Pharmacokinetics of Intravenous Conivaptan in Subjects With Hepatic or Renal Impairment

Conivaptan is a non-peptide dual antagonist of vasopressin V_1A and V₂ receptors that is approved in the United States as an intravenous formulation for the treatment of euvolemic and hypervolemic hyponatremia in hospitalized patients. The pharmacokinetics of intravenous conivaptan had not been studied in patients with hepatic or renal impairment.

The objective of this study was to assess the pharmacokinetics and tolerability of intravenous conivaptan in subjects with mild or moderate hepatic or renal impairment compared with subjects with normal function.

These studies were phase I, open-label pharmacokinetic studies conducted at two sites in the US.

Men and non-pregnant women 30–70 years of age were allocated to the mild (Child-Pugh classification score of 5–6) or moderate (Child-Pugh classification score of 7–9) hepatically impaired groups (n = 8–9 per group) based on their liver function assessed at screening. For the renal study, men and non-pregnant women between 18 and 70 years of age were assigned to renal function groups (n = 8–9 per group) based on estimated glomerular filtration rate (eGFR) assessed at screening. Normal renal function was defined as an eGFR >80 ml/min, mild renal impairment as 50–80 ml/min, and moderate renal impairment as 30–49 ml/min. Subjects with normal hepatic or renal function were selected to match the race, sex, age, and body mass index of subjects enrolled in the impaired groups.

Subjects were administered a 20-mg/30-min intravenous loading dose of conivaptan on day 1, followed by a 20-mg/23.5-h continuous conivaptan infusion. On day 2, immediately following the end of the day 1 infusion, a 20-mg/24-h continuous conivaptan infusion was administered.

Primary pharmacokinetic parameters estimated were the area under the plasma conivaptan concentration–time curve from time 0 to infinity (AUC_∞), plasma conivaptan concentrations at the end of the 20-mg loading dose (C _LD), and plasma conivaptan concentrations at the end of the second day 20-mg/24-h continuous infusion (C ₄₈).

For each of C _LD, C ₄₈, and AUC_∞, the mean values were similar for subjects with mild hepatic impairment and subjects with normal hepatic function. Subjects with moderate hepatic impairment had a 73 % higher C ₄₈ and an 80 % higher AUC_∞ compared with subjects with normal hepatic function. There were no clinically relevant changes in conivaptan exposure in the mild and moderate renal impairment groups compared with subjects with normal renal function. Intravenous conivaptan was generally well tolerated in subjects with mild or moderate hepatic or renal impairment. Infusion-site reaction was the most commonly reported adverse event.

Overall exposure to conivaptan increased in subjects with moderate hepatic impairment compared with subjects with normal hepatic function. Therefore, in patients with moderate hepatic impairment, conivaptan should be initiated with a loading dose of 10 mg over 30 min followed by 10 mg per day as a continuous infusion for 2–4 days, which is half the approved dose. No dose adjustment is necessary in patients with mild or moderate renal impairment and in patients with mild hepatic impairment.