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      Pharmacokinetics of conivaptan use in patients with severe hepatic impairment

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          Abstract

          Purpose

          Conivaptan is an intravenous dual V 1A/V 2 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 (AUC INF), 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.

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          Most cited references 9

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          Hyponatremia in cirrhosis: Results of a patient population survey.

          Low serum sodium concentration is an independent predictor of mortality in patients with cirrhosis, but its prevalence and clinical significance is unclear. To evaluate prospectively the prevalence of low serum sodium concentration and the association between serum sodium levels and severity of ascites and complications of cirrhosis, prospective data were collected on 997 consecutive patients from 28 centers in Europe, North and South America, and Asia for a period of 28 days. The prevalence of low serum sodium concentration as defined by a serum sodium concentration < or =135 mmol/L, < or =130 mmol/L, < or =125 mmol/L, and < or =120 mmol/L was 49.4%, 21.6%, 5.7%, and 1.2%, respectively. The prevalence of low serum sodium levels (<135 mmol/L) was high in both inpatients and outpatients (57% and 40%, respectively). The existence of serum sodium <135 mmol/L was associated with severe ascites, as indicated by high prevalence of refractory ascites, large fluid accumulation rate, frequent use of large-volume paracentesis, and impaired renal function, compared with normal serum sodium levels. Moreover, low serum sodium levels were also associated with greater frequency of hepatic encephalopathy, spontaneous bacterial peritonitis, and hepatorenal syndrome, but not gastrointestinal bleeding. Patients with serum sodium <130 mmol/L had the greatest frequency of these complications, but the frequency was also increased in patients with mild reduction in serum sodium levels (131-135 mmol/L). In conclusion, low serum sodium levels in cirrhosis are associated with severe ascites and high frequency of hepatic encephalopathy, spontaneous bacterial peritonitis, and hepatorenal syndrome.
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            Assessment of the Efficacy and Safety of Intravenous Conivaptan in Euvolemic and Hypervolemic Hyponatremia

            Background: Most cases of hyponatremia – serum sodium concentration ([Na + ]) 1A /V 2 -receptor antagonist, in treating euvolemic and hypervolemic hyponatremia. Methods: Eighty-four hospitalized patients with euvolemic or hypervolemic hyponatremia (serum [Na + ] 115 to + ], measured by the baseline-adjusted area under the [Na + ]-time curve. The secondary measures included time from first dose to a confirmed ≧4 mEq/l serum [Na + ] increase, total time patients had serum [Na + ] ≧4 mEq/l higher than baseline, change in serum [Na + ] from baseline to the end of treatment, and number of patients with a confirmed ≧6 mEq/l increase in serum [Na + ] or normal [Na + ] (≧135 mEq/l). Results: Both conivaptan doses increased area under the [Na + ]-time curve during the 4-day treatment (p + ] increase associated with placebo was 0.8 ± 0.8 mEq/l; with conivaptan 40 mg/day, 6.3 ± 0.7 mEq/l; and with conivaptan 80 mg/day, 9.4 ± 0.8 mEq/l. Conivaptan significantly improved all secondary efficacy measures (p + ] and was well tolerated.
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              Consequences of Inadequate Management of Hyponatremia

              Dilutional hyponatremia is a commonly observed disorder in hospitalized patients. It represents an excess of water in relation to prevailing sodium stores and is most often associated with a high plasma level of arginine vasopressin, including that found in patients with the syndrome of inappropriate antidiuretic hormone secretion. Hyponatremia may be classified as either acute or chronic depending on the rate of decline of serum sodium concentration, and can lead to a wide range of deleterious changes involving almost all body systems. Serious complications of dilutional hyponatremia most frequently involve the central nervous system. In fact, acute severe hyponatremia is potentially life-threatening and must be treated promptly and aggressively. Chronic hyponatremia often develops in patients with nonrenal diseases and is associated with increased morbidity and mortality. In patients hospitalized for congestive heart failure, hyponatremia is linked to a poor prognosis and increased length of hospital stay. Prompt recognition and optimal management of hyponatremia in hospitalized patients may reduce in-hospital mortality and symptom severity, allow for less intensive hospital care, decrease the duration of hospitalization and associated costs, and improve the treatment of underlying comorbid conditions and patients’ quality of life. The proper treatment of dilutional hyponatremia, especially when chronic, must avoid increasing serum sodium too rapidly, which can lead to permanent or fatal neurologic sequelae. The treatment of hyponatremia may be facilitated by emerging therapies that block the actions of arginine vasopressin at V 2 and V 1a receptors to promote aquaresis, the electrolyte-sparing elimination of free water, and elevate serum sodium concentrations.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2017
                13 February 2017
                : 11
                : 373-382
                Affiliations
                [1 ]Orlando Clinical Research Center, Inc., Orlando, FL
                [2 ]Department of Research and Development, Cumberland Pharmaceuticals, Inc., Nashville, TN, USA
                Author notes
                Correspondence: Jerry Fox, 2525 West End Avenue, Suite 950, Nashville, TN 37203, USA, Tel +1 615 255 0068, Email jfox@ 123456cumberlandpharma.com
                Article
                dddt-11-373
                10.2147/DDDT.S125459
                5315214
                © 2017 Marbury et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine

                cirrhosis, avp antagonist, hyponatremia, liver

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