Data from an open-label, multicenter study were used to evaluate the pharmacokinetics of
conivaptan in hyponatremic patients. Patients received a 20-mg loading dose intravenously over 30 minutes, followed by a continuous 4-day infusion of 20 or 40 mg/d. In the entire cohort, plasma
conivaptan concentrations were determined at baseline, at the end of the loading dose (0.5 hour), at 24 hours, on days 3 and 4, and at the follow-up visit on day 11. A subset of patients at 2 study sites (the "pharmacokineticrich" subset) provided additional samples for pharmacokinetic analysis on day 1 at 1, 4, and 24 hours; on day 2 at 24 hours; and on day 5 at 1, 2, 7, 12, and 24 hours.
RESULTS: Plasma
conivaptan concentrations were evaluated in 31 patients who received
conivaptan 20 mg/d (mean [SD] age, 73.1 [14.3] years; weight, 68.1 [17.2] kg; 71.0% female; 87.1% white, 9.7% black, 3.2% other) and 172 patients who received co-nivaptan 40 mg/d (mean [SD] age, 71.5 [14.4] years; weight, 65.6 [15.9] kg; 64.0% female; 90.1% white, 6.4% black, 3.5% other). The pharmacokinetic-rich subset included 8 patients who received conivap-tan 20 mg/d (mean [SD] age, 76.3 [12.4] years; weight, 71.5 [14.7] kg; 87.5% female; 100% white) and 8 who received
conivaptan 40 mg/d (mean [SD] age, 78.3 [7.9] years; weight, 71.3 [15.6] kg; 37.5% female; 100% white). In the overall patient group, plasma
conivaptan concentrations were the highest after the 30-minute (C(0.5h)) loading dose (mean [SD] C(0.5h) = 733 [323] and 701 [343] ng/mL with conivap-tan 20 and 40 mg/d, respectively) and then declined during day 1 to concentrations (C(24h)) (mean [SD] C(24h) = 84 [78] and 215 [129] ng/mL with
conivaptan 20 and 40 mg/d, respectively) that were maintained by the continuous infusion of 20 or 40 mg/d. At the end of infusion (96 hours), the mean (SD) plasma
conivaptan concentrations were 176 (196) and 308 (321) ng/mL for
conivaptan 20 and 40 mg/d, respectively. A ratio of 1.75 indicated near dose proportionality; however, interpatient variability was evident. No apparent differences in plasma
conivaptan concentrations measured at 0.5 or 96 hours were observed between patients with euvolemic or hypervolemic hypona-tremia or between patients with or without
congestive heart failure. In the pharmacokinetic-rich subset, for
conivaptan 20 and 40 mg/d, respectively,
conivaptan clearance was 18.7 and 9.5 L/h, the elimination t1/2 was 5.3 and 10.2 hours, and exposure to
conivaptan in terms of AUC(infinity) was 6996 and 30,771 ng . h/mL.
CONCLUSION: