Tac trough 45!

[MooseMom]

I know to take may tac AFTER having my monthly blood draw, but yesterday I had a brain fart and accidentally took it beforehand.  Just as I swallowed the last of three capsules, I realized what I had just stupidly done.  So I raced to the lab and explained what happened.  It was the last day that my standing order was valid, plus I had been feeling just a bit under the weather, so I wanted to see my WBC.  Otherwise, I would have just made an appointment for another day.  The phlebotomist added a note outlining my mistake.

She told me that it would probably be OK since it had only been a half hour since I'd taken my tac.  (Well, she turned out to be wrong.)

I tried calling my tx coordinator to warn her in case my results got red flagged, but her voicemail box was full, so I couldn't even leave a message.

Well, I just got a call from her, telling me that she had been informed that my tac trough (although it wasn't really a trough at all!  ) was (or, at least, had been at the time my blood was taken) 45!  I had no idea that it would ever get that high!  My trough has been very consistent at around 6, which is just where they want it, so neither of us were concerned (and she had correctly suspected that I had taken my tac too early), but I didn't realize that this drug level had such peaks and valleys over just a 12 hour period.  No wonder they so closely monitor your tac trough, and no wonder a tx patient has to take it as close to 12 hours apart as possible.

[Deanne]

Interesting information. Thanks for sharing. I never thought to ask what the peak level might be. It really kicks in fast. I bet it still increases a lot from 45 sine that was only a half hour in.

[Angiepkd]

That is very interesting!  I never thought to ask how high the numbers get.  Is the 6 they want you at a standard number throughout the life of your transplant, or has it decreased over time?  I had my clinic visit today and I was at 10.9, which is where the doc said he wanted it. I am less than 2 weeks out from transplant.  I take a pretty large dose of tac to get to that number (12 mg twice a day).  I am hoping that amount will decrease over time. Guess I will have to ask at my appt Monday.  How much do you take to stay at 6, if you don't mind me asking. And do you remember where you started right after transplant? Thanks!

[Deanne]

12 mg twice a day sounds huge. My highest dose was 5 mg twice a day and that was only for a couple of weeks. They wanted my trough level between 10 and 15 for the first month. Now they want it between 5 and 10 and my current dose is 3 mg twice a day. It's an interesting comparison.

[MooseMom]

Angie, my center likes to see a tac trough between 8 and 10 in the first year post tx.  The highest dosage I ever had to take was 4mg and 3 mg per day, but I did not stay with that for long since my tac level went all over the place (not unusual).  After one year, they like to see the tac trough between 6 and 8.  I take 3mg twice daily, 12hours apart on an empty stomach.  This seems to have done the trick.

[obsidianom]

 Tacrolimus is dosed at   .1 to  .2  mg per kg per day in divided doses at 12 hours..  So it is weight based entirely with a 100% variance possible.
So a 50 kg person could take from 2.5 mg BID  to 5 mg BID.    A 80 kg person could take from  4mg BID to 8 mg BID.   
Also there are rules on kidey function . Lower kidney function would lower the dose as it is not excreted as fast.
Also some people metabolize slower or faster and absorb meds at different levels . That is why they check blood levels and peaks and troughs. So the dosing is effected by this also. Also proteins that bind or carry the medication vary and that effects blood levels as do liver enzymes. The liver enzymes are  a major factor in blood levels. The vary so much from one person to the other.

[obsidianom]

More info on dosing of Tacrolimus.
It has a narrow therapeutic window. There is a huge variability between patients in pharmakokinetics meaning the way the drug is metabolized and utilized to obtain blood levels.  That is why blood levels are checked. There is simply a poor coorelation between dose and blood levels.
The blood levels are effected by weight , sex, proportion of body fat, lipid fraction of the organs, hematocrit, intrinsic clearance of the system , other drugs taken by the patient that effect the CPY3A4 enzymes in the liver, the patients own CYP3A5 fenotype.
So to make a long winded story short, this drug has a wide variance in dose to get the required blood levels and it is effected by a lot of factors. One person may require 3 mg while another may require 15 mg to obtain the same blood levels. 

Blood levels just before next dose vary from 5 to 20 ng/ml. and change at different times after transplant .  They are constantly modified over time.

[cattlekid]

I'm another person who is at 7 mg per day....3 in the morning and 4 in the evening.  I take mine with meals as it's easier for me to remember.  The team said that was okay as long as it's always done the same way - either always with meals or always without.  I take the bulk of my prescriptions with breakfast, a large dose of vitamins and other supplements at lunch and then a smaller amount of prescriptions at dinner and then again at bedtime.  When I am with others for meals and they see me bust out my pill box, I always joke about my meal after my meal.   

[MooseMom]

The team said that was okay as long as it's always done the same way - either always with meals or always without.

Yep, that's right.  Find what works for you and stick to it.

I take the bulk of my prescriptions with breakfast, a large dose of vitamins and other supplements at lunch and then a smaller amount of prescriptions at dinner and then again at bedtime.  When I am with others for meals and they see me bust out my pill box, I always joke about my meal after my meal.   

