Towards Better Control in CKD: Improving Anemia Management

ANNA CE Satellite Symposium - New Orleans, Louisiana, October 17, 2004

Characteristics of Available Iron Products



David B. Van Wyck, MD
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This satellite symposium is sponsored by an unrestricted educational grant from American Regent Laboratories, Inc. This activity has been planned and produced in accordance with CE guidelines and policies. From a CE symposium held on October 17, 2004 at the American Nephrology Nurses' Association (ANNA) Fall Meeting in New Orleans, LA. This symposium was approved by ANNA. It was not part of the official ANNA Annual Meeting.
This activity has been awarded 1.5 contact hours by the American Nephrology Nurses Association (ANNA) which is accredited as a provider and approver of continuing education in nursing by the American Nurses Credentialing Center-Commission on Accreditation (ANCC-COA).
Posting Date: January, 2005
CE Credit Eligible Through: May, 2006
CE Credit Hours/Completion Time: 1.5
Target Audiences: Nurses, nurse practitioners, and other healthcare professionals who treat and manage patients with CKD.
Method of participation: Listen to the talk, read the PubMed abstracts linked to data slides and talk references, take the post-test, read the linked abstracts in the post-test answer feedback material.
LEARNING OBJECTIVES:
After participating in this program, the participant should be able to:
  1. Describe the benefits of anemia management in chronic kidney disease (CKD).
  2. Outline the results of a U.S. clinical trial of iron sucrose and erythropoietin in the treatment of anemia in CKD.
  3. Appraise the characteristics of available parenteral iron products.
  4. Explain the critical role of the nephrology nurse in anemia management.
SPEAKER DISCLOSURE STATEMENT:
Speaker is a member of the Speakers Bureau for American Regent Laboratories Inc.

ANNA and HDCN CE POLICY STATEMENTS:
The CE policy and disclosure statements of the American Nephrology Nurses' Association are given in detail on the Symposium Home Page. The CE policy statements of HDCN are listed on this page.

David B. Van Wyck:
I just want to thank you again for that wonderful opportunity. That was really a pleasure

00:00



Characteristics of available iron products
Today, we are going to talk about the characteristics of available IV iron products. When I mean characteristics, I mean the structure and chemistry and their implications for both safety and bioactivity. We have been using IV iron products since 1950 or so - that is when iron dextran came out. Iron sucrose was released shortly thereafter. Ferric gluconate in the 1960s. It was sometime later that they were then used for IV use, but later means 1960s and 1970s. We have some 50 years of experience iwth administration of IV iron without really knowing what these compounds are and how they work. It is as if we had used calcium channel blockers, and we did not know that they blocked calcium channels. This has been a problem for us, because now that we have several available IV iron products to use, and we talk about safety on the one hand with an increasing information about safety and bioactivity on the other hand, which is about efficacy, then we need some way of sorting this in our heads, about how it happens, why it happens, and in what order it happens. That will only be more important in the future as new IV iron products are introduced.

00:00



Objectives
Today, we are going to talk about chemistry and structure of IV iron. The really big new information comes from Dina Kudasheva and Mary Cowman, who are colloid chemists in New York and who have just done some really wonderful breakthrough work. A little bit about pharmacokinetics - I will tell you now and I will tell you then that pharmacokinetics has very little to do with IV iron except perhaps for how often you give a dose. Then, we will talk about the understanding of safety and bioactivity when we talk about labile iron or the so-called free iron business.

00:00



Source: Kudasheva & Cowman, J Biol Chem 98:1757-1769, 2004.
IV iron agents are spheroid particles with an iron core and carbohydrate shell
IV iron agents are all spheroidal particles with an iron core and a carbohydrate shell. The core is most of the particle, with just a thin shell around it. The core is all iron oxyhydroxide. The core of each agent is the same - from one to the other. It is the carbohydrate that is different among them, and it is the size of the core that is different among them.

00:00



Source: Kudasheva & Cowman, J Biol Chem 98:1757-1769, 2004.
IV iron agents differ by core size and shell chemistry
For iron sucrose, the shell is bound sucrose around an oxyhydroxide core. For ferric gluconate, the shell is bound gluconate around a weakly associated sucrose, and weakly associated sucrose around a somewhat smaller oxyhydroxide core.

