Pharmacodynamics
Conivaptan hydrochloride is a dual AVP antagonist with nanomolar affinity for
human V1A and V2 receptors in vitro. The level
of AVP in circulating blood is critical for the regulation of water and electrolyte
balance and is usually elevated in both euvolemic and hypervolemic hyponatremia.
The AVP effect is mediated through V2 receptors, which are functionally
coupled to aquaporin channels in the apical membrane of the collecting ducts
of the kidney. These receptors help to maintain plasma osmolality within the
normal range. The predominant pharmacodynamic effect of conivaptan hydrochloride
in the treatment of hyponatremia is through its V2 antagonism of
AVP in the renal collecting ducts, an effect that results in aquaresis, or excretion
of free water. The pharmacodynamic effects of conivaptan hydrochloride include
increased free water excretion (i.e., effective water clearance [EWC]) generally
accompanied by increased net fluid loss, increased urine output, and decreased
urine osmolality. Studies in animal models of hyponatremia showed that conivaptan
hydrochloride prevented the occurrence of hyponatremia-related physical signs
in rats with the syndrome of inappropriate antidiuretic hormone secretion.
Pharmacokinetics
The pharmacokinetics of conivaptan have been characterized in healthy subjects, special populations and patients following both oral and intravenous dosing regimens. The pharmacokinetics of conivaptan following intravenous infusion (40 mg/day to 80 mg/day) and oral administration are non-linear, and inhibition by conivaptan of its own metabolism seems to be the major factor for the non-linearity. The intersubject variability of conivaptan pharmacokinetics is high (94% CV in CL).
The pharmacokinetics of conivaptan and its metabolites were characterized in
healthy male subjects administered conivaptan hydrochloride as a 20 mg loading
dose (infused over 30 minutes) followed by a continuous infusion of 40 mg/day
for 3 days. Mean Cmax for conivaptan was 619 ng/mL and occurred at the end of
the loading dose. Plasma concentrations reached a minimum at approximately 12
hours after start of the loading dose, then gradually increased over the duration
of the infusion to a mean concentration of 188 ng/mL at the end of the infusion.
The mean terminal elimination half-life after conivaptan infusion was 5.0 hours,
and the mean clearance was 15.2 L/h.
In an open-label safety and efficacy study, the pharmacokinetics of conivaptan were characterized in hypervolemic or euvolemic hyponatremia patients (ages 20 - 92 years) receiving conivaptan hydrochloride as a 20 mg loading dose (infused over 30 minutes) followed by a continuous infusion of 20 or 40 mg/day for 4 days. The median-plasma conivaptan concentrations are shown in Figure 1 and pharmacokinetic parameters are summarized in Table 1.
Figure 1. Median Plasma Concentration-Time Profiles From
Rich PK Sampling After 20 mg Loading Dose and 20 mg/day (open circle) or 40
mg/day (closed circle) Infusion for 4 Days
Table 1. Pharmacokinetic Parameters After 20 mg Loading Dose
for 30 Minutes and 20 mg/day or 40 mg/day Infusion for 4 Days
| Parameter |
IV Conivaptan
20 mg/day |
IV Conivaptan
40 mg/day |
| Conivaptan concentration at the end of loading dose (ng/mL,
at 0.5 hours) |
| N* |
31 |
170 |
| Median (range) |
659.4 (144.5-1587.6) |
679.5 (0.0-1910.8) |
| Conivaptan concentration at the end of infusion (ng/mL,
at 96 hours) |
| N* |
30 |
172 |
| Median (range) |
117.6 (4.9-938.3) |
215.7 (2.1-1999.3) |
| Elimination half-life (hr) |
| N** |
8 |
8 |
| Median (range) |
5.3 (3.3-9.3) |
8.1 (4.1-22.5) |
| Clearance (L/hr) |
| N** |
8 |
8 |
| Median (range) |
16.1 (7.2-37.6) |
8.73 (2.1-20.9) |
*: number from the rich and the sparse PK sampling
**: number from the rich PK sampling |
Distribution
Conivaptan is extensively bound to human plasma proteins, being 99% bound over the concentration range of approximately 10 to 1000 ng/mL.
Metabolism and Excretion
CYP3A4 was identified as the sole cytochrome P450 isozyme responsible for the
metabolism of conivaptan. Four metabolites have been identified. The pharmacological
activity of the metabolites at V1A and V2 receptors ranged
from approximately 3-50% and 50-100% that of conivaptan, respectively. The combined
exposure of the metabolites following intravenous administration of conivaptan
is approximately 7% that of conivaptan and hence, their contribution to the
clinical effect of conivaptan is minimal.
