Clinical congestion, commonly characterized by signs and symptoms of fluid retention and extracellular volume expansion, is a frequently encountered complication of congestive heart failure. Congestion is not a benign condition, and the presence of congestion, both at the time of hospital admission and in the weeks after discharge, is associated with increased long-term mortality.1-3 Diuretic therapy is the foundation of treatment for congestion driven largely by decades of clinical practice and supported by consensus guidelines published by major cardiovascular professional organizations.4-6 Unfortunately, the use of conventional diuretics for the treatment of congestion is associated with a variety of undesirable effects. including activation of the renin-angtiotensin-aldosterone system, vasoconstriction, decline in renal function, and various electrolyte disorders (eg, hyponatremia and hypokalemia) resulting in neurologic7 and cardiac8 complications, including possible death. Several experts have discussed the potential importance that vasopressin V2 antagonists might have in the therapy of volume-overloaded states, especially when used in tandem with a loop or thiazide diuretic.9,10
Arginine vasopressin (AVP) is a neuropeptide synthesized in the paraventricular and supraoptic nuclei of the hypothalamus, transported to the posterior pituitary gland, and released into the bloodstream.11 Decreases in blood pressure or volume can lead to profound increases in circulating levels of AVP. Similarly, decreases in “effective” arterial blood volume or pressure, such as what might be sensed by carotid baroreceptors in the setting of a failing heart, also stimulate secretion of AVP. Stimulation of AVP V2-receptors increases cAMP production by adenyl cyclase, which leads to synthesis and insertion of aquaporin-2 water channels in cells of the collecting tubules, allowing water reabsorption in the hypertonic medulla.12 The absence of AVP or the inhibition of AVP activity by V2-receptor antagonists leads to excretion of large volumes of water (aquaresis).
Tolvaptan is an orally effective nonpeptide AVP V2-receptor antagonist discovered by Otsuka Pharmaceutical Company.13 The compound inhibits AVP-induced water reabsorption in the kidney by competitively blocking the binding of AVP to V2-receptors. In rats, a dose-dependent water diuresis was produced without significantly changing total electrolyte excretion.14 In HeLa cells expressing cloned human AVP receptors, tolvaptan inhibited cAMP production induced by AVP with no intrinsic agonist activity.13
Tolvaptan is currently being evaluated for use in both the short-term and long-term management of patients hospitalized with acute decompensated heart failure. In this clinical setting, it is likely that tolvaptan may be coadministered, either simultaneously or sequentially, with diuretic agents such as furosemide and hydrochlorothiazide (HCTZ).
Furosemide is in a group of diuretics commonly classified as loop diuretics because of their ability to block the Na+-K+-2Cl− symporter in the thick ascending limb of the loop of Henle. Blockade of the Na+-K+-2Cl− symporter leads to significant increases in the urinary excretion of Na+, Cl−, Ca2+, Mg2+, and, importantly, K+. The Na+-K+-2Cl− symporter is the primary mechanism by which a hypertonic medullary interstitium, and hence concentrated urine, is produced. Blockade of the Na+-K+-2Cl− symporter therefore leads to an increased urine output. HCTZ is a member of the thiazide-like (shortened to thiazide for convenience) class of diuretics that have as their principal mechanism inhibition of Na+-Cl− symport in the distal convoluted tubule. Thiazide diuretics increase Na+ and Cl− excretion, but they are only moderately efficacious because approximately 90% of the filtered load is reabsorbed before reaching the distal convoluted tubule.15
A set of standard criteria to guide the evaluation of diuretics emerged approximately 15 years ago and emphasized the measurement of effects of single oral doses of diuretic formulations on 24-hour diuresis and natriuresis in normal individuals, primarily for reasons of biologic homogeneity.16 As emphasized by researchers in diuretic pharmacology, the 24 hours that follow oral administration of a diuretic may be the best evaluative period in part because it is a consistent reference standard that captures most rebound phases and in part because diuretics are frequently prescribed once daily by the oral route.17 This standard has evolved as the most relevant method for evaluating the urinary excretory potency of different diuretic formulations because both intersubject and intrasubject variability in the setting of various disease states, particularly rebounds in urinary excretions within 24 hours of the first dose, make it difficult to establish a consistent, disease-specific, classification framework. Determining the effect of tolvaptan on urinary excretions of fluid and solutes in healthy subjects relative to that of 2 commonly used diuretic agents is an important step in the study of this new drug and, more broadly, this new class of agents.
