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Pharmacokinetics of Conivaptan Use in Patients with Severe Hepatic Impairment

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Pharmacokinetics of Conivaptan Use in Patients with Severe Hepatic Impairment Journal name: Drug Design, Development and Therapy Article Designation: Original Research Year: 2017 Volume: 11 Drug Design, Development and Therapy Dovepress Running head verso: Marbury et al Running head recto: Conivaptan pharmacokinetics in patients with severe hepatic impairment open access to scientific and medical research DOI: http://dx.doi.org/10.2147/DDDT.S125459 Open Access Full Text Article ORIGINAL RESEARCH Pharmacokinetics of conivaptan use in patients with severe hepatic impairment 1 Thomas Marbury Purpose: Conivaptan is an intravenous dual V1A/V2 vasopressin antagonist approved for the Jerry Fox2 treatment of euvolemic and hypervolemic hyponatremia. Earlier studies showed that patients Byron Kaelin2 with moderate liver disease could be safely treated with conivaptan by reducing the dose by Leo Pavliv2 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 1Orlando Clinical Research Center, Inc., Orlando, FL, 2Department of 48 h of conivaptan infusion in individuals with severe hepatic impairment. of Research and Development, Patients and methods: Eight subjects with severe hepatic impairment (Child–Pugh Cumberland Pharmaceuticals, Inc., score 10–15) and nine subjects with normal liver function were enrolled. Intravenous conivaptan Nashville, TN, USA (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 For personal use only. defined times. Subjects were followed through Study Day 5. Results: Hepatically impaired individuals exhibited higher concentrations of plasma conivap- tan 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. Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 137.108.70.13 on 11-Jan-2020 Keywords: liver, hyponatremia, AVP antagonist, cirrhosis Introduction Hyponatremia (defined as serum sodium 135 mEq/L) is the most common electrolyte disorder encountered in clinical practice, estimated to be present in 15%–20% of hospital admissions.1 It is associated with significant morbidity and mortality.2 Some of the common etiologies that result in hyponatremia include liver cirrhosis, heart failure, syndrome of inappropriate antidiuretic hormone (SIADH), various drug treat- ments, and the presence of malignancies.3 Euvolemic hyponatremia is classified by a normal amount of total body sodium with increased body water, resulting in a dilution Correspondence: Jerry Fox 2525 West End Avenue, Suite 950, of sodium in the plasma. In hypervolemic hyponatremia, the total body sodium is Nashville, TN 37203, USA increased; however, the total body water is elevated by an even greater amount rela- Tel +1 615 255 0068 Email [email protected] tive to the sodium. This category is commonly found in liver cirrhosis and cardiac submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2017:11 373–382 373 Dovepress © 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 http://dx.doi.org/10.2147/DDDT.S125459 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. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Powered by TCPDF (www.tcpdf.org) 1 / 1 Marbury et al Dovepress disease. Edema or ascites are often a presenting symptom. over a 24 h period for a cumulative treatment period of 48 h. Other symptoms of general hyponatremia include fatigue, The medication was well tolerated in both populations; hence, confusion, muscle weakness, seizures, and coma. this dose was chosen for the current study. Urine levels of Treatment for hyponatremia is not standardized across the conivaptan detected a small signal where excretion increased medical community. Often, no treatment is ordered despite with the severity of hepatic impairment; this evaluation was the likelihood of treatment benefits to patient well-being continued in the current study. Results from the previous and outcomes. Intervention for hospitalized hyponatremic study concluded that the pharmacokinetics of conivaptan in patients has historically included fluid restriction, hypertonic patients with mild liver impairment were similar to those of saline, and demeclocycline. Vaprisol® (conivaptan HCl) healthy patients, whereas the overall exposure of conivaptan (Cumberland Pharmaceuticals, Inc., Nashville, TN, USA) in patients with moderate dysfunction was ~80% higher than was first approved in 2005 and represented a more targeted normal patients.6 This suggested the need for reduced dosing treatment option. Conivaptan is a nonpeptide antagonist of in patients with moderate liver impairment. the two main arginine vasopressin (AVP) receptors, V1A The current study allowed the first detailed review of and V2. It is approved in the USA as an intravenous treatment conivaptan pharmacokinetics in patients with severe liver for euvolemic and hypervolemic hyponatremia. Inhibition impairment, defined per clinical convention, as a Child–Pugh of V2 receptor activity in the kidney promotes aquaresis score of 10–15. Safety assessments were also recorded and (solute-free excretion) of water, which increases the relative analyzed. concentration of sodium in the plasma, contributing to the correction of hyponatremia. Conivaptan is extensively bound Patients and methods to human plasma proteins after intravenous infusion. After Study drug metabolism primarily by the CYP3A enzyme in the liver, Conivaptan HCl is represented by the molecular formula 4 83% of conivaptan is eliminated through the feces. The use C32H26N4O2⋅HCl and has a molecular weight of 535.04 g/mol. of the vaptan class of drugs represents a potentially better It is an antagonist of AVP at both the V and V receptors For personal use only. 1A 2 treatment option for hyponatremia, given the control over free in humans. water excretion without direct modification of electrolytes. In addition, in 90% of hyponatremia cases, the patients’ Patient population level of AVP is inappropriately elevated, beyond that which The study recruited male and female subjects between 30 is expected in the presence of negative feedback mechanisms, and 75 years of age, inclusive. A total of 16 subjects were further contributing to the low sodium levels.5 Therefore, an intended to be enrolled into two groups of eight subjects AVP antagonist is a targeted treatment for this syndrome.6 each based on their baseline level of hepatic function. Conivaptan is approved for use in patients who are Group 1 patients had a Child–Pugh score from 10 to 15, hospitalized. Conivaptan is predominantly metabolized by thereby categorizing them with severe hepatic impairment. the liver so an understanding of the drug kinetics in a patient Subjects with normal liver function comprised Group 2 for with impaired liver metabolism is important to prescribing comparison purposes; they were selected to approximately Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 137.108.70.13 on 11-Jan-2020 treatment. This is especially of value given that liver cirrhosis match the Group 1 subjects with respect to race, sex, age, is a contributing factor for hyponatremia. and body mass index (BMI). A clinical study of the pharmacokinetics of conivaptan Eligible subjects in both groups weighed at least 45 kg in patients with either mild or moderate hepatic impairment and had a BMI between 18 and 40 kg/m2. Their baseline was completed and published.7 In that study, the degree of serum sodium was between 115 and 140 mEq/L, inclusive, liver impairment was defined by each subject’s Child–Pugh and systolic blood pressure was under 140 mmHg while score, which is based on the presence or absence of encephal- diastolic was 56 mmHg. Subjects were negative for human opathy and ascites together with measures of serum bilirubin, immunodeficiency virus (HIV)-1 and HIV-2 antibodies and albumin, and prothrombin time. Mild hepatic impairment must not have routinely consumed 15 units of alcohol
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