00:00



Source: Kudasheva & Cowman, J Biol Chem 98:1757-1769, 2004.
Order of core size & particle size
Differences between ferric gluconate and iron sucrose - those differences are minor compared to the size differences between those two and iron dextran. Iron dextran is a huge molecule with a huge core. As iron oxyhydroxide crystallizes, it become ellipsoidal - sort of like a football - actually more like a rugby ball. The dextran then sizes up around it and makes the whole unit into a spheroid.

00:00



Chemistry determines therapeutics
When I think about the molecular weight - the whole molecular weight of the agent - I think that is probably the primary determinant in the pharmacokinetics - of how quickly it is cleared from the blood stream. It may be something related to how many carbohydrates are on the molecule, so that like the difference between epoetin alfa and darbepoetin, the carbohydrate is more on darbepoetin and slows the clearance of these things down - but the primary determinants of iron bioactivity are not the total molecular weight, but the size of the core and the surface area to volume ratio.

00:00



Disappearance of iron from plasma - ranges
Pharmacokinetics is reviewed in this slide. The disappearance of IV iron after you inject it into the venous system is very slow for the iron dextran products. It is slowest for the largest molecular weight product, which is Dexferrum, a little bit less slow for iron dextran INFeD, which is close to Imferon. How many in the room remember Imferon? Okay, now I know how old you are! At the other end of the spectrum is free iron, absolutely free iron - ferric ammonium citrate for example - that iron is totally 100% bioavailable immediately. It enters the plasma space and just binds onto something else and it is gone immediately.

00:00



Plasma kinetics of IV iron agents
In between those extremes are iron sucrose with a half-life of about 6 to 7 hours, and ferric gluconate, which has a half-life of about an hour. There seems to be sort of a direct link between plasma half-life and molecular weight. Having said that, the significance of all of pharmacokinetics is probably that the larger the agent you have like an iron dextran, the more it makes sense to give that once a week. The smaller the molecular weight agent, like ferric gluconate or iron sucrose, the more it makes sense to give that one as often as once a day or certainly 3 times a week on dialysis would be your maximum frequency for administering that drug and that has to do with a circulating agent that can interfere with iron tests.

00:00



Source: Beshara S, et al. Br J Hematol 104:296-302, 1999.
Reticuloendothelial System (RES) processing of IV iron sucrose
Where does IV iron go after you give it? It goes into the reticuloendothelial system. We knew that about iron dextran - the same is true about the other iron agents. This is a more recent study with labeled iron 59, iron sucrose. You can see that the uptake is into the liver and spleen. Liver is the high blood flow organ, so more goes into the liver than in the spleen, but quantitatively that is the difference - qualitatively it is the same rate for both of them - and then it is transferred slowly into the marrow by that intermediate step of binding to transferrin, and then the transferrin delivers the iron to the marrow. Look at the time course here. This is in minutes. The uptake of iron sucrose into the liver and the spleen is nearly complete within an hour to two hours, and then the transfer to the marrow is taking place.

00:00



Source: Beshara S, et al. Br J Hematol 104:296-302, 1999.
RBC utilization of iron sucrose is prompt
Ultimately - change the time period here to days rather than hours - what happens is that the iron that went into the marrow then transfers into new blood cells and becomes part of the circulating red cell mass, so that in a patient who is very iron-avid - the patient with rapid erythropoiesis and hungry for iron - that patient will transfer all the injected dose into the circulating red cell mass within 10-20 days. When I say all, I mean 90% to 100% - something along that line. This is not to suggest that you would get the same sort of curve with a patient with very slow erythropoiesis, who for example had no erythropoietin treatment and cancer. It is a very slow rate of erythropoiesis and that is why the anemia happens. In that patient, the iron would be left in the RES, and would not be transferred into new red blood cells and the RBC uptake curve would be relatively flat. It is very interesting how that happens. It is totally not understood what regulates RBC uptake of iron, and whether this is regulated or not.