The purpose of this study was to evaluate both the potential pharmacokinetic and pharmacodynamic (eg, diuretic potency, time course of the renal excretory effects, etc.) interactions between tolvaptan and furosemide or HCTZ using a methodology consistent with that recommended by clinical pharmacologists specializing in diuretic therapy (ie, a 24-hour evaluation period after single oral dosing in normal healthy subjects).
This was a single-center, randomized, 3-period crossover, open-label, parallel-arm, study reviewed by the institutional review board of and conducted at PPD Pharmaco Inc, Austin, TX. A total of 12 subjects were enrolled in the study, with 6 subjects assigned to each of two treatment arms. This study was designed as a pilot study in order to determine if large (>50%) changes in pharmacokinetic (PK) or pharmacodynamic (PD) endpoints might exist; therefore sample size was not formally determined. Subjects in Arm 1 received 30 mg of tolvaptan, 80 mg of furosemide, and 30 mg of OPC-41061 + 80 mg of furosemide. Subjects in Arm 2 received 30 mg of tolvaptan, 100 mg of HCTZ, and 30 mg of tolvaptan + 100 mg of HCTZ. Six treatment sequences were used for each arm.
An 80-mg dose of furosemide was chosen because this is the largest recommended initial dose for treatment of edema, and this was a single-dose comparison. A 100-mg dose of HCTZ was used because this is the highest recommended single daily dose for the treatment of edema. A 30-mg dose of tolvaptan was studied because it is the lowest dose to consistently increase urine output by at least 1 L in previously studied subjects and maintain measurable plasma concentrations for at least 12 hours. The 80-mg furosemide dose was given as 2 × 40-mg tablets Lasix (Aventis Pharmaceuticals, Inc). The 100-mg HCTZ dose was given as 2 × 50-mg tablets HydroDIURIL (Merck & Co., Inc.). The 30-mg tolvaptan dose was given as 2 × 15-mg tablets.
Screening evaluations were performed before administration of the study drug. A complete physical examination including vital signs, 12-lead ECG, and laboratory tests (serum chemistry, hematology, urinalysis, urine drug screen and serum alcohol) was done. Subjects checked in at the investigational site to begin the inpatient procedures on day-2. All subjects abstained from xanthine-containing food and drinks, grapefruit and grapefruit juice, and alcohol for 72 hours before admission and for the duration of the study. Subjects were not allowed to consume tobacco products for the duration of the study. Subjects abstained from food from midnight on the evening before dose administration until lunch after the administration of each dose.
Twelve white (Caucasian) men, 18 to 29 years of age (mean 24 years) and with body weight within 15% of ideal body weight (mean, 82 kg; range, 69 to 101 kg) were enrolled. On day-1, subjects consumed a minimum of 1500 mL of clear liquid. Blood and urine samples for PD analysis were collected. On day 1, subjects were randomized to their treatment arm. At 1 hour before dosing, subjects consumed 150 mL of water. All subjects then received a single oral dose administered with 240 mL of room temperature water. At 1, 2, 3, 4, 5, and 6 hours after dose, subjects were to consume 100 mL of water. Lunch was served at 4.5 hours after dose and contained 480 mL of fluid. On days 3 and 5, subjects completed the crossover. Dose administration, water consumption, and lunch were as described as for day 1. At 6 hours after dose on sampling days and on days 2 and 4, clear liquid (fluid) consumption was ad libitum.
For PK analysis, blood samples were taken before dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours after dose. Urine samples were collected hourly for 8 hours after dose and then from 8 to 12 and 12 to 24 hours after dose. Samples were analyzed for tolvaptan, furosemide, and/or HCTZ where appropriate.
