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Pharmacokinetics, Pharmacodynamics, and Safety of Tolvaptan, a Nonpeptide AVP Antagonist, During Ascending Single-Dose Studies in Healthy Subjects

From Clinical Pharmacology, Otsuka Pharmaceutical Development & Commercialization, Inc, Rockville, Maryland.

Address for correspondence: Susan E. Shoaf, PhD, 2440 Research Blvd, Rockville, MD 20850; e-mail: susan.shoaf{at}otsuka.com.

	ABSTRACT

TOP ABSTRACT STUDY DESIGN PHARMACOKINETIC METHODS PHARMACOKINETIC PARAMETERS PHARMACODYNAMIC METHODS STATISTICAL METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Two single-center, double-blind, randomized, placebo-controlled, sequentially enrolled studies were conducted. In study 1, 8 subjects (6 active/2 placebo) received 60-, 90-, 120-, 180-, or 240-mg tolvaptan/matching placebo. In study 2, 9 subjects (6 active/3 placebo) received 180-, 240-, 300-, 360-, 420-, or 480-mg tolvaptan/matching placebo. Increases in tolvaptan C_max were less than dose-proportional and plateaued at doses greater than 240 mg; AUC increased proportionally with dose. Changes in serum K⁺, creatinine clearance, and Na⁺, K⁺, and osmolality urinary excretion were similar to the placebo group for the 0- to 24-hour interval following dosing. Changes were observed in plasma arginine vasopressin, serum aldosterone, and plasma renin activity but were not clinically significant. Increases were seen in mean serum Na⁺ concentrations (4-6 mEq/L), plasma osmolality (8 mOsm/kg), and free water clearance (6 mL/min) throughout 0 to 24 hours; none of these increases was dose dependent. Only total urine volume excretion (0-72 hours postdose) increased linearly with dose. As plasma tolvaptan concentrations increased, the duration that the urine excretion rate remained above baseline rates also increased. The most frequent adverse events—excess thirst, frequent urination, and dry mouth—appeared to be related to the pharmacological action of tolvaptan. No dose-limiting toxicities were observed.

Key Words: Tolvaptan • pharmacokinetics • pharmacodynamics • aquaretic • arginine vasopressin

Tolvaptan is an orally effective nonpeptide AVP V₂-receptor antagonist.³ 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.⁴ In HeLa cells expressing cloned human AVP receptors, tolvaptan inhibited cAMP production induced by AVP with no intrinsic agonist activity.³ In vitro studies have shown that tolvaptan appears to be metabolized by CYP3A4/5 (data on file).

Clinical congestion, commonly characterized by signs and symptoms of fluid retention and extracellular volume expansion, is a frequently encountered complication of congestive heart failure (CHF).⁵ 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.^6-8 Unfortunately, the use of conventional diuretics in these conditions can cause electrolyte disorders (eg, hyponatremia and hypokalemia), resulting in neurologic⁹ and cardiac complications,¹⁰ including possibly death. Therefore, there is an unmet need for agents that would relieve the congestion without causing electrolyte imbalances.

A common theme underlying the occurrence of hyponatremia, whether in the setting of CHF, hepatic failure with ascites, or syndrome of inappropriate antidiuretic hormone secretion (SIADH), is the nonosmotic secretion of AVP. The presence of excess AVP leads to fluid retention and hyponatremia.¹¹ Agents that antagonize AVP, causing proportionally more water diuresis than solute excretion, could offer a significant treatment advance for patients with hyponatremia.

Patients with human autosomal dominant polycystic kidney disease (ADPKD) have elevated plasma AVP concentrations or exaggerated response of AVP to sodium challenge, and their cyst fluid cAMP concentrations are elevated by AVP.^12,13 Cyclic AMP concentrations are elevated in the kidneys, and this is believed to increase cyst fluid accumulation and epithelial cell growth, thereby displacing normal kidney and accelerating the kidney's failure.¹³ Antagonists of the V₂-receptor have been shown to suppress renal cAMP concentrations and inhibit renal disease development and progression in models orthologous to human cystic diseases.¹⁴

Tolvaptan is being developed as an oral aquaretic agent for the treatment of fluid volume-overload conditions, hyponatremia of any origin in hypervolemic and euvolemic subjects, and ADPKD. These studies were conducted to assess the pharmacokinetics (PK), pharmacodynamics (PD), and safety and tolerability profile of ascending single doses of tolvaptan, beginning with a 60-mg dose, in healthy male and female subjects.

