Levels and Goals

#1

So the question posed to me was around dosing.

The minimal level we see in the literature where organ rejection in combination with other agents, is avoided is a sirolimus level of 3 ng/mL. Monotherapy needs to be 8-12 ng/mL as a trough (lowest level).

I think it is reasonable to think that threshold of 3 ng/mL and above is providing a therapeutic inhibition of mTORC1, but fails to some extent below that. So my approach has been to have weekly dosing patients get a 20-24 hr level of ~6 ng/mL. That usually works out well - doing a level at 48 hours after usually has a level <3 by a bit.

Single doses have a T1/2 more in the range of 24-36 hrs, it is only daily dosing that has the longer T1/2 of 63 hrs.

For folks doing dosing for neuroprotection - we sometimes push this up and go for a level of 9 or so, and then dose q14 days.

Again, lots of assumptions - and I’m just telling you how I usually do things with my patients in this space.

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#2

Do you have typical dosing schedules that will obtain those blood level goals?

Here in Hong Kong, I cannot get a Sirolimus blood test, so I’m forced to used anecdotal dosing info.

Thanks in advance.

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#3

What I’ve been finding is someone who is 120-150 lbs usually does well with 7-8 mg to get a sensible weekly dose, and then our 150-190 lbs usually 10 mg, and above that usually 12 mg. That would be what I’m observing from data coming back from my patients and myself.

There is some variability in levels, but most are coming in to a reasonable range I’m happy with for weekly dosing with this.

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#4

Since you seem to be the local expert on rapa kinetics, would you mind if I pollute your thread with two related-ish points?

  • How do you understand the reduced elimination half life for single doses?
  • You stick with sirolimus vs. everolimus. What are the trade-offs in this decision?
#5

I’m not certain I’m an expert yet - but I get to see a lot of levels. My last was 5 mg with GFJ 8 oz 3 hrs prior, then 4 oz with. I know my metabolism is around 30 hrs for T1/2. I had a 20 hour level of 9.5, so essentially 1.7 or so more half lives to get below 3 ng/mL. So 51 hrs from that level, anticipate not being therapeutic, so total time from dose to non-therapeutic is 71 hours give or take. I goal for ~30% of the time above this threshold, so I’m pretty happy with a dosing interval for myself with this of 10 days.

This is simply that way I’ve chosen to put some structure on this, until we have better evidence of pros-cons of rapamycin, and dosing.

#1 Elimination half-life, getting a 20-24 hr level, then another one in 48 hours gives a good understanding, and there are certainly individual variations to a modest extent. We can get a good estimate of T1/2 with having these 2 values. If you look on ePocrates, for example, they give T1/2 62h or 113h with impaired liver function. They also used to list single dose half life of 35 hrs.

  1. I’ve not used everolimus, no good reason, apart from cost in the U.S. generic is a lot more than sirolimus. Certainly the shorter half life could require higher or repetitive dosing, depending on goals, and I don’t have experience with that, and would be unclear on the advantage of going to everolimus. I’m sure once can accomplish the same thing with that, I’d just need to map it out with levels, IF one buys into the theory that a serum level above a certain threshold is a sensible thing to achieve and maintain.
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