Effect of N-acetylcysteine on thiopurine related hepatotoxicity in IBD patients

Thiopurines such as azathioprine (AZA), 6-mercaptopurine (6-MP) and
6-thioguanine (6-TG) are frequently prescribed drugs for the treatment of
inflammatory bowel diseases including ulcerative colitis and Crohns disease.
Hepatotoxicity is a frequently encountered adverse event of thiopurines. The
pathophysiology is not completely elucidated. Rodent models showed that
thiopurine related hepatotoxicity correlated with glutathion depletion leading
to livercell injury. These models also showed that suppletion of glutathion via
N-acetylcysteine increased glutathion and cell viability by reducing oxidative
stress.
This principle is has not been studied in vivo. Hypothetically supplementation
of N-acetylcysteine could attenuate thiopurine related hepatotoxicity. If
supplementation of N-acetylcysteine reduces hepatotoxicity than thiopurine
therapy could be continued. This keeps the risk of relapse low and saves the
use of expensive biological rescue drugs.

1. Determine the influence of acetylcysteine on thiopuirine related
hepatotoxicity

2. Determine the relation between hepatotoxicity, thiopurine metabolism, amino
acid availablility and markers for oxidative stress

3. Determine the effect of acetylcysteine co-administration on thiopurine
metabolites, amino acid availability and markers for oxidative stress

Open label phase II paralell group cross-over intervention study with a
duration of 16 weeks. The aimed total of participants to include is 30. After
screening ,within these 16 weeks the patients will visit the outpatient clinic
five times. During four out of the 16 weeks, acetylcysteine will be
administered in a dose of 1200mg twice daily.

Group 1: Thiopurine therapy will be continued during the first eight weeks of
the study. During the fisrt four weeks acetylcysteine 1200mg twice daily will
be co-administered. Weeks 5 to 8 no acetylcysteine will be administered. During
the weeks 9 to 12 thiopurine therapy will also be discontinued. Rechallenge of
thiopurine therapy is during the weeks 13 to 16.

Group 2: Thiopurine therapy will be continued during the first eight weeks of
the study. During the weeks 5 to 8 acetylcysteine 1200mg twice daily will be
administered. Both thiopurine therapy and acetylcysteine will be discontinued
during the weeks 9 to 12. Rechallenge of thiopurine therapy is during the weeks
13 to 16.

All patients, after screening, visit the outpatient clinic the first day of
weeks 1, 5, 9, 13 and 17 for blood drawing and urine colection. Any adverse
events will be reported and disease activity will be scored. The study visit in
week one, also body weight and length will be ascertained.

Patients will visit the outpatient clinic five times with an interval of four
weeks if the outcome of screening tests permits enrolment in the study. In case
of mild hepatotoxicity, thiopurine therapy continues for the first eight weeks
and the last four weeks of the study. This could result in worsening of liver
test abnormalities. In addition, patients receive 2400mg NAC for four weeks
daily during the first or the second four week period of this study. Every
visit blood will be drawn and the patient will be asked about adverse events.
The potential benefit of participation in this study is that NAC may attenuate
hepatotoxicity, hence patients might be able to continue thiopurine therapy
when indicated. This is particularly interesting when alternative (medicinal)
therapies lack.