For PD analysis, blood samples were taken before dose and 1, 2, 3, and 4 hours after dose for determination of plasma osmolality, before dose and 2 and 24 hours after dose for determination of plasma renin activity (subjects were seated for at least 10 min before sampling), before dose and 2 and 4 hours after dose for determination of plasma AVP, before dose and 1, 2, 3, 4, 5, 6, 7, 8, 12, and 24 hours after dose for determination of plasma Na+ and K+. Urine samples collected for the PK analysis also had total volume recorded and aliquots taken for analysis of Na+ and K+ concentrations and osmolality. Fluid intake was recorded from day-1 to 24 hours after dose on day 5.
Blood samples (5 mL) were collected in sodium heparin tubes for determination of tolvaptan, furosemide, or HCTZ. Samples were centrifuged for 10 min at 2500 rpm to obtain plasma. Urine was kept refrigerated until the end of the collection interval if voids occurred before the end of the collection interval; all voids within a collection interval were pooled before sampling. For the determination of urinary tolvaptan, furosemide, and HCTZ concentrations, four 15-mL aliquots were pipetted for each interval and stored in polypropylene screw-capped liquid scintillation vials. Plasma and urine samples were frozen at a slant at −20°C or colder.
Plasma and urine samples were analyzed separately for tolvaptan, furosemide, and HCTZ using reverse-phase high-performance liquid chromatography (HPLC) systems with ultraviolet detection. Before analyzing the samples, it was determined that there was no interference in the HPLC assays between tolvaptan and either furosemide or HCTZ. For tolvaptan in plasma, the assay was linear in the range of 5.0 to 1000 ng/mL, with the limit of quantitation (LOQ) being 5.0 ng/mL. For tolvaptan in urine, the assay was linear in the range of 2.5 to 500 ng/mL, with the LOQ being 2.5 ng/mL. For furosemide in plasma, the assay was linear in the range of 20.0 to 2000 ng/mL, with the LOQ being 20.0 ng/mL. For furosemide in urine, the assay was linear in the range of 1.0 to 100 μg/mL, with the LOQ being 1.0 μg/mL. For HCTZ in plasma, the assay was linear in the range of 10 to 500 ng/mL, with the LOQ being 10 ng/mL. For HCTZ in urine, the assay was linear in the range of 1.0 to 50 μg/mL in urine, with the LOQ being 1.0 μg/mL. Values below the LOQ (BQL) were set to 0 for determination of descriptive statistics.
For tolvaptan, the analytical site was Kansas City Analytical Services (KCAS; Shawnee, KS). For furosemide and HCTZ, the analytical site was Bioassay Laboratory, Inc. (Houston, TX).
Nominal blood sample times were used for PK evaluations. For PK calculations, concentration values BQL before the first sample with measurable concentrations were set to 0. Concentration values BQL after the last sample with a measurable concentration were excluded from the analysis. The plasma drug concentration-time data were analyzed using noncompartmental methods.18 The following parameters were determined for tolvaptan, furosemide, and HCTZ: maximum plasma concentration (Cmax), time of the maximum plasma concentration (tmax), area of the plasma concentration-time curve from time 0 to the time (t) of the last measurable plasma concentration (AUCt), area under the plasma concentration-time curve from time 0 to time infinity (AUC∞), apparent clearance of parent drug from plasma after extravascular administration (CL/F), terminal-phase elimination half-life (t1/2,z), the amount (Ae,u) and percent excreted unchanged in 24 hours (%fe,u), and renal clearance (CLr).
Cmax and tmax were taken directly from the observed plasma concentration data. The terminal-phase elimination rate constant (λz) was estimated by log-linear regression using at least 3 timepoints with measurable plasma concentrations. AUCt was calculated using the linear trapezoidal rule. If the 24-hour timepoint was BQL, then CLr was determined by Ae,u divided by AUC∞. Other parameters such as AUC∞, t1/2,z, and CL/F were calculated by standard methods.18 PK calculations were performed using WinNonlin Professional (version 1.5).