00:00



Conclusions
In conclusion, on the first part, where we talked about chemistry and structure - all IV iron agents are colloidal particles. They differ by core size and by shell carbohydrate type and by the strength of that bond. The pharmacokinetics is - it follows core size and total molecular weight. All iron agents have principal movement of iron from the plasma into RES, from the RES onto transferrin, from transferrin into the marrow, and from marrow into red blood cells. About 5% or less of iron will short circuit the cells in the RES and go directly onto transferrin. We will talk about how that works.

00:00



Pharmacokinetics of IV iron agents: implications for patients
Pharmacokinetics - if somebody is talking to you about pharmacokinetics, often your eyes glaze over and you walk away - because really the only important thing I think about pharmacokinetics is that it determines how often you give the dose. If you are giving doses in the range that we give, which is 100 mg to 200 mg, iron dextran is no more often than once a week, and iron sucrose and ferric gluconate are probably as frequently as once a day or whatever fits logically with your patient group.

00:00



Direct release of bioactive iron from IV iron agents
That brings us to labile iron effects. This is bioactive iron. Bioactive iron is how the iron gets from the compound to do its work. This is both an issue of efficacy because it cannot be effective unless iron gets off that core to where it is going to go ultimately to the marrow - but, however effective it is it must also have some safety issues, because bioactive iron is also the core of the safety issue. We will examine those things together.

00:00



Manifestations of labile iron
We have known for a long time about the manifestations of labile iron and the evidence is accumulating in the literature rather quickly. We know that this falsely elevates serum transferrin level. If you gave iron dextran tomorrow to a patient on a Monday, Wednesday, and Friday schedule and you did a T-sat on Friday, your T-sat would be high because of the circulating iron dextran in the plasma of that patient. We know that in addition, there is direct transfer of iron onto transferrin. That happens very quickly - it goes right from the agent onto transferrin without having to go through the cells, and it happens with all of these agents. We know that this provokes oxidative stress. No surprise - it is bioactive iron. It will have an oxidative manifestation. It impairs neutrophil function. It can stimulate bacterial growth because iron is needed for replication of bacteria.

00:00



Source: Geisser P et al. Drug Res 42(11):1439-1452, 1992.
Iron release from IV iron agents is inversely related to overall MW
We knew that there was some relationship between molecular weight and the degradation rate of agents. Peter Geisser had shown this in 1992, just in vitro. He had shown with all the available iron products that he could get his hands on, that there was this relationship between molecular weight and degradation kinetics, but that does not explain the whole thing.

00:00



Source: Henderson PA & Hillman RS. Blood 34:357-375, 1969.
Source: Esposito BP et al Eur.J.Clin.Invest 32 Suppl 1:42-49, 2002.
Source: Van Wyck D et al. Nephrol Dial Transplant. 2004 Mar;19(3):561-5.
Source: Agarwal R. Kidney Int 66:1139-1444.

Evidence that IV iron agents donate iron directly to transferrin
The evidence that iron agents donate iron directly to transferrin is old - it has recently been confirmed, and we have some sense of the sequence in which that happens. So old is - iron dextran from the 1960s, about the time that iron dextran was first used intravenously. Esposito showed that ferric gluconate donated more than iron sucrose that donated more than iron polymaltose in a test system that he reported on in 2002, but there was no quantitative difference. Polymaltose, by the way, is a slightly larger molecular weight than iron sucrose and is used in some countries around the world. Ferric gluconate greater than iron sucrose greater than iron dextran was something that I demonstrated earlier this year and Rajiv Agarwal demonstrated in June, and I will show you that data.

00:00



Source: Van Wyck D et al. Nephrol Dial Transplant. 2004 Mar;19(3):561-5.
Iron agents donate iron directly to Tf
When we mixed agents in serum and then we took the agent out of the serum through a column, we looked at transferrin saturation before and transferrin saturation after adding the agent. What we found was that indeed there was some donation - it was not very much - it was only in the order of 4% or 6% maximum, but that sequence ferric gluconate greater than iron sucrose greater than iron dextran and among the iron dextrans INFeD greater than Dexferrum - that was the sequence that worked.

