a study to assess the effect of severe hepatic impairment on the pharmacokinetics of intravenous conivaptan

Conditions: Liver Disease

Summary: 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.

Eligibility criteria:
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

Keywords: pharmacokinetics protein binding conivaptan vaprisol liver disease ym087