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Dear all,
When cyclosporin is given for treatment of autoimmune disorders like =
rheumatoid arthritis or SLE, what is the recommended sampling time for =
its monitoring? Is it trough or 2h postdose level like in renal =
transplantation?
=20
Thanks,
=20
Ehab ELDesoky
Pharmacology Dept,
Faculty of medicine
Assiut University
Assiut, Egypt
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Dear Ehab,
In my personal opinion, 2h levels do not seem to be better that troughs. They may be like moving targets considering that 2-hr may be 0, 15, or 30 min away from Tmax even within patients so that you may not know what you are measuring. Furthermore, it would be inconvenient and impractical to give the dose and wait for 2-hr until blood collection. Suppose there were 15-min delay in blood drawing due to busy schedule of blood collecting staff. The change in CsA levels due to 15 min delay around 2-hr post dose compared with the delay near troughs would be much greater.
My question is what is the purpose of CsA monitoring for RA patients assuming that much lower CsA dose is given as compared with the dose for renal transplant pts?
I hope it helps.
--
Jang-Ik Lee, Pharm.D., Ph.D.
Senior Reviewer for Biologics
Division of Clinical Pharmacology 3
Office of Clinical Pharmacology
Center for Drug Evaluation and Research
U.S. Food and Drug Administration
10903 New Hampshire Ave. Building 51, Room 3154
Silver Spring, MD 20993-0002
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Dear all,
Further more, for my question about cyclosporin monitoring in autoimmune disorder. Is there any accepted therapeutic range one should follow?
eheb
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I do disagree. 2 hr levels are much better than trough for CSA. For Tac 2 hr levels have no value. Most studies related to CSA AUC and 2h/Tr, R is close to 0.7-0.8 for 2 hour levels while 0.3-0.4 for 12 hr trough. However, not very practical in large centers with more than 200 Tx/yr. thank you, Ali
Ali J. Olyaei, PharmD, BCPS
Professor of Medicine and Pharmacy Practice
Director of Clinical Research
Division of Nephrology and Hypertension
Oregon State University/Oregon Health & Sciences University
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It appears that the CsA exposure-efficacy and safety response relationships have not been adequately determined in autoimmune diseases so that there seems to be no consensus in TDM goals. Many clinicians use low fixed dosing without TDM. TDM should be done on no improvement of disease or CsA-associated adverse events in my opinion. There are several articles in Medline search that showed efficacy and renal toxicity after long term use of CsA in autoimmune diseases. Thanks. Ike
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Dear All:
About cyclosporine sampling times. I really do not see the
usefulness of an approach based either on C0 or C2 or C anything. I think
the utility of monitoring serum concentrations should be based on some sort
of solid approach based at least on pop modeling and Bayesian
individualization techniques employed in the last quarter of the last
century. I am really surprised that little if anything seems to have changed
since the TDM meeting in DC and that horrible conference on C0 versus C2 in
September 2001.
I would strongly suggest that you contact Dr. Nathalie Bleyzac in
Lyon, France. She has done, several years ago, what I think is a very good
study of the utility of monitoring cyclo levels in kids getting bone marrow
transplants, and has made significant reductions in the incidence of graft
versus host disease in them, with significant cost savings. I have her
slides and I admire her work greatly. Her problem is that she has done a
comparative rather that a randomized prospective study.
I think she is a good scientist and clinical pharmacist. I would
suggest that you ask her for her slides. I bet she will give them to you.
She models the behavior of cyclo with a linear model, which she and all of
us know is not optimal. But it has let her set and achieve target troughs on
these kids. Yes, we all need to improve our modeling of the behavior of
cyclo, but she has really done a good job with the tools at her disposal,
making, and then controlling the behavior of these models in kids. She has
saved a lot of hospital stay and a whole bunch of $$$ and significantly, in
my view, reduced complications of GVHD from cyclo therapy. You don't need to
get and "interpret" C0 or C2. You need to get levels to make MODELS of the
behavior of the drug, and then to control these models for each patient.
That is what she has done. Her other problem is that she is so modest. Send
her an email. Ask her about all this stuff. See what she says. I bet she
will be quite helpful.
Very best regards,
Roger Jelliffe
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Thanks for reply.
Based on the the different replies I have got as regards cyclosporin sampling time in autoimmune diseases, I may formulate the issue as follows:
In autoimmune diseases, the dose size of cyclosporin is much less than that given for example in kidney transplantation. So, no place for C2h! and if TDM is carried out, it would be for avoidance of developed drug toxicity or adverse effects but not efficacy. The problem clinically is theat the clinicians insist to measure the drug level (although there is no rational).
Please for comments on my interpretation!
Ehab
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Dear Dr. Jelliffe,
You made a great point. I agree with you that neither C0 nor C2 is ideal to accurately estimate the CsA exposure and therefore its impacts on efficacy and safety. Furthermore, the site of action of CsA is located inside the cell. However, we do not measure the intracellular but blood concentrations.
I guess, the debate until now has been comparing C0 vs C2 based on the assumption that one would be better than another for patient care. I actually believe, the CsA TDM should be based on robust scientific findings. At the same time, we should also consider which one is most practical for patient care purpose.
