APAP-CYS Protein Adduct Concentrations in Patients With Liver-Directed Therapy Intended to Treat Hepatic Tumors

Acetaminophen-cysteine protein adducts (APAP-CYS) are formed when acetaminophen is oxidized
by CYP 2E-1. When hepatocytes die, these proteins are released into the serum and can be
detected. APAP-CYS can therefore be an experimental biomarker of acetaminophen exposure. It
is possible that massive necrosis of hepatocytes that contain APAP-CYS from therapeutic doses
of acetaminophen can be misinterpreted as acetaminophen overdose as the cause of liver
injury. This study aims to describe serum APAP-CYS concentrations in patients taking a
therapeutic dose of acetaminophen who develop a liver injury from a cause other than
acetaminophen. This study will seek to enroll subjects undergoing a hepatic embolization
procedure to treat a secondary liver tumor. This procedure is a reproducible model of
non-acetaminophen induced hepatic injury. A small number of subjects who are otherwise
eligible to participate but are unwilling to take acetaminophen will be offered participation
in the observational arm of the study. They will undergo the same assessments with the
exception of acetaminophen dosing. Subjects willing to take acetaminophen will be asked to
take extra strength acetaminophen (4g/day) for the 3 days prior to their embolization
procedure. All subjects will be asked to keep a detailed medication diary for the three days
prior and up to their embolization procedure. Blood samples for the measurement of APAP-CYS
concentrations and markers of liver function will be collected prior to acetaminophen dosing,
prior to the embolization procedure, and at several time points after the procedure.

Inclusion Criteria:

- Subjects of any gender or ethnic background who are between 21 and 80 years old

- Subjects who are able to provide written, informed consent

- Subjects with secondary liver cancer

- Subjects undergoing portal vein or bland embolization for the treatment of secondary
hepatic tumor

- Subjects who are willing to have their blood drawn at least 12 times for study
purposes

- Subjects who agree to stay for ~18-21 hours after being discharged from the Department
of Radiology for research purposes

- Subjects who agree to refrain from using acetaminophen, other than the study drug,
during the dosing phase through a minimum of 5 days post-procedure

- Subjects who agree to consume less than 3 alcoholic drinks per day while taking study
drug (acetaminophen group only)

- Subjects who are willing to complete a study diary for 3 days prior to and the day of
the procedure

- Subjects who will be in the Denver metro area for the duration of the study

Exclusion Criteria:

- Subjects with known cirrhosis

- Subjects with a history of moderate to severe anemia at screening as defined by:

1. Moderate: Hemoglobin 8-9.5 g/dL

2. Severe: Hemoglobin <8 g/dL

- Subjects with an ALT or AST greater than 200 IU/L at screening

- Subjects with a total bilirubin greater than 1.5 mg/dL at screening

- Subjects with an INR greater than 1.3 at screening

- Subjects with a platelet count less than 125 10^9/L at screening

- Subjects who are currently taking warfarin (acetaminophen group only)

- Subjects with anorexia nervosa (self-reported; acetaminophen group only)

- Subjects who weigh ≤50 kg at screening (acetaminophen group only)

- Subjects who adhere to a fasting type diet (self-reported; acetaminophen group only)

- Subjects with a known hypersensitivity or allergy to acetaminophen (acetaminophen
group only)

- Subjects who are currently taking isoniazid (acetaminophen group only)

- Subjects who are currently taking disulfiram (acetaminophen group only)

- Subjects who are pregnant or breastfeeding (female participants only)

- Subjects who are currently enrolled in a clinical trial, have participated in a
clinical trial within the 30 days prior to the procedure, or who plan to participate
in a clinical trial during the 5 day post-procedure follow-up period