	STUDY DESIGN

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Both studies were randomized, double-blind, placebo-controlled, ascending single-dose studies reviewed by the institutional review board of and conducted at Quintiles Phase I Services (Lenexa, Kansas). During the study, subject safety was assessed through the monitoring of adverse events, vital signs (sitting 3 minutes, study 1; supine 3 minutes, study 2), safety laboratory tests, 12-lead electrocardiograms (ECGs), and physical examinations at scheduled intervals and upon discharge from the study. Escalation to the next dose level was determined after a review of the clinical laboratory values and safety assessments of each dose.

Screening evaluations were performed prior to administration of the study drug. Subjects were healthy, as determined by a medical history, physical examination, 12-lead ECG, and serum/urine biochemistry, hematology, and serology tests. Subjects also had body weights within ±15% of ideal body weight. In both protocols, subjects checked into the investigational site to begin the inpatient procedures on day -2. A minimum of 1500 mL of clear liquid was to be consumed on day -1. 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 and beverages, other than water, from midnight on the evening before dose administration until lunch (4.5 hours postdose) following the administration of each dose. Subjects received doses under fasting conditions. Doses were administered with 240 mL of water, but otherwise, subjects were required to abstain from water for 2 hours before dose administration through 2 hours postdose. Subjects were then allowed to consume purified water (not tap) ad libitum. Adverse events were monitored throughout the study. Prior to discharge, subjects received a physical examination, 12-lead ECG, and serum/urine biochemistry and hematology tests.

Study 1
See Table I for a summary of subject demographics. Subjects 18 to 45 years of age were randomized into 5 sequential dose treatment groups (6 active/2 placebo); active treatments were 60-, 90-, 120-, 180-, and 240-mg doses of tolvaptan (15-mg tablets), and placebo treatments were a matching number of placebo tablets. Subjects remained in the clinic from day -1 to 168 hours postdose.

Sample collection. Blood samples for tolvaptan PK analysis were collected predose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose. For PD analysis, blood samples were taken at predose and 2, 4, 6, 8, 12, and 24 hours postdose for determination of plasma osmolality and serum sodium (Na⁺) and potassium (K⁺) concentrations; predose and 2, 4, 8, and 12 hours postdose for determination of plasma AVP; predose and 2, 4, and 24 hours postdose for determination of plasma renin activity; predose and 2 and 24 hours postdose for determination of serum aldosterone concentrations; and -12 hours predose and 12 hours postdose for determination of serum creatinine. Fluid intake was recorded, and urine volumes were determined for the intervals from 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, and 12 to 24 hours postdose and for the same relative intervals on day -1, day 2, and day 3. Urine creatinine, Na⁺, K⁺, and osmole concentrations were determined for each collection interval. Urine volumes for 0 to 24, 24 to 48, and 48 to 72 hours post-dose were also determined.

Blood (10-mL) samples for tolvaptan concentrations were collected into sodium heparin tubes, gently mixed, and then centrifuged at approximately 4°C for 10 minutes at 2500 rpm to obtain plasma. Plasma was then stored at -70°C or below in polypropylene tubes.

During each collection interval, urine specimens were kept refrigerated, and at the end of each collection interval, the samples were pooled before aliquots were taken for analysis. Blood and urine for PD endpoints were processed according to instructions from the clinical chemistry laboratory.

Study 2
See Table I for a summary of subject demographics. Subjects 18 to 55 years of age were randomized into 6 sequential dose treatment groups (6 active/3 placebo); active treatments were 180-, 240-, 300-, 360-, 420-, and 480-mg doses of tolvaptan (60-mg tablets), and placebo treatments were a matching number of placebo tablets. Subjects remained in the clinic from day -1 to 144 hours postdose.

Sample collection. Sampling for PK and PD was the same as for study 1 with the exception that PK blood sampling ended at 144 hours; serum creatinine was determined at 2, 4, 6, 8, 12, and 24 hours postdose; fluid intake was not determined; postdose urine samples were taken for the determination of tolvaptan concentrations to calculate the fraction of dose excreted in the urine from 0 to 72 hours postdose (%f_e,u); and daily 24-hour urine volumes were determined for 72 to 144 hours postdose for the 480-mg dose group. Urine samples (20 mL) for tolvaptan were stored at -70°C or below in polypropylene tubes.