Sample Processing and Bioanalytical Analyses
Plasma and urine samples were processed according to requirements of the clinical chemistry laboratories. Laboratory samples for plasma and urine sodium, potassium and osmolality, and plasma renin activity were assayed by LabCorp (Austin, TX) according to their standard operating procedures. Laboratory samples for plasma AVP were assayed by UCT Laboratories [Farmingdale, NY (now ICON)] according to their standard operating procedures.
For plasma concentrations, the before-dose value on each dosing day was considered the baseline value. For urine measurements, the value obtained at the corresponding time on day-1 was considered the baseline value.
Free water clearance was estimated using19: CLH2O = V− CLosm, where V = urine excretion rate (mL/min) and CLosm = osmolar clearance or Uosm × V/Posm, where Uosm = urine osmolality (mOsm/kg H2O), and Posm = plasma osmolality (mOsm/kg H2O) at the end of the collection interval.
For plasma AVP, a value of 0.5 pg/mL was substituted for concentrations that were BQL (ie, <1 pg/mL). For urine sodium, a value of 5 mEq/L was substituted for concentrations that were BQL (ie, <10 mEq/L).
All plasma concentration data and PK parameter estimates were summarized by treatment/Arm using descriptive statistics. Pharmacodynamic parameters and changes from baseline in PD parameters were summarized by treatment/Arm using descriptive statistics.
Tests of statistical significance for the PK parameters were done by pairwise comparison of treatment regimens (ie, tolvaptan alone versus tolvaptan + furosemide, tolvaptan alone versus tolvaptan + HCTZ, furosemide alone versus tolvaptan + furosemide, and HCTZ alone versus tolvaptan + HCTZ). Analysis of variance (ANOVA) was performed on natural logarithmic transformations of the pharmacokinetic parameters, with the model terms of sequence, subject within sequence, period, and treatment. Standard bioequivalence tests (ie, contrast, least square means, and 1-sided t test) were used to compare the treatment pairs. All tests were conducted at the 0.05 significance level unless otherwise specified. The software used for the statistical analyses was WinNonlin Professional, version 1.5. Test of statistical significance for the pharmacokinetic parameter tmax was also done by pairwise comparison of the above-mentioned treatment regimens, using the nonparametric Wilcoxon-Mann-Whitney test. The software used for this test was SAS (SAS Institute Inc., Cary, NC) version 6.12 with StatXact (Cytel Software Corp., Cambridge, MA). Tests of statistical significance for PD parameters (before-dose concentrations of serum sodium and potassium, plasma renin activity, and AVP on days 1, 3, and 5) were performed using the LinMix Fixed Effects module in WinNonlin Professional, version 4.0 with the model terms of sequence, subject within sequence, study day, and treatment. All tests were conducted at the 0.05 significance level unless otherwise specified.
The washout of 48 hours between doses appeared to be adequate. Fluid intake on days 2 and 4 was very similar to the baseline day (data not shown). Before-dose values for serum sodium and potassium, plasma renin activity, and AVP on days 3 and 5 were similar to and not significantly different from before-dose values on day 1. Treatment sequence appeared to have no effect on the results.
All enrolled subjects completed the study and were included in the analysis. Mean (SD) tolvaptan plasma concentration-time profiles after tolvaptan alone or with furosemide in Arm 1 (A) or tolvaptan alone or with HCTZ in Arm 2 (B) are presented in Figure 1. A summary of tolvaptan PK parameters is presented in Table 1.
Mean plasma furosemide concentration-time profiles after furosemide alone or with tolvaptan are presented in Figure 2A. A summary of furosemide PK parameters is presented in Table 2. Mean plasma HCTZ concentration-time profiles after HCTZ alone or with tolvaptan are presented in Figure 2B. A summary of HCTZ PK parameters is presented in Table 3.
Urine Volume and Urine Flow
Overall, tolvaptan alone produced a 24-hour urine volume that was approximately 50% greater than for either furosemide alone or HCTZ alone, which had similar 24-hour volumes of 3200 and 3500 mL, respectively (Figure 4). As expected, furosemide increased urine output more quickly and to a larger extent in the first 2 hours after dose compared with tolvaptan or HCTZ, but tolvaptan and HCTZ were effective for a longer period of time. At 4 hours after dose following furosemide alone, urine excretion rates had returned to baseline; 6 hours after dose, even though water was available ad libitum, urine excretion rates remained below baseline values through 12 hours (Figure 4).
