CMYKP
`
`EDITORIAL
`
`Port J Nephrol Hypert 2012; 26(1): 13-24
`Advance Access publication 12 March 2012
`
`Iron isomaltoside 1000:
`a new high dose option
`for parenteral iron therapy
`
`Philip A. Kalra1, Klaus Bock2, Morten Meldal3
`1 Department of Renal Medicine, Salford Royal Hospital, Salford, United Kingdom.
`2 Department of Chemistry, University of Copenhagen, Copenhagen, Denmark.
`3 Nano Science Center, University of Copenhagen, Copenhagen, Denmark.
`
`Received for publication:
`Accepted:
`
`02/03/2012
`08/03/2012
`
` (cid:132)
`ABSTRACT
`
` (cid:132)
`INTRODUCTION
`
`Iron isomaltoside 1000 (Monofer®) is a new dex-
`tran-free parenteral iron product, currently approved
`in 22 EU countries. Iron isomaltoside 1000 consists
`of iron and a carbohydrate moiety where the iron
`is tightly bound in a matrix structure, which enables
`a controlled and slow release of iron to iron-binding
`proteins, avoiding toxicity. The carbohydrate,
`isomaltoside 1000, is a purely linear chemical struc-
`ture with low immunological activity. Due to the
`structure of iron isomaltoside 1000 and the low
`anaphylactic potential, there is no requirement for
`a test dose, and it can be administered in high
`doses with a maximum dosage of 20 mg/kg within
`30-60 minutes in one visit. Thus, iron isomaltoside
`1000 offers the broadest dosage range compared
`to other parenteral iron products on the market.
`Due to the dose flexibility, the possibility of provid-
`ing full iron correction in one single visit makes iron
`isomaltoside 1000 highly convenient for both the
`health care professional and the patient. Clinical
`studies of iron isomaltoside 1000 show that it is an
`effective and well-tolerated treatment of iron defi-
`ciency anaemia with a favourable safety profile.
`Furthermore, iron isomaltoside 1000 does not seem
`to induce hypophosphataemia.
`
`Key-Words:
`High dose; iron deficiency anaemia; iron isomaltoside;
`iron treatment.
`
`The ability to give high doses of iron is important
`in the management of iron deficiency anaemia (IDA)
`in a number of clinical conditions where demands
`for iron are high, such as chronic kidney disease
`(CKD), chronic blood loss associated with inflamma-
`tory bowel disease (IBD) or other gastrointestinal
`disease, pregnancy, and blood loss during surgery.
`Parenteral iron offers a fast iron correction, and it is
`superior to oral iron in many circumstances, especially
`in the treatment of anaemia associated with chronic
`diseases where the patients may be intolerant of
`oral iron or because the iron absorption may be
`blocked, in cases with large iron deficits as the maxi-
`mum capacity for oral iron absorption is very limited,
`or when patients are treated with erythropoiesis-
`stimulating agents (ESAs).
`
`The currently available parenteral iron preparations
`include high molecular weight iron dextran (Dexfer-
`rum®), low molecular weight iron dextran (Cosmofer®/
`Infed®), iron gluconate (Ferrlecit®), iron sucrose
`(Venofer®), ferumoxytol (Feraheme®), iron carboxy-
`maltose (Ferinject®/Injectafer®), and iron isomaltoside
`1000 (Monofer®). They are generally considered equal-
`ly efficacious, but most of them have limitations in
`dosing, administration (duration and frequency), and
`safety profile. High molecular weight iron dextran has
`been associated with an increased risk of anaphylaxis/
`anaphylactoid reactions and is not available in
`
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`Philip A. Kalra, Klaus Bock, Morten Meldal
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`CMYKP
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`Europe1-5. These side effects are significantly reduced
`with low molecular weight iron dextran1-4, but this
`still requires a test dose and has a long infusion time
`of four to six hours for larger doses6. Iron gluconate,
`iron sucrose, and ferumoxytol (only available in US
`and use limited to CKD patients) can only be admin-
`istered in moderate doses since they are limited to
`a maximum total single dose of 125 mg, 200 mg, and
`510 mg, respectively7-9. In addition, treatment with
`iron sucrose requires a test dose in Europe8, and it
`has been found associated with acutely increased
`proteinuria at 100 mg weekly infusions10,11. Iron glu-
`conate has also been found to be associated with a
`mild transient proteinuria in CKD patients11.
`
`Iron carboxymaltose does not require a test dose,
`and it can be administered in doses of 20 mg/kg up
`to a maximum of 1000 mg per infusion12. Iron carboxy-
`maltose infusion has been associated with hypophos-
`phataemia of unknown aetiology. The clinical signifi-
`cance of the hypophosphataemia is unknown13.