	PHARMACOKINETIC METHODS

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Tolvaptan Assay
Plasma and urine samples were analyzed for tolvaptan using a reverse-phase high-performance liquid chromatographic system with tandem mass spectrophotometric detection (LC/MS/MS). OPC-41100, an analog containing an additional methyl group, was employed as an internal standard. The precursorproduct ion was m/z 449252 for OPC-41061 and m/z 463266 for OPC-41100. The samples were quantitated against calibration standards prepared in blank plasma or urine and processed with the samples. In addition, quality control samples in matrix were processed to monitor analytical performance. For the quality control (QC) sample results, accuracy, as measured by mean deviation of measured results from nominal, was within 10.0%, and precision, as measured by the relative standard deviations of measured concentrations for each QC sample, was within 12.5%. The plasma and urine assays were linear over the range of 5.00 to 1000 ng/mL. The lower limit of quantitation (LOQ) was 5.00 ng/mL.

	PHARMACOKINETIC PARAMETERS

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Actual blood sample times were used for PK evaluations. Tolvaptan concentrations below the LOQ were assigned a value of 0. The plasma drug concentration-time data were analyzed using noncompartmental methods.¹⁵ The following parameters were determined for tolvaptan: maximum plasma concentration (C_max), time of the maximum plasma concentration (t_max), area of the plasma concentration-time curve from time 0 to the time (t) of the last measurable plasma concentration (AUC_t), 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 (t_,z), and f_e,u.

C_max and t_max were taken directly from the observed plasma concentration data. The terminal phase elimination rate constant (_z) was estimated by log-linear regression using at least 3 time points with measurable plasma concentrations. AUC_t was calculated using the linear trapezoidal rule. Other parameters such as AUC, t_,z, and CL/F were calculated by standard methods.¹⁵ Pharmacokinetic calculations were performed using WinNonlin Professional (Version 3.01).

	PHARMACODYNAMIC METHODS

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Urine creatinine, Na⁺, and K⁺ concentrations, urine osmolality, serum Na⁺, K⁺, aldosterone and creatinine concentrations, plasma AVP concentrations, plasma osmolality, and plasma renin activity were determined as part of clinical chemistry panels.

Creatinine clearance was determined using the following: CL_cr = (A_e,24/1440)/S_cr,12, where A_e,24 is the amount of creatinine excreted in the urine over 24 hours, 1440 is the number of minutes in 24 hours, and S_cr,12 is the serum creatinine concentration at 12 hours.

Free water clearance was estimated using the following¹⁶: C_H2O = V - C_osm, where V = urine excretion rate (mL/min) and C_osm = osmolar clearance or U_osm x V/P_osm, where U_osm = urine osmolality (mOsm/kg H₂O) and P_osm = plasma osmolality (mOsm/kg H₂O) at the end of the collection interval.

Baseline for PD blood endpoints was the value of the predose sample.

	STATISTICAL METHODS

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All plasma concentration data of tolvaptan and all PK parameter estimates were summarized within each dose group using descriptive statistics. Regression analysis was performed on log-transformed AUC and C_max versus log-transformed dose.¹⁷ Ninety-five percent confidence intervals (CIs) of the slope were calculated for the above analyses. A P value of .05 or less was considered significant. The statistical analyses were performed using Microsoft Excel 2000. Linear regression analysis was done on CL/F versus dose, total urine volume for 0 to 72 hours postdose versus dose, and maximal change in serum sodium concentration versus fluid balance. Statistical analyses were performed in Sigma Plot (Version 8).

	RESULTS

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Disposition of Subjects
In study 1, 30 subjects were treated with tolvaptan and 10 subjects treated with placebo. A total of 27 tolvaptan-treated subjects and 9 placebo-treated subjects completed the study. In study 2, 35 subjects were treated with tolvaptan (only 5 subjects received tolvaptan in the 180-mg dose group; see Table IV) and 18 subjects were treated with placebo. A total of 34 tolvaptan-treated subjects and 18 placebo-treated subjects completed the study.

Pharmacokinetics
Mean plasma tolvaptan concentration-time profiles for 48 hours postdose for all the dose groups in study 1 and study 2 are presented in Figure 1A and 1B, respectively. A summary of tolvaptan PK parameters (both studies combined) is presented in Table II.

View larger version (16K): [in this window] [in a new window]   Figure 1. Mean plasma tolvaptan concentration-time profiles for 48 hours following single oral doses of tolvaptan as (A) 15-mg tablets or (B) 60-mg tablets.