00:00



Source: Agarwal R. Kidney Int 66:1139-1144, 2004.
In vitro iron donation to Tf is inversely related to core size & directly related to concentration & incubation time
That sort of made sense, it was the first quantitative in vitro study. Rajiv Agarwal just published in June in KI, this interesting study, in which he did the same sort of thing. He incubated iron and then he looked at evidence for transferrin saturation. At first, he fixed the incubation time at 60 minutes - that is the first frame - and varied the drug concentration. He found that there was a concentration-related increase in transferrin saturation, if the incubation time was 60 minutes. 60 minutes is a long time to be incubating because these agents are cleared from the plasma fairly quickly. On the other hand then, he fixed the concentration at 100 mcg/dL, and he varied the incubation time. What he showed was that there was some donation that occurs right away, but as incubation time progresses, there is more donation over time. In general, the sequence of effect was ferric gluconate greater than iron sucrose greater than iron dextran as everybody else had demonstrated.

00:00



Source: Kudasheva & Cowman, J Biol Chem 98:1757-1769, 2004.
For equal amounts of iron, the smaller the core, the greater the surface area available for iron release.
How do you explain this? I think it is just simple math - that for equal amounts of iron, the smaller the core, the greater the surface area available for iron release. The surface area to volume ratio is not linear. Just remember volume is radius cubed. It is not linear. Iron dextran is way out to the edge because it is a really big effective radius, and although there are small differences between iron sucrose and ferric gluconate in radius, because they are on the steep part of the curve as small molecules, there are measurable differences in surface area to volume ratio.

00:00



Given equal aggregate volume, smaller core size yields greater surface area for iron release
That is shown in this cartoon where you have sort of grapes. The volume - the red part here - of the core is the same on both sides. You have small molecules with small cores, large molecules with large cores. The volume is the same. The surface area to volume ratio is obviously much greater among the small molecular weight agent, and I believe that iron bioactivity comes from that - that is just simple.

00:00



Source: Zager RA et al. Am J Kidney Dis 40 (1):90-103, 2002
Source: Esposito BP et al. Eur J Clin Invest 32 Suppl 1:42-49, 2002
Source: Sturm B et al. Eur J Biochem 270 (18):3731-3738, 2003
Redox-active iron release follows pattern similar to that of iron donation to Tf
If you think about redox-active iron, oxidative stress is probably on the unsafe side - that is the safety issue rather than the effectiveness issue of these agents - you would expect to see the same sequence of oxidative stress results. Ferric gluconate greater than iron sucrose greater than iron polymaltose as was shown by Esposito. Ferric gluconate greater than iron sucrose greater than iron dextran also is shown by others. In some studies, things get reversed or it is close or there are no differences. I think the whole oxidative stress story is not very important at doses - infusion doses and cumulative doses - that we give in standard practice in our dialysis patients.

00:00



Source: Esposito BP, et al. Eur J Clin Invest 32(Supp 1):42-49, 2002.
Iron agents release redox-active iron in vitro: The smaller the core size, the greater the effect
Redox-active iron for example in Esposito was in this sequence. That having been said, I do not think that the contribution of iron to oxidative stress is very significant unless you get into very high doses - single doses or very high cumulative doses of iron with very high ferritins.

00:00



True free iron reactions have been described
If you are thinking about free iron reactions, I just want to remind you about the article in 1932, which you probably have, from famous now not living hematologists, who were experimenting in the days before the IRB.

00:00



Free iron reaction
We know that we can give free iron at about 4 mg, that is if you took ferrous sulfate and you dissolved the tablet completely and you gave an injection of that, you could safely give only about 4 mg, because that is your iron binding capacity that has not been bound already. The only safe way for iron to exist in your plasma is to be bound to transferrin and that is about 4 mg's worth - it is not very much. They increased the dose - to 8, then 16, then 32, then 48, and so on up to 80 mg - and they noticed how much more serious the reactions got as they got higher. By the time they got to 48 and 80 mg in two patients, there were much more severe reactions. Five minutes after the injection, there was a flushing of the face, engorgement of the neck veins, the appearance of intense anxiety, vomiting occurred much as it does after the administration of morphine, the pulse was rapid and full, the heart sounds loud, and there was moderate hyperpnea. They are really describing cardiovascular collapse without taking the blood pressure. That is a free iron reaction. That does not happen. We do not have free iron in any of these IV iron compounds, and we do not have free iron. You cannot dialyze iron off these compounds either in vitro or in vivo. It has been done. We have that evidence. It is pretty significant.