After intravenous (10 mg) or oral (20 mg) administration of conivaptan hydrochloride in a mass balance study, approximately 83% of the dose was excreted in feces as total radioactivity and 12% in urine over several days of collection. Over the first 24 hours after dosing, approximately 1% of the intravenous dose was excreted in urine as intact conivaptan.
Special Populations
Hepatic Impairment
The effect of hepatic impairment (including ascites, cirrhosis, or portal hypertension) on the elimination of conivaptan after intravenous administration has not been systematically evaluated. However, increased systemic exposures after administration of oral conivaptan (up to a mean 2.8-fold increase) have been seen in patients with stable cirrhosis and moderate hepatic impairment. Intravenous VAPRISOL resulted in higher conivaptan exposure than did oral conivaptan, in study subjects without hepatic function impairment. Caution should be exercised when administering VAPRISOL to patients with impaired hepatic function.
Renal Impairment
The effect of renal impairment on the elimination of conivaptan after intravenous
administration has not been evaluated. However, following administration of
oral conivaptan, the AUC for conivaptan was up to 80% higher in patients with
renal impairment (CLcr < 60 mL/min/1.73 m2) as compared to those
with normal renal function. Intravenous VAPRISOL resulted in higher conivaptan
exposure than did oral conivaptan, in study subjects without renal function
impairment. Caution should be exercised when administering VAPRISOL to patients
with impaired renal function.
Geriatric Patients
Following a single oral dose of conivaptan hydrochloride (15, 30 or 60 mg), drug exposure (AUC) in elderly male and female volunteers (65 to 90 years of age) compared to that seen in young male subjects was similar for the 15 and 30 mg doses but increased nearly 2-fold at the 60 mg dose.
In an open label study to assess the safety and efficacy of conivaptan, a subset
of geriatric hypervolemic or euvolemic hyponatremia patients (65 to 92 years
of age) received a 20 mg intravenous loading dose followed by a 20 mg/day (N=27)
or 40 mg/day (N=135) intravenous infusion for 4 days. The median conivaptan
plasma concentration in these patients at the end of the loading dose infusion
was 654 ng/mL. The median conivaptan plasma concentrations at the end of the
4-day continuous infusion were 118 and 215 ng/mL for the 20 mg/day and 40 mg/day
regimens, respectively.
Pediatric Patients
The pharmacokinetics of conivaptan in pediatric patients have not been studied.
Drug-Drug Interactions
(See CONTRAINDICATIONS and PRECAUTIONS:
DRUG INTERACTIONS)
CYP3A4
Conivaptan is a sensitive substrate of CYP3A4. The effect of ketoconazole, a potent CYP3A4 inhibitor, on the pharmacokinetics of intravenous conivaptan has not been evaluated. Coadministration of oral conivaptan hydrochloride 10 mg with ketoconazole 200 mg resulted in 4- and 11-fold increases in Cmax and AUC of conivaptan, respectively.
Conivaptan is a potent inhibitor of CYP3A4. The effect of conivaptan on the pharmacokinetics of CYP3A4 substrates has been evaluated with the coadministration of conivaptan with midazolam, simvastatin, and amlodipine. Intravenous conivaptan hydrochloride 40 mg/day increased the mean AUC values by approximately 2- and 3-fold for 1 mg intravenous or 2 mg oral doses of midazolam, respectively. Intravenous conivaptan hydrochloride 30 mg/day resulted in a 3-fold increase in the AUC of simvastatin. Oral conivaptan hydrochloride 40 mg twice daily resulted in a 2-fold increase in the AUC and half-life of amlodipine.
Digoxin
Coadministration of a 0.5-mg dose of digoxin, a P-glycoprotein substrate, with oral conivaptan hydrochloride 40 mg twice daily resulted in a 30% reduction in clearance and 79% and 43% increases in digoxin Cmax and AUC values, respectively.
Warfarin
The effect of intravenous conivaptan on warfarin pharmacokinetics or pharmacodynamics has not been evaluated. The potential drug-drug interaction of oral conivaptan with warfarin, which undergoes major metabolism by CYP2C9 and minor metabolism by CYP3A4, was investigated in a clinical study.
The effects of oral conivaptan hydrochloride 40 mg twice daily on prothrombin time was assessed in patients receiving stable oral warfarin therapy. After 10 days of oral conivaptan administration, the S- and R-warfarin concentrations were 90% and 98%, respectively, of those prior to conivaptan administration. The corresponding prothrombin time values after 10 days of oral conivaptan administration were 95% of baseline. No effect of oral conivaptan on the pharmacokinetics or pharmacodynamics of warfarin was observed.