Yep, it's my understanding that you shouldn't take any vitamins or supplements with immunosuppressants.  "Meal after my meal"...

[MooseMom]

Obsidianom, as I've explained, just 30 minutes after I took my tac, my level was measured to be 45.  Do you have any idea at which point in time the concentration of tacrolimus would be at its highest?  Would it have peaked at 45, do you think?

"CYP345 Phenotype".  Sounds like a good title for a low-budget sci-fi flick.  LOL!  (Actually, "Phenotype CYP345" sounds spookier.)

[jeannea]

Trough level of 45. That's a good one. I assume they gave you a new script. I can't remember exactly my trough level when I went into a coma. I think it was in the upper 20s. I hate that feeling you had right after taking meds where you think Damnit! I screwed it up.

My trough level varies but I'm usually between 5-6. They try to keep mine a little low due to my previous CMV and PRES problems. But it really depends on so much including how far from your transplant, what other immunosuppressant meds you take, any recent rejection, etc.

I'm jealous you're on monthly blood draws. I'm still on every two weeks although 4 times in the last 2 weeks due to issues.

[MooseMom]

Trough level of 45. That's a good one. I assume they gave you a new script. I can't remember exactly my trough level when I went into a coma. I think it was in the upper 20s. I hate that feeling you had right after taking meds where you think Damnit! I screwed it up.

My trough level varies but I'm usually between 5-6. They try to keep mine a little low due to my previous CMV and PRES problems. But it really depends on so much including how far from your transplant, what other immunosuppressant meds you take, any recent rejection, etc.

I'm jealous you're on monthly blood draws. I'm still on every two weeks although 4 times in the last 2 weeks due to issues.

Nah, they didn't give me a new script because my current dosage had kept my trough steady at around 6 for almost a year now. I've been on the same meds/dosages for coming up to a year.  I have my 2 year post tx annual appointment coming up in early May, but I don't anticipate any major changes as all of my numbers have been thankfully boring and normal for many months now.

I know you've sorta been through the wars lately, and I'm really hoping that things right themselves very soon for you.   

[Angiepkd]

I think I am more confused than ever haha!  My liver enzymes have been out of whack, so maybe that is partly the problem.  The transplant doc is hoping the liver issues are from the Percocet, so no more pain meds for me. Another possible cause is the maintenance dose of Bactrim I am on.  Hopefully, stopping the pain meds fixes the problem. I have to say that I am missing being pain free, but guess it will be worth it.  Right now, I just hurt!  I am 6 feet tall and normally weigh around 70kgs, but since the transplant I am up to around 79 kgs.  The fluid overload is getting better, but taking more time than I would like.  My brother takes 5mgs in the am and 4 at night as his maintenance dose, and he is 8 years post transplant. Maybe our family are tac metabolizers. 

[obsidianom]

Obsidianom, as I've explained, just 30 minutes after I took my tac, my level was measured to be 45.  Do you have any idea at which point in time the concentration of tacrolimus would be at its highest?  Would it have peaked at 45, do you think?

"CYP345 Phenotype".  Sounds like a good title for a low-budget sci-fi flick.  LOL!  (Actually, "Phenotype CYP345" sounds spookier.)

From the pharmakokinetic tables I looked at, it appears the max. levels peak at about 1 to 1.5 hour but are effected a lot by food. An empty stomach will greatly speed up the absorbtion so the levels will rise much faster.  So will the amount of albumin you have that binds the drug.   Also troughs of up to 30 are seen in some patients normally,  with a peak of up to 60  or more so your 45 is not out of line with what occurred.  You were probbaly not quite peaked yet. Also taking the pills every day raises the peak levels over time so they go higher . There are a lot of drugs that also raise the levels , such as calcium channel blockers for blood pressure as an example. So any other meds you are on effect the levels.

[obsidianom]

