Trilostane Questions for Dr. Bruyette

[labblab]

Dr. David Bruyette is a nationally known veterinary endocrinologist and the medical director of VCA West Los Angeles Animal Hospital. Dr. Bruyette has recently joined us as a member here at k9cushings.com, and has graciously agreed to "field" general questions regarding trilostane treatment and monitoring. Of course, by answering our questions, he will not be assuming responsibility for overseeing the specific treatment of our dogs. Rather, his replies can help us to consult more knowledgeably with our own vets.

If you have questions about trilostane treatment and monitoring, please feel free to add a reply to this thread for Dr. Bruyette's consideration. Here is a quick dosing summary that he has already provided to us:

"In general about 80% of our patients do well on once a day dosing. We start at 3-5 mg/kg once a day in the AM and perform the ACTH stim test in 7-10 days. We switch to BID dosing when we don't have control of clinical signs and the 4 hours post ACTH stim is less than 9 ug/dl but the 24 hour ACTH stim is greater then 9 ug/dl. If we go BID we start at 2 mg/kg BID and recheck the stim again in 7-10 days."

Also, please take a look at this video summary of an interview with Dr. Bruyette that is included on our "Resources" forum:

"Trilostane dosing, monitoring, switching from mitotane to trilostane."

Many thanks in advance to Dr. Bruyette, and may the questions begin!

[labblab]

One of the benefits of starting this thread is that I can be the first one to ask a question (actually, two questions).

First off, I am wondering why the prevailing recommendation is to begin dogs on once-daily rather than twice-daily trilostane dosing regimens since, as you have noted in your video, recent research seems to indicate that dogs being treated with twice-daily doses can often be maintained on a lower overall daily dose. Even if there were no other benefit, this would be a "plus" for owners from a financial standpoint. Additionally, from my lay perspective, it just seems as though twice-daily dosing would tend to keep cortisol levels maintained more consistently throughout a 24-hour time period for all dogs. But perhaps this is either not the case or not a big benefit for the majority of dogs?

Secondly, you mention utilizing a 24-hour ACTH to aid in identifying those dogs that specifically benefit from twice-daily dosing. We have read that the folks at UC Davis (at least in the past) have suggested looking at a morning (pre-Trilostane dose) UC:CR to help gauge the desirability of making the dosing shift. Would you ever recommend using a UC:CR in this way?

Marianne

[David Bruyette]

Both good questions. With regards to once vs twice a day dosing if we look at all the studies throughout the world you will see that about 80% of dogs do well with once daily dosing. One huge advantage of once daily dosing is owner compliance which goes up substantially when owners only have to dose once a day. While twice a day dosing may result in a lower amount of trilostane being used pre day it will require closer monitoring as the ACTH stimulation tests tend to be lower so we have to look for both hypocortisolemia and electrolyte abnormalities.

Urine cortisols can be a problem. Many studies have shown that the only way to accurately gauge urine cortisol levels is to obtain the first morning voided urine sample on 3 consecutive days and then pooling the urine to run a UCCR. When done in this fashion it is likely an accurate test. Otherwise there is likely too much day to day variation to make a single random cortisol very helpful.

Dave Bruyette DVM DACVIM

[labblab]

Dr. Bruyette, you have no idea how excited I am to be able to ask you my accumulation of trilostane questions! People who know me here know that I have a LOT of them. So I'm going to keep on firing away (and anybody else who has a question -- please join in!).

Urine cortisols can be a problem. Many studies have shown that the only way to accurately gauge urine cortisol levels is to obtain the first morning voided urine sample on 3 consecutive days and then pooling the urine to run a UCCR. When done in this fashion it is likely an accurate test. Otherwise there is likely too much day to day variation to make a single random cortisol very helpful.

This is not a "trilostane question" per se, but I did want to ask a follow-up regarding the validity of urine cortisols. Is it the case that when the UC:CR is being used as an initial general Cushing's diagnostic, the testing should involve the pooled 3-day sample that you have described above? (And to get down to specifics, would the owner "pool" and refrigerate the daily samples as gathered at home, and then take the combined result in to the vet for analysis?).

And one more follow-up trilostane question: Even though it is ideal to obtain a 24-hour ACTH when making the decision to switch to twice daily dosing, as a practical matter, do you ever recommend making the switch solely on the basis of recurrent symptoms later in the day? Assuming, of course, that the 4-hour ACTH is within the desired therapeutic range and symptoms have been effectively controlled during the early hours after once daily dosing.

