Drug Design, Development and Therapy (Feb 2017)
Pharmacokinetics of conivaptan use in patients with severe hepatic impairment
Abstract
Thomas Marbury,1 Jerry Fox,2 Byron Kaelin,2 Leo Pavliv2 1Orlando Clinical Research Center, Inc., Orlando, FL, 2Department of Research and Development, Cumberland Pharmaceuticals, Inc., Nashville, TN, USA Purpose: Conivaptan is an intravenous dual V1A/V2 vasopressin antagonist approved for the treatment of euvolemic and hypervolemic hyponatremia. Earlier studies showed that patients with moderate liver disease could be safely treated with conivaptan by reducing the dose by 50%, whereas patients with mild hepatic impairment needed no dose adjustment. The objective of this Phase 1, open-label study was to assess the pharmacokinetics, protein binding, and safety of 48 h of conivaptan infusion in individuals with severe hepatic impairment.Patients and methods: Eight subjects with severe hepatic impairment (Child–Pugh score 10–15) and nine subjects with normal liver function were enrolled. Intravenous conivaptan (20 mg) was given as a 30 min loading dose on Day 1 followed by two consecutive 20 mg continuous infusions over 24 h each. Subjects were monitored for adverse events and changes in clinical laboratory parameters. Plasma and urine pharmacokinetic samples were collected at defined times. Subjects were followed through Study Day 5.Results: Hepatically impaired individuals exhibited higher concentrations of plasma conivaptan throughout the treatment period. Overall exposure, as measured by area under the plasma conivaptan concentration-time curve from time zero through infinity (AUCINF), was ~60% higher in impaired individuals compared to those with normal liver function. Terminal elimination half-life was slightly longer in impaired subjects (12 h) as compared to normal subjects (9 h), and clearance was 65% higher in subjects with normal liver function, while urinary excretion was higher in impaired individuals. Albumin levels directly, and alkaline phosphatase inversely, correlated with conivaptan clearance.Conclusion: A 20 mg conivaptan loading dose given >30 min followed by two daily infusions of 20 mg each was well tolerated by patients with severe hepatic impairment as monitored by adverse events and clinical laboratory values. Based on pharmacokinetic data, however, a 50% reduction in the conivaptan dose is recommended for patients with severe liver impairment. Keywords: liver, hyponatremia, AVP antagonist, cirrhosis