Captopril and Furosemide
The effects of captopril (25 mg) on the pharmacokinetics of conivaptan hydrochloride (30 mg) and furosemide (40 mg or 80 mg once daily for 6 days) on the pharmacokinetics of conivaptan hydrochloride (20 mg, and 40 mg) were assessed in separate studies. The pharmacokinetics of conivaptan were unchanged with coadministration of either captopril or furosemide.
Electrophysiology
The effect of VAPRISOL 40 mg IV and 80 mg IV on the QT interval was evaluated after the first dose (Day 1) and at the last day during treatment (Day 4) in a randomized, single-blind, parallel group, placebo- and positive-controlled (moxifloxacin 400 mg IV) study in healthy male and female volunteers aged 18 to 45 years. Digital ECGs were obtained at baseline and on Days 1 and 4. The placebo-corrected changes from baseline in individualized QT correction (QTcI) in the VAPRISOL 40 mg and 80 mg dose groups on Day 1 were -3.5 msec and -2.9 msec, respectively, on Day 1, and -2.1 msec for both dose groups on Day 4. Similar results were obtained using either the Bazett's or Fridericia's correction methods. Moxifloxacin elicited placebo-corrected changes from baseline in QTcI of +7 to +10 msec on Days 1 and 4, respectively.
Table 2. Individualized QT Correction (QTcI) Mean Change
from Baseline at Day 4
| Drug and Dose |
QTcI |
| Placebo |
-3 msec |
| Vaprisol 40 mg IV |
-5.1 msec |
| Vaprisol 80 mg IV |
-5.1 msec |
| Moxifloxacin 400 mg IV |
+7.4 msec |
The results of the central tendency analysis of QTc indicate that VAPRISOL had no effect on cardiac repolarization.
Clinical Studies
In a double-blind, placebo-controlled, randomized, multicenter study, 84 patients with euvolemic or hypervolemic hyponatremia (serum sodium 115 -130 mEq/L) due to a variety of underlying causes (malignant or nonmalignant diseases of the central nervous system, lung, or abdomen; congestive heart failure [CHF]; hypertension; myocardial infarction; diabetes; osteoarthritis; or idiopathic) were treated for 4 days with VAPRISOL or placebo. All patients received standard care for hyponatremia, primarily fluid restriction (daily fluid intake restricted to less than or equal to 2.0 liters). Study participants were randomized to receive either placebo IV (N=29), or VAPRISOL 40 mg/day IV (N=29), or VAPRISOL 80 mg/day IV (N=26). VAPRISOL was administered as a continuous infusion following a 30 minute IV infusion of a 20 mg loading dose on the first treatment day. Serum or plasma sodium concentrations were assessed at predose (Hour 0) and at 4, 6, 10, and 24 hours post dose on all treatment days. Mean serum sodium concentration was 123.3 mEq/L at study entry.
The mean change in serum sodium concentration from baseline over the 4-day treatment period is shown in Figure 2.
Figure 2. Mean (SE) Change from Baseline in Sodium Concentrations
with VAPRISOL 40 mg/day
Following treatment with 40 mg/day of intravenous VAPRISOL, 79% of patients achieved an increase of ≥ 4 mEq/L in serum sodium concentration. The mean change from baseline in serum sodium concentration at the end of 2 days of treatment with VAPRISOL was 5.3 mEq/L (mean concentration 128.6 mEq/L). At the end of the 4-day treatment period, the mean change from baseline was 6.5 mEq/L (mean concentration 129.8 mEq/L). In addition, after 2 days and 4 days of treatment with VAPRISOL, 41% (after 2 days) and 69% (after 4 days) of patients achieved a ≥ 6 mEq/L increase in serum sodium concentration or a normal serum sodium of ≥ 135 mEq/L. Although 80 mg/day was also studied, it was not significantly more effective than 40 mg/day. The maximum daily dose of VAPRISOL (after the loading dose) is 40 mg/day. Additional efficacy data are summarized in Table 3.
