Clinical Pharmacology
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 51-89 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 after 20 mg loading dose and 20 mg/day (open circle) or 40 mg/day (close 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
Median (range) |
12
575.8 (144.5-764.3) |
14
781.1 (194.5-1373.5) |
| | |
|
Conivaptan concentration at the end of infusion (ng/mL, at 96 hours)
| | |
|
N
Median (range) |
9
107.9 (14.7-588.8) |
11
227.5 (4.5-1454.1) |
| | |
|
Elimination half-life (hr)
| | |
|
N
Median (range) |
12
6.7 (3.6-16.9) |
14
8.6 (4.7-25.6) |
| | |
|
Clearance (L/hr)
| | |
|
N
Median (range) |
12
10.1 (2.0-37.6) |
14
9.5 (1.5-42.5) |
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 (67 to 89 years of age) received a 20 mg intravenous loading dose followed by a 20 mg/day (N=11) or 40 mg/day (N=12) intravenous infusion for 4 days. The median conivaptan plasma concentration in these patients at the end of the loading dose infusion was 628 ng/mL. The median conivaptan plasma concentration at the end of the 4-day continuous infusion was 117 and 258 ng/mL for the 20 mg/day and 40 mg/day regimens, respectively.
Pediatric Patients
The pharmacokinetics of conivaptan in pediatric patients has 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 a 4- and 11-fold increase 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 a 79% and 43% increase 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% 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) and furosemide (40 mg or 80 mg once daily for 6 days) on the pharmacokinetics of conivaptan hydrochloride (30 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 change from baseline in individualized QT correction (QTcI) in the VAPRISOL 40 mg and 80 mg dose groups on Day 1 was -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 a placebo-corrected change 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.
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