sodium levels prompting the dose withdrawals in many patients. Lower doses of 100 and 200 mg/day were better tolerated and treatment was associated with normalization of serum sodium in 50% of patients.13 Tolvaptan (Otsuka Pharmaceuticals Inc., Tokyo, Japan) is a selective non-peptide V2 receptor antagonist and when this drug was added to standard diuretic therapy for periods ranging from 25 to 60 days in patients with heart failure,14, 15 treated patients had significantly lower weight, and improvement in edema as well as serum sodium levels compared with those who received placebo.

The results of our current study are similar to other studies that have studied other vasopressin antagonists. Compared with healthy volunteers from a previous study, the pharmacokinetics of an oral single dose of RWJ-351647 is different in cirrhotic patients with ascites on a stable diuretic regimen. For the same doses, greater exposure to RWJ-351647 and the M3 metabolite RWJ-800017 was seen (AUC measurements). This was due to slower elimination and longer t1/2 of both parent and metabolite. These differences of pharmacokinetic parameters were perhaps due to differences in the hepatic metabolism of the compound. The incidence and nature of adverse events after single doses of RWJ-351647 was generally similar to that observed with placebo. Two serious adverse events reported for this study were not considered to be treatment-related. Although no drug- or dose-related trends were observed in mean serum creatinine concentrations, review of individual data did reveal occasional elevations in serum creatinine and/or urea after a single dose of RWJ-351647. These increases were often within the normal range, and in all cases were not considered to be clinically significant. However, this could indicate a potential risk of excessive diuresis when combined with other diuretics in the context of fluid restriction, and this risk should be carefully managed in future studies. There was no clear evidence that single oral doses of RWJ-351647 resulted in an increase in the incidence of postural orthostasis or systolic hypotension. Furthermore, there was no evidence of QT prolongation or other effects on cardiac intervals. Prior experience with the compound VPA-985 has shown that while the drug is generally well tolerated in the dose-finding phase,5 studies involving sicker patients tend to produce a greater incidence of side effects. The study by Wong et al.12 enrolled the patients with mean CPT score >9 (Child class C cirrhosis) and had a significant proportion of patients that required discontinuation of dosing because of adverse events. The patient population in the study by Gerbes et al.13 contained >35% of patients with Child class C cirrhosis, and this study too reported a higher incidence of side-effects including thirst and renal impairment than the prior dose-finding studies. Although the side-effect profile of a single dose-finding study such as this is encouraging, it must be interpreted with caution, as adverse events are more likely to occur after repeated administration in an unselected population with greater co-morbidities.

In conclusion, single ascending oral doses of V2-receptor antagonist RWJ-351647 have been shown to have significant dose-dependent aquaretic effect without any significant effect on the pharmacokinetics of furosemide or spironolactone. Future studies should determine the efficacy and safety of prolonged use of oral V2-receptor antagonists in combination with furosemide and spironolactone in patients with cirrhosis, ascites and hyponatremia.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

This study was sponsored by Johnson & Johnson Pharmaceutical Research Development, High Wycombe, Bucks, UK.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
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