Values of CL/F (Figure 2) were independent of dose across the dose range of 60 to 480 mg. The correlation between mean AUC and dose was significantly positive (P < .0001), and log-log regression analysis of AUC versus dose had a slope of 0.97 with 95% CI (0.82, 1.10), which included the value 1, indicating a dose-dependent increase with increasing dose.¹⁷ However, a log-log regression analysis of C_max versus dose had a slope of 0.51 and 95% CI (0.37, 0.65), which did not include the value 1, indicating nonlinearity with increasing dose. Peak plasma concentrations of tolvaptan appeared to plateau for doses greater than or equal to 300 mg (Table II).

View larger version (13K): [in this window] [in a new window]   Figure 2. Values of CL/F following a single oral dose of tolvaptan plotted versus dose (study 1, open circles; study 2, filled circles).

Renal excretion of unchanged tolvaptan was consistently less than 1% of the dose for 180- to 480-mg doses of tolvaptan (study 2). Renal clearance of tolvaptan (f_e,u x CL/F) would therefore be less than 1% of CL/F.

Pharmacodynamics
From 0 to 12 hours postdose on day 1, mean urinary excretion volumes and the maximal excretion rate (12 mL/min, data not shown) were similar for all groups, indicating that tolvaptan concentrations for all groups were equal to or greater than that needed to produce a maximal response by the kidney (Figure 3A). Mean urine volumes from 0 to 24 hours postdose generally tend to increase with increasing dose. As dose increased and plasma concentrations remained elevated for longer periods of time, the duration that urine excretion rates remained greater than baseline rates was also increased. The correlation between mean 0 to 72-hour cumulative urine volume and dose was highly significant, with P < .0001 (Figure 3B). Following 480 mg, the mean 24-hour total urine volume on day 4 was equivalent to placebo.

View larger version (12K): [in this window] [in a new window]   Figure 3. Mean urine volume (A) and correlation between 0 to 72-hour urine volume versus dose (B) following a single oral dose of tolvaptan or placebo.

View larger version (20K): [in this window] [in a new window]   Figure 4. Mean free water clearance for the collection intervals 2 to 4 hours and 12 to 24 hours postdose following a single oral dose of tolvaptan or placebo.

Following tolvaptan administration (all dose strengths), mean serum Na⁺ concentrations were increased approximately 4 to 6 mEq/L at 4 hours post-dose, and the increase was maintained for at least 24 hours (Figure 5). The maximal change from baseline in serum sodium concentration was well correlated (P < .0001) with 24-hour fluid balance (Figure 6). Mean plasma osmolality was increased approximately 8 mEq/L, and the increase was maintained for at least 24 hours (data not shown). Mean serum K⁺ concentrations were unchanged (data not shown).

View larger version (14K): [in this window] [in a new window]   Figure 5. Mean change from baseline in serum sodium (Na+) concentrations following a single oral dose of tolvaptan or placebo.

View larger version (11K): [in this window] [in a new window]   Figure 6. Correlation between 24-hour fluid balance and the maximal change from time 0 in serum sodium concentration following a single oral dose of tolvaptan or placebo.

View larger version (17K): [in this window] [in a new window]   Figure 7. Mean changes from baseline in plasma arginine vasopressin (AVP) concentrations at 2, 4, 8, and 12 hours postdose following a single oral dose of tolvaptan or placebo.

Safety
There were no deaths and no severe or serious adverse events reported in these studies. There were no laboratory values that were considered clinically significant. Changes in sitting or supine blood pressure, vital signs, ECGs, and physical examinations were also not clinically significant. In study 1, 1 subject (180-mg dose group) was withdrawn from the study because of an adverse event (delusion) that was not considered as treatment related. No other subjects had adverse events that warranted discontinuation of treatment. Table IV provides a summary of treatment-emergent adverse events (TEAEs) and the incidence of specific TEAEs that were reported by at least 2 tolvaptan-treated subjects. The most commonly reported TEAEs for tolvaptan-treated subjects were thirst, urinary frequency, and dry mouth, all most likely caused by the pharmacological action of tolvaptan, but neither these nor any other reported TEAEs showed a dose response.

	DISCUSSION

TOP ABSTRACT STUDY DESIGN PHARMACOKINETIC METHODS PHARMACOKINETIC PARAMETERS PHARMACODYNAMIC METHODS STATISTICAL METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
For single oral doses ranging from 60 to 480 mg, tolvaptan AUC showed a dose-proportional increase with increasing dose. The apparent clearance was independent of dose. Increases in tolvaptan C_max were not dose proportional, and C_max values appeared to plateau at tolvaptan doses greater than or equal to 300 mg. This may be due to saturation of tolvaptan absorption or dissolution rate-limited absorption in the upper small intestine.