A brief hopefully understandable explanation of drug metabolism. To simplify what occurs to a drug when you orally take it.
 The first thing is the drug has to be absorbed in the gut so it enters the blood stream. Everyones ability and speed doing this varies. It is also effected in some cases by whether the stomach is empty which tends to speed it up or full of food which slows it down. In addition, fatty foods slow it down even more.
Once in the blood drugs are usually carried by being bound up or capture by protiens like albumin. "this is called protein binding" . Many drugs are 99% prorein bound and only the 1% that is unbound is measured by blood tests as that is the actual active drug. So your ALBUMIN which is tested a lot in kidney patients is critical as it is a primary agent to bind or hold the drug so only a small fraction of the drug is actually active. 
Now the blood levels after initial absorbtion in the gut are highest in the first 1 to 2 hours usually . Some drugs can be absorbed as quickly as 15 minutes on an empty stomach.  As you keep taking a drug every day you add to the amount in the blood stream until you reach what is known as steady state . This occurs usually in 3 to 4 days in many drugs but there are some that can take considerably longer. This is effected by what is known as the half life ofthe drug. Half life is the time for half the drug to be eliminated from the blood .    Example if the half life is 12 hours, in 12 hours the blood levels of 1 dose drop by half. At 24 hours which is two half lives , the drug levels drop to 1/4 of the original. This continues every 12 hours until all the drug is eliminated in about 4  to 5  half lives.  Basically the rule is 4 half lives deactivates a drug.  Now as you keep taking the drug daily it builds up by exceeding the speed it is excreted.
 Now the metabolism or excretion of the drug occurs in various ways in different drugs. Some are simply urinated out in thier same form or some metabolite that it has been changed into by the body. That is why these type drugs are effected a lot by kidney issues. As the GFR slows down , so does the excretion of the drug so it can build up in the blood to toxic levels if not monitered.  The more common way many drugs are metabolised or broken down is by the LIVER.
The liver has enzymes that are designed to break down toxins which are what drugs really are. one common system is the Cytochrome P450 system which has many subsystems that are known to exist within it. These enzymes in the P450 system break down many of our common drugs like Tacrolimus. After this occurs and the drug is broken down to some other deactive chemical ( although some are actually active ), the chemical is either excreted by the urine or through the feces. So again the kidneys are involved even in liver metabolism if the urine is used to excrete.
Now, the liver enzymes like the P450 system are SO variable for patien to patient . That is why the drugs like Tacrolimus are given or dosed in so many different sizes. Here is where actually checking the blood levels is critical as it effectively indirectly measures the liver enzymes by looking at the speed the drug is excreted through the actual blood level at peak and then trough.    Other drugs you are taking that are also metabolized by the same enzymes also can slow down or speed up in some cases (by actually increasing the enzymes) the excretion. So that is why it is important to know what drugs you are taking .
 I hope this helps a little wiith understanding the different doses of Tacrolimus.

[MooseMom]

Obsidianom, thank you so much for all of the time and effort in posting your very interesting and coherent explanations!  The role of the liver does help to possibly explain some of the difficulties experienced by Angiepkd.  And I had never given much thought to a drug's "half life" nor to the idea of a "steady state".  Again, thanks!

[jeannea]

Thanks for the flashbacks Obsidianom. I used to work in Regulatory Affairs at a pharmaceutical company.

MooseMom, thanks for the good wishes. I'm plugging along.

I think Prograf is right up there with drugs we love to hate. We need it so much but it is hard to manage. Pain in the a** but life saving.

[MooseMom]

http://www.marketwatch.com/story/us-fda-accepts-veloxis-new-drug-application-for-envarsus-for-the-prevention-of-organ-rejection-in-kidney-transplant-patients-2014-03-13

For some reason, I just can seem to copy and paste whole articles any more, but the link above leads to an article about a new, once daily tablet form of tacrolimus.  It's supposed to have "reduced peak to trough variability", which fits in nicely with this discussion.  Wouldn't it be great if we had to take only one tablet of tac a day?

[Angiepkd]

Thank you, Obsidianom!  Makes much better sense!  You took me back to my days as a health physics technician, only we were looking at half lives of radioactive elements. Same general idea, though. Thanks again!

[obsidianom]

http://www.ncbi.nlm.nih.gov/pubmed/24409044#
This is an abstract about pharmakokinetics and Tacrolimus.

[obsidianom]

.http://www.ncbi.nlm.nih.gov/pubmed/24135441#
This is info on once daily use and satisfaction.

[MooseMom]

http://www.ncbi.nlm.nih.gov/pubmed/24409044#
This is an abstract about pharmakokinetics and Tacrolimus.

So, do you think that determining a patient's genotype is part of the pre-tx workup?  It doesn't sound like there is not enough evidence to sufficiently guide a tx nephrologist as to the specific dosage that's best for a specific patient, but I do wonder if most tx centers DO look for that CYP3A5 genotype.

[MooseMom]

.http://www.ncbi.nlm.nih.gov/pubmed/24135441#
This is info on once daily use and satisfaction.

Well yeah, I'd think that most patients would report a higher degree of satisfaction in anything that reduced their medication load!  I'd rather take one tablet a day than 6 capsules whose coating is like mercury.  It's hard to pin down those little buggers.

[obsidianom]

http://www.ncbi.nlm.nih.gov/pubmed/24409044#
This is an abstract about pharmakokinetics and Tacrolimus.

So, do you think that determining a patient's genotype is part of the pre-tx workup?  It doesn't sound like there is not enough evidence to sufficiently guide a tx nephrologist as to the specific dosage that's best for a specific patient, but I do wonder if most tx centers DO look for that CYP3A5 genotype.

I see this as the FUTURE of medicine, but it is not there yet for now. We will be seeing more of this in all areas of medicine in the years to come as it will make it easier to dose medicines safely for any given patient. Right now its guess work.
For now the trough blood levels of tacrolimus is the best way to dose it. It is accurate. It just means a lot of expensive blood tests.