`
`The newest parenteral iron preparation, iron
`isomaltoside 1000 (Monofer®), was introduced in
`Europe in 2010. The ambition with iron isomaltoside
`1000 was to develop an efficacious parenteral iron
`product with a favourable safety profile without test
`dose requirement and without dose limitations in
`order to optimise dosing flexibility and user conve-
`nience. Iron isomaltoside 1000 fulfils these require-
`ments and can be administered with a maximum
`dosage of 20 mg/kg, no test dose, and within 30-60
`minutes in a single visit14. Due to the dose flexibility
`that iron isomaltoside 1000 offers, the possibility of
`providing full iron correction in a single infusion makes
`it highly convenient for both the health care profes-
`sionals and the patient. The present review describes
`the physiochemical characteristics, pharmacological,
`pharmacokinetic, and immunogenic properties, pre-
`clinical and clinical data, and cost analysis of iron
`isomaltoside 1000.
`
` (cid:132)
` PHYSIOCHEMICAL CHARACTERISTICS
`OF IRON ISOMALTOSIDE 1000
`
`Iron isomaltoside 1000 consists of iron and a car-
`bohydrate moiety. The carbohydrate isomaltoside 1000
`consists predominantly of 3-5 glucose units and origi-
`nates from isomalto-oligosaccharides produced by
`
`hydrolysis of dextran, followed by subsequent fractiona-
`tion and chemical modification to provide a product
`with the desired molecular weight distribution. Further-
`more, isomaltoside 1000 is isolated after chemical
`reduction of the reducing sugar residues to avoid com-
`plications due to redox reactions or degradation of the
`aldehyde group at the anomeric centre. The absence
`of reducing sugar prevents any complex redox reactions
`and thereby degradation of the iron complexes16. Apart
`from differences in molecular weight between dextran
`in iron dextran and isomaltoside 1000, the latter is also
`completely devoid of any branching structures as evi-
`denced by 13C and 1H NMR spectroscopic analysis and
`it does not contain any reducing sugar residues15. Thus,
`although isomaltoside 1000 is manufactured by a chemi-
`cal modification and hydrolysis of dextran, isomaltoside
`1000 is not a dextran. The chemical structure of iso-
`maltoside 1000 is very different from the dextran struc-
`ture, in which the α-(1,3) linked branches of the molecule
`are wound around the main chain α-(1,6) linked polymer
`in a tight helical arrangement15 while isomaltoside 1000
`has a purely linear oligomer structure of α-(1,6) linked
`glucopyranose residues, on average repeating 5.2 times,
`and contains no reducing sugar units.
`
`Electron microscopy16 presented the nano structure
`of iron isomaltoside 1000 as spheroidal while 13C NMR
`and associated molecular modelling have indicated
`that it is composed of a matrix structure in which the
`iron atoms are predominantly bound and dispersed in
`the matrix. From the masses of the components it can
`be calculated that there are approximately 10 iron atoms
`bound per oligosaccharide molecule. It is not yet known
`if these constitute coordinated single iron oxide moie-
`ties or small clusters of coordinated iron oxide. The
`iron isomaltoside 1000 matrix is composed of inter-
`changing strands of linear isomaltoside 1000 with iron
`atoms placed in cavities between and within the iso-
`maltoside molecules15. The matrix structure enables a
`controlled and slow release of iron which attaches to
`iron-binding proteins with little risk of free iron toxicity
`(Fig. 1). This is a unique structure and quite different
`from other iron products which are described as a pure
`iron core surrounded by a carbohydrate shell. The for-
`mation of this molecular matrix structure is possible
`due to the short, linear, and non-ionic isomaltoside
`1000 structure combined with the production technol-
`ogy for complexing iron and isomaltoside 1000.
`
`Iron is tightly bound in the iron isomaltoside 1000
`molecule; assessment of an iron isomaltoside 1000
`
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`CMYKP
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`Iron isomaltoside 1000: a new high dose option for parenteral iron therapy
`
`Figure 1
`
`Matrix structure of iron isomaltoside 1000 wich enables a controlled and slow release of iron.
`
`Comparative free iron content in high dose IV iron products
`
`Figure 2
`
`Free iron content in high dose parenteral iron products. The data is obtained without pH adjustment. The detection limit was 0.002 %. [Modified from Jahn et
`al., 2011 (Ref. 16)].
