A Study to Assess the Effect of Severe Hepatic Impairment on the Pharmacokinetics of Intravenous Conivaptan

A Phase 1, Open-Label Study to Assess the Effect of Severe Hepatic Impairment on the Pharmacokinetics of Intravenous Conivaptan

The purpose of this study is to assess the pharmacokinetics and safety of a 48-hour continuous infusion of conivaptan in subjects with severe liver impairment compared to subjects with normal liver function.

Subjects will be admitted to the Phase 1 unit Day -2 and will remain confined to the unit until discharge on Study Day 5 after completion of all study procedures.

Inclusion Criteria:

Subjects with Normal Hepatic Function:

Female subject must be either:

• post-menopausal prior to Screening, or

• premenarchal prior to Screening, or

• documented surgically sterile or post hysterectomy, or

• if of childbearing potential, must have a negative pregnancy test at Screening and must be using highly effective contraception prior to Screening and throughout the study period and for 28 days after final study drug administration

  • Female subject must not be lactating and must not be breastfeeding at Screening or during the study period, and for 28 days after final study drug administration
  • Female subject must not donate ova starting at Screening or during the study period, and for 28 days after final study drug administration
  • Male subject must:

• be using highly effective contraception consisting of two forms of birth control (one of which must be a barrier method) starting at Screening and continue throughout the study period, and for 28 days after final study drug administration

• not donate sperm starting at Screening and throughout the study period, and for at least 28 days after final study drug administration

  • Subject weighs at least 45 kg and has a body mass index between 18 and 40 kg/m2 inclusive
  • The subject must have clinical laboratory test results within normal range, including liver function tests (LFTs)
  • The subject must have had a normal 12-lead electrocardiogram (ECG)

Hepatic Impaired Subjects:

• Female subject must be either:

  • post-menopausal prior to Screening, or
  • premenarchal prior to Screening, or
  • documented surgically sterile or post hysterectomy, or
  • if of childbearing potential, must have a negative pregnancy test at Screening and must be using highly effective contraception prior to Screening and throughout the study period and for 28 days after final study drug administration

• Female subject must not be lactating and must not be breastfeeding at Screening or during the study period, and for 28 days after final study drug administration

• Female subject must not donate ova starting at Screening or during the study period, and for 28 days after final study drug administration

• Male subject must:

  • be using highly effective contraception consisting of two forms of birth control (one of which must be a barrier method) starting at Screening and continue throughout the study period, and for 28 days after final study drug administration
  • not donate sperm starting at Screening and throughout the study period, and for at least 28 days after final study drug administration

• Subject meets criteria for severe hepatic impairment defined by Child-Pugh method

• Subject weighs at least 45 kg and has a body mass index between 18 and 40 kg/m2 inclusive

• The subject must have clinical laboratory test results within therapeutic range except for hepatic disease

• The subject must have had a normal 12-lead electrocardiogram (ECG)

Exclusion Criteria:

Subjects with Normal Hepatic Function:

• Subject has a history of a clinically significant illness, and associated clinical symptoms, medical condition, or laboratory abnormality within past 3 months that would preclude participation in the study
• Subject has evidence of biliary obstruction or other causes of hepatic impairment
• Subject is known to have hepatitis or is a carrier of hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, or is known to be HIV positive or has HIV antibodies
• Subject has an impaired ability to sense thirst
• Subject has serum sodium less than 115mEg/L or greater than 140 mEg/L
• Subject has either a systolic blood pressure (BP) of greater than 140 mmHg or a diastolic BP of less than 56 mmHg
• Subject has taken any prescription or over-the-counter medications except for contraceptives, hormone replacement therapy and occasional acetaminophen, or alternative and complementary medicines within past 14 days
• Subject has a history of carcinoma, except for basal cell or cutaneous squamous cell carcinoma within past 5 years
• Subject drinks greater than 14 units of alcohol per week (Note: one unit = 12 ounces of beer, 4 ounces of wine, or 1 ounce of spirits)
• Subject has a history of substance abuse within past 6 months prior to Screening Visit or the subject tests positive at Screening or clinic admission for alcohol or drugs of abuse
• Subject is currently participating in another clinical trial or has received an investigational medication within past 30 days
• Subject is known to have hypersensitivity to conivaptan or its derivatives
• Subject has had a blood transfusion or donated/lost more than 550ml of blood within past 8 weeks
• Subject is incapable of being compliant with the protocol

Subjects with Hepatic Impairment:

• Subject has a history of a clinically significant illness, and associated clinical symptoms, medical condition, or laboratory abnormality within past 3 months that would preclude participation in the study. Subjects with controlled hypertension may be allowed
• Subject has a condition associated with hepatic disease including; biliary obstruction, or other cause of hepatic impairment not related to parenchymal disorder and/or disease of the liver, fluctuating or rapidly deteriorating hepatic function, biliary liver cirrhosis, history or presence of hepatic encephalopathy greater than Grade 1 within past 3 months or unstable encephalopathy prior to Screening, tense ascites, esophageal/gastric variceal bleeding with past 6 months, server portal hypertension, surgical portal systemic shunt or peritoneal venous shunt, thrombocyte level below 50,000 x 10^9/L and prothrombin time (PT) above 18 seconds
• Subject is hypovolemic or has evidence of orthostatic hypotension
• Subject has an impaired ability to sense thirst
• Subject has serum sodium less than 115mEg/L or greater than 140 mEg/L
• Subject has either a systolic blood pressure (BP) of greater than 140 mmHg or a diastolic BP of less than 56 mmHg
• Subject is known to be HIV positive or has HIV antibodies
• Subject has had a change in dose regimen of medication needed for their underlying medical condition with the past four weeks
• Subject is currently taking a prohibited medication
• Subject drinks greater than 14 units of alcohol per week (Note: one unit equals 12 ounces of beer, 4 ounces of wine, or 1 ounce of spirits)
• Subject has a history of substance abuse within past 6 months prior to Screening Visit or the subject tests positive at Screening or clinic admission for alcohol or drugs of abuse
• Subject is currently participating in another clinical trial or has received an investigational medication with past 30 days
• Subject has had a blood transfusion or donated/lost more than 550ml of blood within past 8 weeks
• Subject is known to have hypersensitivity of conivaptan or its derivatives
• Subject is incapable of being compliant with the protocol