Drug Induced Liver Injury
Conditions
Keywords
acetaminophen, protein adducts, hepatic function, drug safety, non drinkers
Brief summary
Acetaminophen is commonly used to treat fever or pain. Your body clears acetaminophen by processing it in the liver. During the processing, some of the acetaminophen may bind to proteins in the liver. The protein-acetaminophen product is called an adduct. After a large acetaminophen overdose, the liver has to process a lot of acetaminophen, so large amounts of adducts are formed. However, we have found that lower levels may be formed even when people take recommended doses. The purpose of this study is to measure the amount of adducts formed when healthy people who do not drink alcohol take normal doses of acetaminophen for 10 days.
Interventions
DRUGacetaminophen
4 g/day for 10 consecutive days
Sponsors
McNeil Consumer & Specialty Pharmaceuticals, a Division of McNeil-PPC, Inc.
Kennon Heard
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
1. age 21 years or older 2. provide written informed consent 3. consume, on average, less than 1 alcoholic beverage daily for the previous 3 months and would be considered non-drinkers
Exclusion criteria
1. History of ingesting more than 4 grams of acetaminophen per day for any of the 4 days preceding study enrollment 2. Currently taking isoniazid 3. Consumption of any alcoholic beverage during the run-in period 4. A detectable serum acetaminophen at baseline 5. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels greater than 50 IU/L at the start of the run-in period or at baseline 6. Platelet count less than 125,000/cc at baseline 7. Positive pregnancy test at baseline (female participants only) 8. Currently adheres to a fasting type diet as determined by self report 9. Currently has anorexia nervosa as determined by self report 10. Subject appears clinically intoxicated, psychiatrically impaired or unable to give informed consent for any reason 11. Known hypersensitivity to acetaminophen
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Serum Level of Acetaminophen-cysteine (APAP-Cys) Protein Adducts | Day 0, 4, 7, 9, 11, and 14. | Acetaminophen-cysteine (APAP-Cys) protein adduct concentrations were measured at Day 0, 4, 7, 9, 11 and 14. All units are in nmol/mL serum. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Alanine Aminotransferase (ALT) | Day 0, 4, 7, 9, 11, and 14. | ALT was measured at Day 0, 4, 7, 9, 11, and 14. |
Countries
United States
Participant flow
Recruitment details
Study was conducted from August 2007 through January 2008. Healthy volunteers were recruited through flyers posted in community settings.
Pre-assignment details
Thirty-five subjects were consented for the study. Of these, eight were excluded (six did not meet inclusion criteria and two refused to participate). The 27 eligible subjects were assigned to the treatment arm to receive 4 grams of acetaminophen per day, for 10 consecutive days.
Participants by arm
| Arm | Count |
|---|---|
| Acetaminophen all subjects receive 4 g/day of acetaminophen for 10 consecutive days in this open-label study | 27 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Protocol Violation | 3 |
Baseline characteristics
| Characteristic | Acetaminophen |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 27 Participants |
| Age Continuous | 37.3 years STANDARD_DEVIATION 12.2 |
| Region of Enrollment United States | 27 participants |
| Sex: Female, Male Female | 19 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 12 / 27 |
| serious Total, serious adverse events | 0 / 27 |
Outcome results
Primary
Serum Level of Acetaminophen-cysteine (APAP-Cys) Protein Adducts
Acetaminophen-cysteine (APAP-Cys) protein adduct concentrations were measured at Day 0, 4, 7, 9, 11 and 14. All units are in nmol/mL serum.
Time frame: Day 0, 4, 7, 9, 11, and 14.
Population: Analysis is based upon the 24 subjects who completed all study visits.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Acetaminophen | Serum Level of Acetaminophen-cysteine (APAP-Cys) Protein Adducts | Day 0 | 0.0 nmol/mL | Standard Deviation 0 |
| Acetaminophen | Serum Level of Acetaminophen-cysteine (APAP-Cys) Protein Adducts | Day 4 | 0.3 nmol/mL | Standard Deviation 0.1 |
| Acetaminophen | Serum Level of Acetaminophen-cysteine (APAP-Cys) Protein Adducts | Day 7 | 0.3 nmol/mL | Standard Deviation 0.2 |
| Acetaminophen | Serum Level of Acetaminophen-cysteine (APAP-Cys) Protein Adducts | Day 9 | 0.4 nmol/mL | Standard Deviation 0.2 |
| Acetaminophen | Serum Level of Acetaminophen-cysteine (APAP-Cys) Protein Adducts | Day 11 | 0.4 nmol/mL | Standard Deviation 0.2 |
| Acetaminophen | Serum Level of Acetaminophen-cysteine (APAP-Cys) Protein Adducts | Day 14 | 0.2 nmol/mL | Standard Deviation 0.1 |
Secondary
Alanine Aminotransferase (ALT)
ALT was measured at Day 0, 4, 7, 9, 11, and 14.
Time frame: Day 0, 4, 7, 9, 11, and 14.
Population: Analysis is based upon the 24 subjects who completed all study visits.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Acetaminophen | Alanine Aminotransferase (ALT) | Day 0 | 24.0 IU/L | Standard Deviation 8.1 |
| Acetaminophen | Alanine Aminotransferase (ALT) | Day 4 | 25.9 IU/L | Standard Deviation 10.1 |
| Acetaminophen | Alanine Aminotransferase (ALT) | Day 7 | 41.3 IU/L | Standard Deviation 27.3 |
| Acetaminophen | Alanine Aminotransferase (ALT) | Day 9 | 41.3 IU/L | Standard Deviation 27.3 |
| Acetaminophen | Alanine Aminotransferase (ALT) | Day 11 | 41.8 IU/L | Standard Deviation 24.2 |
| Acetaminophen | Alanine Aminotransferase (ALT) | Day 14 | 36.1 IU/L | Standard Deviation 18.6 |