Table 3. Efficacy Outcomes of Treatment with VAPRISOL 40
mg/day
| Efficacy Variable |
Placebo
N=29 |
VAPRISOL 40 mg/d
N=29 |
| |
Day 2‡ |
Day 4 |
Day 2‡ |
Day 4 |
| Baseline adjusted serum Na+ AUC over duration
of treatment (mEq·hr/L) |
| Mean (SD) |
6.2 (81.8 |
61.4 (242.3) |
205.9 (171.6) |
500.8 (365.5) |
| LS Mean ± SE |
3.8 ± 26.9 |
12.9 ± 61.2 |
205.6 ± 26.6* |
490.9 ± 56.8* |
| Number of patients (%) and median event time (h) from first
dose of study medication to a confirmed ≥ 4 mEq/L increase from Baseline
in serum Na+, [95% CI] |
2 (7%) |
9 (31%) |
22 (76%) |
23 (79%) |
| Not estimable |
Not estimable |
23.7* |
23.7* |
| Not estimable |
Not estimable |
[10, 2] |
[10, 2] |
| Total time (h) from first dose of study medication to
Day 2 or Day 4 end of treatment during which patients had a confirmed
≥ 4 mEq/L increase in serum Na+ from Baseline |
| Mean (SD) |
2.2 (5.9) |
13.7 (20.5) |
22.3 (16.0) |
53.4 (34.3) |
| LS Mean ± SE |
2.1 ± 2.3 |
14.2 ± 5.3 |
22.3 ± 2.3* |
53.2 ± 5.2* |
| Serum Na+ (mEq/L) |
| Baseline mean (SD) |
124.3 (4.1) |
124.3 (4.1) |
123.3 (4.7) |
123.3 (4.7) |
| Mean (SD) at end of treatment |
124.5 (4.7) |
125.8 (4.9) |
128.6 (5.9) |
129.8 (4.8) |
| Change from Baseline to end of treatment |
|
| Mean change (SD) |
0.2 (2.5) |
1.5 (4.6) |
5.3 (4.4) |
6.5 (4.4) |
| LS Mean change ± SE |
0.1 ± 0.7 |
0.8 ± 0.8 |
5.2 ± 0.7* |
6.3 ± 0.7* |
| Number (%) of patients who obtained a confirmed ≥ 6 mEq/L increase
from Baseline in serum Na+ or a normal serum Na+
concentration ≥ 135 mEq/L during treatment |
0 (0) |
6 (21%) |
12 (41%)* |
20 (69%)* |
*P 0.001 vs placebo
‡efficacy variables were assessed on Day 2 of a 4-day
treatment period |
The aquaretic effect of VAPRISOL is shown in Figure 3. VAPRISOL produced a
baseline-corrected cumulative increase in effective water clearance of over
3800 mL compared to approximately 1300 mL with placebo by Day 4.
Figure 3. Baseline-Corrected Cumulative Effective Water Clearance
(EWC)
EWC =V × {1-[UNa +UK/PNa +PK],
where V is urine volume (mL/d), UNa is urine sodium concentration,
UK concentration, PNa is plasma/serum sodium concentration,
and PK is plasma/serum potassium concentration.
In an open-label study in patients with euvolemic or hypervolemic hyponatremia, 251 patients were treated for 4 days with VAPRISOL 20 or 40 mg/day IV as a continuous infusion following a 30 minute IV infusion of a 20 mg loading dose on the first treatment day. The results are shown in Table 4.
Table 4. Efficacy Outcomes of Treatment with VAPRISOL 20
or 40 mg/day
| Primary Efficacy Endpoint |
20 mg/day
N=37 |
40 mg/day
N=214 |
| Baseline adjusted serum Na+ AUC over duration of treatment
(mEq·hr/L) Mean (SD) |
753.8 (429.9) |
689.2 (417.3) |
| Secondary efficacy endpoints |
| Number of patients (%) and median event time (h) from first doseof study
medication to a confirmed ≥ 4 mEq/L increase from Baseline in serum
Na+, [95% CI] |
29 (78%)
23.8 [12.0, 36.0] |
178 (83%)
24.0 [24.0, 35.8] |
| Total time (h) from first dose of study medication to
end of treatment during which patients had a confirmed ≥ 4 mEq/L increase
in serum Na+ from Baseline |
| Mean (SD) |
60.6 (35.2) |
59.5 (33.2) |
| Serum Na+ (mEq/L) |
| Baseline mean (SD) |
122.5 (5.2) |
123.8 (4.6) |
| Mean (SD) at end of treatment |
131,8 (3.9) |
132.5 (4.6) |
| Mean Change (SD) from Baseline to End of Treatment |
9.4 (5.3) |
8.8 (5.4) |
| Mean (SD) at Follow-up Day 11 |
129.9 (6.2) |
131.8 (5.8) |
| Mean Change (SD) from Baseline to Follow-up Day 11 |
7.1 (8.2) |
8.0 (6.5) |
| Mean (SD) at Follow-up Day 34 |
134.3 (4.5) |
134.3 (5.2) |
| Mean Change (SD) from Baseline to Follow-up Day 34 |
11.5 (7.3) |
10.7 (6.7) |
| Number (%) of patients who obtained a confirmed ≥ 6 mEq/L increase
from Baseline in serum Na+ or a normal serum Na+ concentration
≥ 135 mEq/L during treatment |
26 (70%) |
154 (72%) |
The effectiveness of VAPRISOL for the treatment of congestive heart failure has not been established.
Last updated on RxList: 12/22/2008