DTPA Chelation of various GBCA agents: How much Gd is retained, how much coming out, and as what ?

I have gathered experience for 6 years before attemptong to address reporting this information. This represent my experience and research over this 6 year period. As background, the earliest report of amount of Gd retained in humans was by a group including Henrik Thomsen, in which was reported that in subjects with renal failure after approximately 2 weeks, 20-25 % of omniscan was not eliminated. In 2004 and 2006 Gibby, White et al reported initially and then subsequently revised that 2.5 then 4 x more linear agent was retained in bone comparing a linear agent to Prohance. In 2009 Darrah reported there was no difference in the amount of Gd retained between linear and macrocyclic. I would have liked to see the FDA step in and request an independent group look at this question to see which group is correct.

As with almost everything the truth lies most likely in the middle ground.

Some of the best of other work was reported by Lancelot et al from Guerbet where they described elimination of intact macrocyclic Dotarem and compared the rate and pattern of elimination to linear agents.

To start with, one of the often asked questions, also by the companies themselves, is how much if any Gd is retained in the body for many years. The answer to that question is exceptionally easy: chelate with full dose Ca-DTPA. In so doing you will find how much Gd is removed both early post GBCAs (even in 'normals', GSC subjects) and after years. The short answer is, there is always Gd retained because chelation with Ca-DTPA always results in Gd in 24 hr urine, even well beyond 1 decade with 1 individual injection. This is a simple question with a simple answer.

A much more complicated question is how much Gd is retained? My informed estimate is that stability in the amount of Gd retained is usually achieved at about 1 year, with miniscule continued elimination over the years beyond, probably at 0.1% of the retained Gd per year., At 1 year time, approximately 5% of linear agents are retained, 3-5% of Gadavist, and 1-3% of Porhance and Dotarem/ Clariscan agents. Once you add in multiple additional GBCA agents then you are beginning to play 3 dimensional chess on estimating the amount of Gd retained.. but it is generally a summation of the above percentages. This question may only be knowable by using a large animal surrogate for humans, and separately radiolabelling the Gd and the ligand in GBCAs. Knowable but time-consuming, expensive and involves large animals... the last of which, personally I could not do..

How much Gd is then removed with each chelation. My estimate it is likely 10-20 % for linear agents, 5- 10% for Gadavist, and 1-5% for Prohance, Dotarem/Clariscan. This does not mean that 1o chelations for linear agents removes 100% of Gd, each chelation session removes 10% of what is present/ left behind. In 24 hour urine quantifications for Gd pre- and post-chelation the amount of additional Gd removed post-Ca-DTPA compared to native elimination ( in micrograms per 24 hours). Within 1 year 20-40 fold increased Gd content in urine is present for linears, 10-20 fold for Gadavist, and < 10 fold for Prohance and Dotarem/ Clariscan. Despite this relatively low amount, this is associated with significant clinical improvement, largely because the Gd removed is in the deep interstitial tissue. The distribution of retained Gd and the pattern of removal is knowable with the same described large animal model.

The Gd removed by chelation is > 70% Gd-DTPA and < 30% intact original GBCA for linear agents, with the 70% Gd-DTPA largely coming from Gd removed from proteins, and some as Gd removed from phosphates/ carbonates, and some removed from the original agent. With Gadavist the amounts are probably similar but with probably less Gd removed as Gd-DTPA and more removed as the original GBCA. With Prohance and Dotarem/Clariscan the great majority of Gd removed is as fully intact original GBCA agent. This information is knowable, by speciating Gd removed with chelation in urine.

At this point many of you may be thinking, wait a minute Dr S, not so fast, isn't the whole reason you keep saying that DTPA is the best chelator for Gd based on stability,. and now you are saying here that chelation of Gd in Prohance and Dotarem/Clariscan, that the Gd is coming out as fully intact GBCA agent? And your point has been that Gd-DTPA has very little early redistribution? What's the deal , especially since fully intact of the macrocyclic GBCAs Prohance and Dotarem/Clariscan made me sick to begin with? Aren't you simply just redistributing back these GBCAs into the body?

Well yes and no. Yes, the linear chelator DTPA is levering retained fully intact GBCA back into the circulation, but since the great majority of these GBCAs are removed by the kidneys, only a small percentage is redistributed. So with these macrocyclic agents, only about 1% of the remobilized Gd is retained/ redistributed (as with the original administration). So 95-99% of the remobilized Prohance and Dotarem/Clariscan are being eliminated. This is also provided renal function is near normal. The advantage in these macrocyclics of using a strong chelator, is not that it will combine to form Gd-DTPA, but it will be more effective at levering Gd out of the tissues (recall the blog on the Magnetic arcade claw game).

An additional opinion is that powerful linear ligand chelators are likely much more effective at removing Gd than even more stable macrocyclic agents. That is Ca-BOPTA (ligand of Multihance) is more effective than Ca-DOTA (ligand of Dotarem/ Clariscan) because the architecture of the ligand allows for the powerful anion, BOPTA to be in closer contact and more amenable to picking up Gd (think of the bowl of the spoon), than when the anionic portion is in the center of the molecule (think of a box where the magnetic part is in the middle of the box. I have termed this phenomenon reverse Kinetic Stability.. This also is readily knowable in the human model without radiolabelling anything.

So with each additional GBCA agent you have to factor in the amount retained by what I have written above.. This is a 3 or 4D chess game, but relatively reasonable estimates are achievable, and a number of the informed opinions described above are knowable. It just takes time and money, and unfortunately some simian models.

Richard Semelka, MD