After coadministration of tolvaptan + furosemide, urine excretion rates remained above baseline from 4 to 12 hours because of the longer activity of tolvaptan but the rates were slower than for tolvaptan alone.
At 2 and 24 hours after dose, mean renin activity was relatively unchanged following tolvaptan administration alone but was increased by 4.4 to 6.5 ng/mL/h for furosemide or HCTZ alone or in combination with tolvaptan (Figure 5).
Mean plasma AVP concentrations were increased by tolvaptan administration alone or in combination with furosemide or HCTZ. AVP concentrations after furosemide alone were only slightly changed and appeared to decrease after HCTZ alone (Figure 6).
Electrolyte Urinary Excretion and Plasma Concentrations
Urinary potassium excretion in the 24-hour postdose period was increased slightly for all treatments compared with baseline (Figure 7A), and all treatments had no effect on plasma potassium concentrations (Figure 7, B and C). Although furosemide and HCTZ are known to be kaliuretic and produce hypokalemia, this effect would not be expected to occur after a single dose in well-hydrated subjects.19,20
Urinary sodium excretion after tolvaptan alone was approximately 50% smaller compared with furosemide or HCTZ alone or furosemide or HCTZ + tolvaptan (Figure 8A). The baseline values for 24-hour urinary sodium excretion (∼210 mEq) are much higher than expected when compared with other tolvaptan studies with similar study conduct (75 to 150 mEq/day; Shoaf SE, Wang Z, Mallikaarjun S, et al, submitted) and the values reported in this study after administration of tolvaptan alone. The high baseline makes it appear that sodium excretion after tolvaptan alone is decreased and excretion after furosemide or HCTZ is only slightly increased compared with baseline. It was previously shown that, for single oral doses up to 480 mg, tolvaptan does not change 24-hour sodium excretion (Shoaf SE, Wang Z, Mallikaarjun S, et al, submitted). It is also well known that furosemide and HCTZ significantly increase sodium excretion.19-21 There is no obvious explanation for the high baseline value.
At 6 hours after dose, mean serum sodium concentrations are increased approximately 3 to 5 mEq/L after tolvaptan alone or with concomitant diuretic; smaller increases in sodium concentrations are maintained up to 24 hours (Figure 8, B and C). Plasma sodium concentrations are decreased after either furosemide or HCTZ alone.
After tolvaptan alone or with concomitant diuretic, plasma osmolality was higher and urine osmolality lower compared with either furosemide or HCTZ alone (data not shown). These results are most likely a reflection of the differences in sodium excretion and free water clearance.
From 2 to 4 hours after dose, mean free water clearance was increased 2.2 to 7.0 mL/min after tolvaptan alone or tolvaptan + diuretic (Figure 9), indicating the rapid formation of hypotonic urine. Mean free water clearances after furosemide or HCTZ alone were −2.2 to 1.1 mL/min.
There were no severe or serious adverse events reported in these studies and, no subject was withdrawn from the study because of an adverse event. There were no laboratory values that were considered clinically significant abnormalities or adverse events. Changes in supine blood pressure and pulse after resting for 3 minutes, ECGs, and physical examinations were unremarkable. In Arm 1, 1 subject experienced a total of 11 treatment-emergent adverse events (TEAEs): eight AEs after treatment with 80 mg of furosemide alone included dry mouth, dizziness, dyspepsia, nausea, vomiting, asthenia, and headache (2); 1 TEAE after treatment with 30 mg of tolvaptan alone (dyspepsia), and 2 AEs after treatment with 30 mg of tolvaptan + 80 mg of furosemide (dizziness and nausea). In Arm 2, 4 subjects experienced a total of five TEAEs. Two TEAEs (dry mouth and thirst) were reported after treatment with 30 mg of tolvaptan alone, 1 AE (thirst) was reported after treatment with 100 mg of HCTZ alone, and 2 AEs (dry mouth and somnolence) were reported after treatment with 30 mg of tolvaptan + 100 mg of HCTZ. All the TEAEs resolved without treatment.