All the best,
Ike
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Dear Lee,
You say neither C0 nor C2 is ideal. You added also that we should also consider which one is most practical for patient care purpose.
I am afraid that our discussion about sampling of cyclosporin has been diverted towards an argument C0 or C2, and to make modeling or not .
I need a one definite answer: when a clinician asks for TDM of cyclosporin in autoimmune disorder, shall I accept the sent sample to measure or not and at what time I recommend the sampling time?
What will be the rational in this situation??
Ehab
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Dear Ike:
Thanks for your note. Yes, we need to get away from simply measuring
levels and then "interpreting" their meaning or significance. We need PK/PD
models to do this, which can accept serum levels measured at any time. This
requires good software. The lack of interest in using such software, and of
using quantitative modeling methods in general is, I think, the most
significant obstacle to optimal drug therapy today. The pharmacologists
don't teach it to medical students because they don't know anything about,
the pharmacists are often still mired in linear regression on the logs of
the levels, and we really need a revolution in the way optimal therapy with
potentially toxic drugs is taught.
You are quite right that the site of action of CsA is inside the
cell. I bet we could take WBC'c or lymphocytes and measure levels in them to
get a better ides of what is going on, to model that as a concentration in a
peripheral compartment of the drug.
What is practical for patient care purposes is what is best for the
patient. The cost of complications is great, both in human terms, and in
hospital stay and in cost. You might go to our web site
http://www.lapk.org/
and
click around on teaching topics, software, and other things. There are
things there that you can see, print out, and think about. You can also
download versions of our software, which employs techniques used in the
aerospace community rather than the PK community, and see what you think of
it.
All the best, and thanks again for your thoughtful note,
Roger
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Dear Ehab,
Monitoring of CyA level in the case of autoimmune diseases should be considered in the following scenarios:
1. Patients with considerable kidney disease (Clcr <50 ml/min) or moderate-severe liver dysfunction in order to minimize toxicity when CyA is needed.
2. Patients who showed little or no clinical improvement on CyA before considering discontinuation of therapy.
In general, C2 is preferred over C0; however, C0 can still be interpreted.
Kind regards,
Khalid M Alkharfy
College of Pharmacy
King Saud University
Riyadh, Saudi Arabia
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Dear Roger,
You wrote "I bet we could take WBC'c or lymphocytes and measure levels in them to
get a better ides of what is going on, to model that as a concentration in a
peripheral compartment of the drug".
Most laboratories use whole blood sample, which obviously contains WBCs, to measure CyA level as apposed to plasma.
Kind regards,
Khalid M Alkharfy
College of Pharmacy
King Saud University
Riyadh, Saudi Arabia
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Dear Khalid:
So? What is to prevent someone from trying to measure it in specific cells?
All the best,
Roger
--
Dear Khalid:
When will we get out of the culture of looking at specific measured
levels rather that making much more capable models of what is happening in
the patient? I am really surprised that so little progress has been made, at
least in this chat box, since that horrible conference in DC in 2001.
Very best regards,
Roger Jelliffe
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Ike,
Roger Jelliffe wrote:
> Yes, we need to get away from simply measuring
> levels and then "interpreting" their meaning or significance. We need PK/PD
> models to do this, which can accept serum levels measured at any time. This
> requires good software. The lack of interest in using such software, and of
> using quantitative modeling methods in general is, I think, the most
> significant obstacle to optimal drug therapy today. The pharmacologists
> don't teach it to medical students because they don't know anything about,
> the pharmacists are often still mired in linear regression on the logs of
> the levels, and we really need a revolution in the way optimal therapy with
> potentially toxic drugs is taught
There is a group in France at the University of Limoges that provides a
web based Bayesian immunosuppressant evaluation service.
https://pharmaco.chu-limoges.fr/
This is part of the revolution which will eventually take away from
clinicians the need to calculate the best dose for a patient. They don't
have the training to do this themselves and computers can do a better job.
Nick
--
Nick Holford, Professor Clinical Pharmacology
Dept Pharmacology & Clinical Pharmacology
University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand
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Dear Ehab:
CSA level should be monitor in ALL patients. C2 has better correlation to AUC, but not very practical for busy center like us, Co still useful to avoid profound toxicity. Hypertension, nephrotoxicity,... are common even at low doses. I have used CSA and TAC for the last 25 years in more than 3000 patients (tx, non-tx, RA,..) and never had a patient that I did not monitor their CSA or TAC levels. Clinical pictures, chemistry (labs) and drug levels guideline us how to manage our patients. Thank you, Ali
Ali J. Olyaei, PharmD, BCPS
Professor of Medicine and Pharmacy Practice
Director of Clinical Research
Division of Nephrology and Hypertension
Oregon State University/Oregon Health & Sciences University
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Dear Nick:
Pierre Marquet does a good job. I hope that in his setup, someone,
hopefully a clinician who knows the patient well, needs VERY MUCH to set the
target goal first. Then the computers can do what the clinician wants.
All the best,
Roger
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Dear Ali,
What common range you have concluded among C0 and C2 levels in your patints? Did you correlate toxicity to certain levels in non-transplanted patients taking cyclosporin or tacrolimus? Do you make models for optimizing the dose or just you correlate the level to the patient clinical condition in your busy lab (like my situation)?
Ehab
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