Conivaptan hydrochloride is a dual arginine vasopressin (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.
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. Moxifloxacin elicited placebo-corrected changes from baseline in individualized QT correction (QTcI) of +7 to +10 msec on Days 1 and 4, respectively, indicating that the study had assay sensitivity. The placebo-corrected changes from baseline in QTcI in the VAPRISOL 40 mg and 80 mg dose groups on Day 1 were -3.5 msec and -2.9 msec, respectively, and -2.1 msec for both dose groups on Day 4. The results suggest that conivaptan has no clinically significant effect on cardiac repolarization.
The pharmacokinetics of conivaptan have been characterized in healthy subjects, specific 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 253.3 mL/min.
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. The median (range) elimination half-life was 5.3 (3.3 — 9.3) or 8.1 (4.1 — 22.5) hours in the 20 mg/day or 40 mg/day group, respectively, based on data from rich PK sampling.
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
CYP3A 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.
In subjects with moderate and severe hepatic impairment, the area under the plasma concentration-time curve for unbound conivaptan was 2.3- to 2.5-fold the values observed in normal volunteers. The plasma protein binding of conivaptan decreased approximately 27% and 50%, respectively in patients with moderate and severe hepatic impairment. No clinically relevant increase in systemic exposure was observed in subjects with mild hepatic impairment [see Dosage and Administration (2.3) and Use in Specific Populations (8.6)].
Mild and moderate renal impairment (CLcr 30 – 80 mL/min) do not affect exposure to VAPRISOL to a clinically relevant extent. Use in patients with severe renal impairment (CLcr < 30 mL/min) is not recommended [see Use in Specific Populations (8.7)].
Conivaptan is a sensitive substrate of CYP3A. The effect of ketoconazole, a potent CYP3A inhibitor, on the pharmacokinetics of intravenous conivaptan has not been evaluated. Coadministration of oral conivaptan hydrochloride 10 mg with ketoconazole 200 mg resulted in Cmax and AUC of conivaptan 4- and 11-fold, respectively, levels with conivaptan alone [see Contraindications (4.2) Drug Interactions (7.1)].
Conivaptan is a potent mechanism-based inhibitor of CYP3A. The effect of conivaptan on the pharmacokinetics of co-administered CYP3A substrates has been evaluated with the coadministration of conivaptan with midazolam, simvastatin, and amlodipine. VAPRISOL 40 mg/day increased the mean AUC values by approximately 100%-for 1 mg intravenous or by 200% for 2 mg oral doses of midazolam. VAPRISOL 30 mg/day tripled the AUC of simvastatin. Oral conivaptan hydrochloride 40 mg twice daily doubled the AUC and half-life of amlodipine.
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 [see Drug Interactions (7.2)].
VAPRISOL (40 mg/day for 4 days) administered with a single 25 mg dose of warfarin, which undergoes major metabolism by CYP2C9 and minor metabolism by CYP3A, increased the mean S-warfarin AUC and S-warfarin Cmax by 14% and 17%, respectively. The corresponding prothrombin time and international normalized ratio values were unchanged.
Captopril and Furosemide
The pharmacokinetics of oral conivaptan (20 — 40 mg/day) were unchanged with coadministration of either captopril 25 mg or furosemide up to 80 mg/day.
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