Renal excretion contributes minimally to tolvaptan elimination as less than 1% of the dose is excreted unchanged in the urine.

Most of the PD endpoints did not show a dose-response relationship. In the first 12 hours postdose, mean urine volumes, free water clearances, and urine osmolality were similar for all doses. In the 12- to 24-hour postdose period, mean urine volumes and free water clearances generally increased and mean urine osmolality generally decreased with increasing dose. The only PD endpoint to show a dose response across all doses was 72-hour urine volume, which was highly correlated to tolvaptan dose (P < .0001). As tolvaptan doses increased and plasma concentrations remained elevated for longer periods of time, the duration that the urine excretion rate remained above the baseline rate was also increased. This indicates that the plasma concentrations of tolvaptan following even the lowest dose tested (ie, 60 mg) elicited the maximal response. Therefore, it is likely that doses lower than 60 mg will produce a pharmacological effect that may very well be sufficient for the desired response.

For tolvaptan- and placebo-treated subjects in study 1, the maximal change from baseline in serum sodium was significantly negatively correlated with 24-hour fluid balance (fluid intake-urine output, P < .0001). This result is not surprising in light of recent studies evaluating changes from baseline in serum sodium in marathon or long-distance runners during a run. In runners, changes in serum sodium concentrations were significantly negatively correlated with changes in body weight (as a measure of fluid changes); that is, the more weight (fluid) that is lost, the greater the increase in serum sodium concentrations.^18,19 Consumption of liquids in excess of that needed to replace fluid lost due to sweating and insensible losses was shown to cause decreases in serum sodium concentrations, even to the level of clinical hyponatremia (<130 mEq/L).¹⁸

It is interesting that mean changes from baseline in serum sodium were 4 to 6 mEq/L for all groups. In study 2, 100% of subjects reported thirst as a TEAE, yet serum sodium concentrations were raised to the same level as in study 1, where only 26.7% (8/30) subjects reported having thirst. Reported incidences of dry mouth were similar for both studies, 26.7% and 20.0%. As noted above, there was no dose response in 24-hour fluid balance, and subjects varied much more widely in their fluid intake than their urine output.

The increases seen in mean AVP concentrations and plasma renin activity appear to be a homeostatic response to counteract the diuretic effect of tolvaptan. However, there does not appear to be any clinically significant response to these increases as systolic and diastolic blood pressures and urinary excretion of Na⁺, K⁺, and osmoles were similar to those of placebo subjects. Tolvaptan administration would not be expected to increase the urinary excretion of Na⁺, K⁺, and osmoles because its mechanism of action affects the transport of water; antagonism of the V₂-receptor decreases cAMP production and thus reduces the number of aquaporin-2 water channels in cells of the collecting tubules and therefore decreases the reabsorption of water.²

The most frequently reported TEAEs were related to the aquaretic effect of tolvaptan, specifically thirst, urinary frequency, and dry mouth. All TEAEs were mild or moderate in severity; there were no TEAEs that indicated dose-limiting toxicity. Single oral doses of tolvaptan up to 480 mg appeared to be safe and well tolerated by healthy adult male and female subjects.

Tolvaptan produced a dose-dependent increase in urine volume without an increase in the excretion of Na⁺ or K⁺, as expected from its pharmacological activity as a V₂-receptor antagonist. This indicates that tolvaptan may be able to reduce congestion without causing the electrolyte imbalances seen with the use of conventional diuretics. Given tolvaptan has a selective effect in increasing serum sodium concentrations, tolvaptan appears to be a promising therapeutic agent for study in various conditions that produce hyponatremia. The ability of tolvaptan to inhibit AVP action at the V₂-receptor in the kidney, as exhibited by the large increases in urine volume and reductions in urine osmolality, indicates that it may inhibit cyst fluid accumulation and epithelial cell growth in human cystic diseases such as ADPKD.

	ACKNOWLEDGEMENTS

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Financial disclosure: None declared.

	REFERENCES

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This Article Abstract Full Text (PDF) All Versions of this Article: 0091270007307877v1 47/12/1498    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Request Reprints Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Shoaf, S. E. Articles by Mallikaarjun, S. Search for Related Content PubMed PubMed Citation Articles by Shoaf, S. E. Articles by Mallikaarjun, S. Social Bookmarking                   What's this?