Optimizing Azathioprine Therapy in IBD Patients

The article, "Optimizing Azathioprine Therapy in IBD Patients" by Carmen Cuffari is found on pages 661-665 of the book, "Advanced Therapy in Inflammatory Bowel Disease" and is supported by 29 references. For any of you interested in the deeper medical side of Crohn's Disease, this book is fantastic. This thread will contain information I feel is useful in the article and I also open it up for discussion.

- "Critical-dose drugs" are medications that are metabolized differently by a different patients. 6-MP and Azathioprine are critical-dose drugs.

- [wiki]6-TGTP[/wiki] (read that link if you want your brain to explode) is a metabolite of 6-TGN that they think may be what makes 6-MP and Azathioprine work. They feel that some people have different levels of enzyme production associated with it which may be why some people have therapeutic levels of 6-TGN in their system but 6-MP/Azathioprine still don't work well.

- The primary reasons to optimize AZA and 6-MP dosage is to improve response, shorten the response time, and minimize the chance of side effects.

- 40-70% of Crohn's Disease and Ulcerative Colitis patients have therapeutic responses to AZA or 6-MP.

- 6-TGN levels of greater than 250 pmol/8 x 10^8 RBCs in patients correlated with a lack of symptoms. Patients with low levels don't do well. One patient with low levels was suspected not to be taking their meds which they later admitted to. Hahah! 6-TGN monitoring plain makes sense.

- 11% of patients are heterozygous carriers of the TPMT deficient allele and at increased risk of [wiki]leukopenia[/wiki] -- a lower dose of 1 mg/kg/day has been shown to achieve a favorable clinical response in these patients.

- Homozygous recessive patients are at great risk of irreversible bone marrow myelosuppression.

- 50% of the population metabolize AZA and 6-MP normally.

- TPMT testing has been shown to predict leukopenia in up to 20% of patients.

- Patients with no TPMT activity should not be given AZA. Those with levels less than 5 should get 1 mg/kg/day. Those with levels between 5 and 12 can get 1.5 mg/kg/day. Those with levels between 12 and 16 can get 2.0 mg/kg/day. Those with greater than 16 can get 2.5 mg/kg/day

- Metabolite monitoring of 6-TGN and 6-MMP can explain poor response to AZA and 6-MP.

- In a study of 25 patients who weren't responding to AZA but had low levels of 6-TGN, when their dose was increased by 25mg/day 18 reached remission.

- Editors note says that he monitors the WBC and if it is 7000 in a non responsive patient then he increases AZA by 25mg/day until the WBC is 6000 or less then he monitors 6-TGN. I assume this is because 6-TGN testing is expensive.

David, I was wondering if you read anything on the efficacy of 6mp and dosing instructions? When my son was prescribed 6mp we recived a sheet with instructions from the Dr. that he was not to eat or drink milk products for 2 hours before and one hour after he took his meds. There were no instructions like this from the pharmacy when we picked up the medication. I have talked to lots of other people on 6 mp who were never given this information. When I researched the information online I found that pediatric cancer patients were given strict dosing instructions with 6 mp about eating but found nothing about crohns. My son's G.I. is just out of med school and I didn't know if this was new found information but many of the parents I have talked to who's children did not respond to 6mp were not given these dosing instructions. For now we have my son take it exactly as prescribed but I am wondering how important it is. 6 mp has worked excellent for him. Thanks for the information. Tiffany

In China, nearly all the doctors have no idea of these TPMT and 6-TGN things, or there is no equipment of test things. So how could i get best use of aza? If I have started aza for 3months or 6months without effect, should I rise the dose by 25mg/d? Now I have Imuran for 2weeks, and just rise the dose from 75mg/d to 100mg/d. My weight is 45kg, and I take blood test weekly. Thanks.

johnnysmom, sorry for the delayed reply, I was out of town. Your mentioning of those dosing instructions is new to me. I'm pretty far behind due to being out of town so don't have time to research it right now, but have it on my list. I'll let you know if I find something of interest. Thanks for mentioning it!

*edit* Ok, you had me intrigued so I looked it up. Milk products can reduce the bioavailability of 6-MP. Interesting!

Jonathanzn, from what I have read, I think your doctors have you on the right track slowly increasing your dose and monitoring your blood levels weekly. Do you know what your WBC (white blood count) was last time you were tested?

Doing a little more research, interestingly, it's the xanthine oxidase in milk that causes the issue. Those of you also taking Allopurinol with your 6-MP and Azathioprine, guess what it is? A xanthine oxidase inhibitor.

David said:

Jonathanzn, from what I have read, I think your doctors have you on the right track slowly increasing your dose and monitoring your blood levels weekly. Do you know what your WBC (white blood count) was last time you were tested?

Click to expand...

After one week 100mg imuran, my white blood is 5.86, still in the safe zone.

Another question David, because of my half-obstruction in my intestine, I can only drink 1000ml EN per day, which is not enough for maintaining my weight. If I use a nasogastric tube feed, could I tolerate more EN per day like 1500-2000ml?

Thanks!

jonathanzn,

1. In this article the author actually states that Leukopenia (low WBC) can lead to faster remission. Obviously they don't want you to go too low though. I've linked to the actual study in the thread.

2. That must be quite a stricture you have. Have they determined if it is caused by scarring or just inflammation?

3. As an NG tube would just be into your stomach and not bypass your stricture, I'm not sure if it would allow for more EN. Though maybe they could feed you at a much slower pace throughout the day. I don't know, sorry. Maybe someone else does.

We were not given any instructions when we were given 6mp.

David,

this hospital could not do such MRI test to tell whether there is an inflammation or scarring. So I wonder maybe I should change a better hospital. Maybe the best hospital still could not do this.

These days, my flare-up is really serious. Today, I only drink 500ml EN and could not have more. the tummy is like a ball and grumbling & gurgling & Bowel protruding. There are several locations on my abdomen where could show bumps. I am very afraid that there are several strictures in my intestine and they are all scarring.