Marianne

[David Bruyette]

Yes. The same would apply when looking at urine cortisols in the initial diagnosis of Cushings. Ideally 3 morning pooled urine samples collected by the owner at home and refrigerated.

With regards to trilostane we have done as you described and made the switch to BID dosing when the 4 hour post ACTH is controlled and the symptoms return at night.

Dave

[SasAndYunah]

That's the way Cushings is diagnosed in The Netherlands, the 3 day urine samples, combined with Dexamethasone pills on the second day. Seems to me much easier, less expensive and much easier on the dogs and even more reliable... I have been writing about this protocol several times on this board.

Is there a specific reason why this diagnostic protocol isn't "the rule" in the USA? Just curious about this

Saskia and Yunah,
The Netherlands.

[Squirt's Mom]

Hi Dr. Bruyette,

First, thank you for your participation and willingness to help our family here. I am very glad to have you on board for several reasons!

My baby, Squirt, is not on either Lyso or Trilo yet. She has been diagnosed with PDH and elevated intermediate/sex hormones and is being treated with melatonin and purified lignans for the time being. She is doing quite well based on her signs and behaviors.

When she was first diagnosed, I was terrified of Lysodren and was inclined to use the Trilo. However, since her Atypical diagnosis, that is no longer an option. Before this diagnosis, I tried to learn what I could about Trilo and really watched members who were using it with their pups. As time passed and the more I read, the less I liked Trilo. Over a year later, my opinion has not changed.

Here are my concerns about Trilostane; would you mind looking at them and telling me if my perceptions are off base?

1. Trilostane is too new, has a much shorter track record than Lysodren, and vets are not as familiar with it

2. Pups on Trilo seem to have inappetence issues; some fairly quickly, some after being on it for a time

3. Smaller pups seem to have more issues than larger dogs

4. Some pups seem to experience a rapid drop in cortisol resulting in an apparent crash when first starting Trilo

5. Shaking and muscle weakness either increases or suddenly appears after starting Trilo

6. The attitude that Trilo is a "safe" drug with no side effects


Finally, why are Trilostane and Anipryl the only drugs approved to treat canine Cushing's? Lysodren has been around and in use much longer, yet has not been approved.

Thanx again!
Hugs,
Leslie and the girls

[David Bruyette]

I think its because pet owners in the United States dont want to handle dog urine

Dave Bruyette DVM DACVIM

[David Bruyette]

1. Trilostane is too new, has a much shorter track record than Lysodren, and vets are not as familiar with it.

While that may be true in the US it is not worldwide and there are numerous publications showing it to be safe and effective. Some bias I think since it was no initially developed in the US.

2. Pups on Trilo seem to have inappetence issues; some fairly quickly, some after being on it for a time.

If you look at the data with respect to op-DDD and trilostane inappetance can occur with both and is usually less frequent, less severe and more rapidly reversed with trilostane.

3. Smaller pups seem to have more issues than larger dogs.

This is simply a dosing issue and occurs with many types of drugs. When you say pups are you referring to puppies as there would be little reason to use either medication in very young animals.

4. Some pups seem to experience a rapid drop in cortisol resulting in an apparent crash when first starting Trilo.

Same as can be seen with trilostane, ketoconazole or op-ddd.

5. Shaking and muscle weakness either increases or suddenly appears after starting Trilo.

Again the data does not support this.

6. The attitude that Trilo is a "safe" drug with no side effects.

It is safe. Thats it was approved. Does it have side effects? Yes, and those are clearly listed on the package insert and in scientific publications.


Finally, why are Trilostane and Anipryl the only drugs approved to treat canine Cushing's? Lysodren has been around and in use much longer, yet has not been approved.

No one has tried to get op-DDD approved for use in the dog. I doubt anyone will as there would be huge hurdles to overcome given its derivation (op-DDT), manufacturing issues, safety profile and the availability of other drugs with equal efficacy and higher safety.


David Bruyette DVM DACVIM

[SasAndYunah]

I think its because pet owners in the United States dont want to handle dog urine

Thanks, that started my day with a huge smile...

Saskia and Yunah,
The Netherlands.