00:00



IV Iron: Adverse reactions
I think probably the only significance is that the labile iron reaction rate simulates some of the more minor reactions that were happening, as they were dose escalating in that study - as you give iron dextran. You can give a lot of iron dextran intravenously quickly - we just tend not to give really large doses of iron dextran because if the patient has anaphylaxis and a large dose, they tend to have long anaphylaxis. So, we keep that to about 100 mg. Iron sucrose 200 mg over 5 minutes is now well described, and ferric gluconate 125 over 10 minutes for an IV push dose, and similarly for IV infusion, so that the different rates break down - iron dextran you could give, theoretically, faster than iron sucrose, and iron sucrose you can give, theoretically, faster than ferric gluconate, and that is it.

00:00



Dosing of iron agents: Review of the literature
I think that just explains the behavior of these agents. Theoretically, if you have a larger molecular weight than iron dextran, you ought to be able to give it even faster. If you had a smaller molecular weight iron compound than ferric gluconate, you would have to give it even slower than ferric gluconate, and that I think is how we make sense out of the current literature and how we can make sense out of the future literature as well.

00:00



Conclusion: Bioactive iron release
If I leave you, it is with the understanding that bioactive iron is common to all agents, that the core radius dictates the effect. It has to do with surface area to volume ratio. The clinical significance of this is really quite limited and probably has to do only with how much you can give and how fast you can give it.

References
  1. Kudasheva DS, Lai J, Ulman A, Cowman MK. Structure of carbohydrate-bound polynuclear iron oxyhydroxide nanoparticles in parenteral formulations. J Inorg Biochem. 2004 Nov;98(11):1757-69.

  2. Beshara S, Lundqvist H, Sundin J, Lubberink M, Tolmachev V, Valind S, Antoni G, Langstrom B, Danielson BG. Pharmacokinetics and red cell utilization of iron(III) hydroxide-sucrose complex in anaemic patients: a study using positron emission tomography. Br J Haematol. 1999 Feb;104(2):296-302.

  3. Geisser P, Baer M, Schaub E. Structure/histotoxicity relationship of parenteral iron preparations. Arzneimittelforschung. 1992 Dec;42(12):1439-52.

  4. Agarwal R. Transferrin saturation with intravenous irons: an in vitro study. Kidney Int. 2004 Sep;66(3):1139-44.

  5. Esposito BP, Breuer W, Slotki I, Cabantchik ZI. Labile iron in parenteral iron formulations and its potential for generating plasma nontransferrin-bound iron in dialysis patients. Eur J Clin Invest. 2002 Mar;32 Suppl 1:42-9.

  6. Zager RA, Johnson AC, Hanson SY, Wasse H. Parenteral iron formulations: a comparative toxicologic analysis and mechanisms of cell injury. Am J Kidney Dis. 2002 Jul;40(1):90-103.

  7. Van Wyck D, Anderson J, Johnson K Labile iron in parenteral iron formulations: a quantitative and comparative study. Nephrol Dial Transplant. 2004 Mar;19(3):561-5.

  8. Sturm B, Goldenberg H, Scheiber-Mojdehkar B. ansient increase of the labile iron pool in HepG2 cells by intravenous iron preparations. Eur J Biochem. 2003 Sep;270(18):3731-8.

  9. Henderson PA, Hillman RS. Characteristics of iron dextran utilization in man. Blood. 1969 Sep;34(3):357-75.

Next Talk (Michelle Turgeon)


This satellite symposium is sponsored by an unrestricted educational grant from American Regent Laboratories, Inc.
This activity has been planned and produced in accordance with CE guidelines and policies. From a CE symposium held on October 17, 2004 at the American Nephrology Nurses' Association (ANNA) Fall Meeting in New Orleans, LA.
This symposium was approved by ANNA. It was not part of the official ANNA Annual Meeting.


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