Chelator evaluation. Two core principles: Safety and Efficacy.

This blog also contains clarification on my approach to HOPO.

There are two core principles essential when considering the use of a chelator for a specific purpose. First and foremost is safety. Second and this determines if they should be used for a specific purpose: efficacy.

Since iv DTPA is the agent that I use and describe the use of. We will start with looking at it.

Safety: DTPA has been used for a ligand for Gd contrast. Magnevist is essentially Gd-DTPA and the worldwide use of Magnevist over the years has been in the order of 100- 150 million doses. Omniscan also is based on DTPA ligand and there is 50 million doses of it that have been used. Add to that, DTPAs other medical uses, probably it has been used in at least 250 million clinical patient studies. Almost nothing has that level of use to show its fundamental safety. This is founded on the basis that extensive preclinical work was performed prior to this showing its safety. In my experience, the reality is that evaluation of extensive clinical use is the most accurate means of assessing safety, so unfortunately we often have to have 100,000 of clinical human experience before recognizing how truly safe any medicine is. Preclinical studies are an important guidance, but there is no substitution for actual 100,000s of clinical doses administered. By the way EDTA was used in many of the preclinical trials of MR contrast agents as the comparator poor chelator for Gd.

So DTPA has had a long track record for safety as a ligand.

The ligand for Dotarem, DOTA also has a very long track record for clinical use and safety.

The caveats with the safety ofcourse is what I have focused on with Gd contrast agents: the risk of NSF with Magnevist and Omniscan, and the risk of GDD with Magnevist, Omniscan and Dotarem, and their also shared risk for severe acute hypersensitivity reaction. These risks are relatively rare, and somewhat controllable.

In contrast an agent like HOPO has relatively little data on its safety, and to date no formal assessment of post-approval clinical experience. But based on preclinical studies it appears also to be very safe. Phase 1 trials are underway.

Efficacy: For the assessment of a chelator there are 2 features that are critical: stability constant and demonstration that it removes the antigen of interest, in this particular case Gd, this could be termed removal effectiveness.

Stability constant: This is a scientifically demonstrable value expressed as log stability constant, also called thermodynamic stability. If this value is not known for the metal of interest (in this case Gd) then I do not recommend its use. If it is considerably lower than DTPA (I would call DTPA the silver standard for chelators) then I do not recommend its use. So for example the stability constant of Gd with EDTA is approximately 17, and Gd with DTPA 22. The stability with DOTA is approximately 25, and with HOPO even higher, 26+. As I previously and consistently described I never recommend EDTA (or DMSA or DMPS) for Gd.

Kinetic stability - the speed at which the combination of metal and ligand comes apart also is of value to know, and at least be aware of the concept.

Emeramide (OSR) is an interesting agent. It is apparently fat-soluble and excreted by the GI tract. GI tract elimination is generally and historically considered to be due to biliary excretion, but actually with the work on Gd, it is now less clear to me if there may be direct elimination through the small bowel. Traditional medicine would say this does not occur. The stability constant of emeramide with Gd is not reported so I do not recommend it for Gd removal. It apparently is very effective for mercury and perhaps other metal removal. So in the future the concept of combining chelators  is intriguing for removal of multimetal toxicity. I would recommend in an alternating fashion with days inbetween and not at the same time,

Removal effectiveness: this has to be shown in living humans (in vivo). This is in contrast to Stability constant which is a lab determined number (in vitro). Most GBCAs are essentially completely eliminated by the kidneys (with the exception of Multihance [5-10% biliary elimination] and eovist/primovist [50% biliary elimination]. As such then measurement of urine for Gd content is the best method to evaluate how much of the metal is removed. We routinely perform pre- and post-chelation 24 hr urine for heavy metals. I prefer pre- being within 1 week, and often 1-2 days, prior to chelation, and measurement of post-chelation to start approximately 1 hour after chelation, with not including urination to be done within 1 hour after chelation. This very early urine will largely be reflective of urine development prior to the chelation, explaining why we do not include it.

So for a metal-ligand combination that primarily goes to non-fat tissue as reservoirs, and essentially completely eliminated in urine these 24 hour measurements are about as good as anything we do in medicine to show the effect of a treatment.

Recommendation for use as a chelating agent: To be considered as a chelating agent for a particular metal then I have to know the in vitro stability constant of the chelator for that metal and how effective it is at removing the metal in vivo in a human. To use an alternate to DTPA, it has to have at least equivalent stability constant.

My philosophy throughout my career as a diagnostic radiologist, if I am not prepared to have performed on me a diagnostic test including the contrast agent, then I am not prepared to consider it very safe for patients to undergo. So I have performed multiple MRIs on myself, starting since since 1989, primarily to evaluate novel MR sequences and protocols, but also in the range of 1995- 2014 to evaluate MR contrast agents. In the year 2014 I had on one occasion had 3 different MR contrast agents administered to me in a blinded fashion. I did this to look for differences in acute hypersensitivity reaction (AHR) between agents. The major thing I learned is administering MR contrast that is stored in the MR machine room, the agent is so cold that it hurts like hell to have it injected in you... so we stopped storing it that way. I tested on myself in advance of considering any IRB trial to compare in patients different agents blinded. My belief, if it wasn't safe enough for me to undergo, I would not subject patients to it..... Ofcourse this was mainly at a time that MR contrast agents were considered as safe as water to inject, and after 2006 (and NSF description) some of the more stable MR agents were still considered very safe. When I became aware of GDD in 2015, I ofcourse stopped giving myself GBCA agents to look at AHR. The net result is I have 13 GBCAs sitting in my body, but I have Gadolinium Storage Condition (GSC) and not GDD, so I do not react to its presence or its removal. The silver lining for me is now I am the perfect candidate for studies where I am comparing GDD and GSC, such as historically for DTPA chelation cytokine studies, and for Gd removal effectiveness.

I am intending to publish original research on the subject of Gd removal effectiveness, so I will not speak further on that aspect, as I do not generally reveal works in concept or in progress, unless I consider the implications exceedingly important for patient welfare.. I want to clarify that I consider the entire gadolinium toxicity community my responsibility to care for, even if they do on themselves things that I would not advise them to do.. I do not advise or prescribe drugs that are not FDA approved for some comparable indication. At the same time I do not ignore individuals that are trialing on themselves strategies that have no FDA approval of any kind yet. To emphasize, this means I do not prescribe or advise individuals to take drugs that lack any FDA approval, that I also do not have an IND on. So I do not prescribe HOPO. That said, I do know that it works, as I have tried it on myself. If I found it did not work on myself, I would then advise the individuals who on their own are taking HOPO, that they should stop, because it does not appear to work and hence may cause more harm than good. At this time, I have high hopes that HOPO will be an effective agent to use for GDD subjects when an FDA-approved version comes available, I will prescribe it at that time, I hope in 2-3 years. In the mean-time I hope to have a very good sense how to best administer it in a treatment regimen.

Writing this also allows me to remind all nonphysician subjects who have GDD or other medical conditions, that if you are not licensed medical practitioners to diagnose and treat patients it is not legal for you to provide medical advice.

Richard Semelka, MD