A statistically significant difference in the PK parameters was observed for the mean Cmax and AUC∞ of tolvaptan (which were higher by 18.0% and 23.5%, respectively) when tolvaptan was administered concomitantly with furosemide compared with tolvaptan administered alone. However, this increase in mean Cmax and AUC ∞ of tolvaptan when coadministered with furosemide did not translate into increases in important pharmacodynamic parameters such as 24-hour cumulative urine excretion or 24-hour cumulative Na+ excretion. All other comparisons of pharmacokinetic parameters among the tolvaptan, furosemide, and HCTZ treatment groups showed no significant differences. The plasma profiles of the subjects in the furosemide treatment group were highly variable, which was expected due to the highly variable and erratic absorption of furosemide.20,21 The PK parameters of furosemide and hydrochlorothiazide determined in this study were similar to previously reported values.20,21
A 3-period, randomized, crossover study of single oral doses of tolvaptan (30 mg), placebo, and furosemide (80 mg) in chronic heart failure patients discontinued from all medications was performed, but assessments were only obtained for 8 hours after dose.22 Similar to the results observed in this study, cumulative urine excretion at 8 hours was comparable and greater than placebo for both tolvaptan and furosemide. Furosemide increased urinary Na+ and K+ excretion, but tolvaptan did not.
Interestingly, the combination of tolvaptan and furosemide or tolvaptan and HCTZ did not appear to be additive, as 24-hour urine output for both combinations was not significantly greater than for tolvaptan alone. This finding is consistent with results observed in a separate trial of similar design conducted in patients with heart failure.23 In this study, 30 mg of tolvaptan produced a statistically greater increase in 24-hour urine output than 80 mg of furosemide alone but not significantly greater than the combination of 30 mg of tolvaptan and 80 mg of furosemide. Other authors have observed and commented on this effect, noting that inhibition of NaCl reabsorption in the thick ascending limb of the Loop of Henle caused by furosemide does not appear to decrease the aquaretic effect (increased free water clearance) of a vasopressin antagonist.24 These results suggest that the aquaretic effects of vasopressin antagonists are independent of the NaCl reabsorption proximal to the renal collecting ducts.
After furosemide alone, urine output was below baseline values from 6 to 12 hours after dose. This rebound effect [ie, decreased urine output (water conservation)], has been observed in similar studies reported elsewhere25 and seems to be a characteristic particular to loop diuretics.16 The 6-hour to 24-hour collection period following loop diuretic dosing is typically accompanied by changes of −12% to −36% in urine output (relative to placebo), significantly reducing the overall 24-hour effect. The rebound effects may be due to changes in renal hemodynamics, or to neurohormonal activation26 as shown by the increased plasma renin activity at 2 and 24 hours after dose following furosemide administration. This finding parallels earlier observations of the marked activation of the renin-angiotensin system caused by loop diuretics in heart failure patients. Because increases in renin activity have been associated with the pathogenesis of worsening CHF,27,28 the neurohormonal profile of tolvaptan may be more favorable when compared with furosemide or HCTZ.
After tolvaptan administration, the body may attempt to increase endogenous AVP secretion to compensate for the decreased AVP activity. Although AVP concentrations were elevated after tolvaptan, the increases were not considered clinically significant as assessed by measurements of blood pressure, which remained stable (data not shown).
The pharmacokinetics of tolvaptan did not appear to be clinically significantly affected when coadministered with furosemide or HCTZ. The pharmacokinetics of furosemide and HCTZ did not appear to be significantly affected when coadministered with tolvaptan. Furosemide and HCTZ did not significantly affect the aquaretic activity of tolvaptan. Tolvaptan did not significantly affect the natriuretic or kaliuretic activity of furosemide or HCTZ. Tolvaptan administered alone did not cause an increase in plasma renin activity. Tolvaptan administered alone or in combination with furosemide or HCTZ was safe and well tolerated at the given doses.
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