`
`solution equivalent to that administered to patients
`showed very low concentrations of free iron close to
`the detection limit of the assay (Fig. 2). A similar low
`
`concentration of free iron has been found with feru-
`moxytol, while the concentration of free iron in iron
`dextran and iron carboxymaltose solutions is significantly
`
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`Philip A. Kalra, Klaus Bock, Morten Meldal
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`CMYKP
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`higher15. Measurement of labile iron showed that the
`newer iron products (iron carboxymaltose, ferumoxytol,
`and iron isomaltoside 1000) have low labile iron content
`when compared to the older products (iron dextran <<
`iron sucrose and iron gluconate)15.
`
` (cid:132)
` IMMUNOGENIC PROPERTIES
`OF ISOMALTOSIDE 1000
`
`Anaphylactoid/anaphylactic reactions may occur with
`all parenteral iron compounds and were seen relatively
`often with the old high molecular weight iron dextran
`products. The pathogenic mechanisms for these reactions
`is not entirely clear, but the reactions seem to occur both
`through specific and non-specific immune reactions, with
`the carbohydrate carrier playing an important role for
`these reactions16. Thus, an important aim of the develop-
`ment of iron isomaltoside 1000 was to develop a product
`with a low risk of anaphylactoid/anaphylactic reactions.
`In order to achieve this, a carbohydrate carrier with a
`low immunogenic potential was sought. In iron isomal-
`toside 1000, the carbohydrate carrier, isomaltoside 1000,
`is based on a chemical modification of oligomers known
`to prevent dextran-induced anaphylactic reactions.
`
`Since it is well known that homopolymers of glucose
`have very low immunogenic potential17, in product
`design, any residual branching units that were α-linked
`to the 3-position of the main chain were removed,
`and the reducing sugar residue was chemically trans-
`formed quantitatively to non-reducing groups.
`
`Thus, from a theoretical point of view, the immu-
`nogenic potential of iron isomaltoside 1000 is expected
`to be very low, and on this basis, the regulatory authori-
`ties decided that no test dose was required in the first
`clinical studies with iron isomaltoside 1000. These
`studies supported the theoretical rationale for low
`immunogenic activity, and iron isomaltoside 1000 was
`therefore approved for use without a test dose.
`
` (cid:132)
` PHARMACOLOGICAL AND
`PHARMACOKINETIC PROPERTIES
`OF IRON ISOMALTOSIDE 1000
`
`Following IV administration, iron isomaltoside
`1000 is rapidly taken up by the cells in the
`
`reticuloendothelial system (RES), particularly in the
`liver and spleen, from where iron is slowly released.
`The plasma half-life is 5 hours for circulating iron
`and 20 hours for total iron (bound and circulating).
`Circulating iron is removed from the plasma by cells
`of the RES which split the complex into iron and
`isomaltoside 1000. Iron is immediately bound and
`stored, mainly in ferritin. The iron replenishes hae-
`moglobin and depleted iron stores. Negligible quan-
`tities of iron are eliminated in the urine and faeces.
`Due to the size of the nanoparticles (20.5 nm), iron
`isomaltoside 1000 is not eliminated via the kidneys.
`The carbohydrate component, isomaltoside 1000,
`is either metabolised or excreted unchanged via
`the kidney14.
`
`An open-label, cross-over, single-centre study was
`performed in 12 patients (5 men/7 women) with
`inflammatory bowel disease (IBD) to assess phar-
`macokinetics18. The patients were allocated to one
`of two single-dose treatments where iron isomal-
`toside 1000 was administered as a single bolus
`dose of 100 or 200 mg with a four-week interval
`between the two doses. The dose was administered
`at a maximum of 50 mg of iron/minute. Pharma-
`cokinetic (PK) variables were analysed for total iron
`(TI), isomaltoside-bound iron (IBI), and transferrin-
`bound iron (TBI) according to a one-compartment
`model. TI and TBI were measured by the Graphite
`GFAAS system and the Advia chemistry system,
`respectively, and IBI was calculated by subtracting
`TBI from TI, assuming that no free iron was present
`and that quantities of ferritin were negligible, so
`that the only iron forms present in plasma were TI,
`TBI, and IBI. The concentration versus time relation-
`ship for IBI and TI showed first-order kinetics with
`small deviations for dose-linearity, and the PK
`parameters for IBI were close to that of TI (Table I).
`Thus, TI could be used as a marker of iron isoma-
`ltoside 1000 PK in future PK studies. Only approxi-
`mately 1 % of the doses administered were excreted
`in the urine. One of the patients was withdrawn
`after receiving a 100 mg dose because of abdominal
`pain and flushing. No serious adverse events (SAE)
`were reported18.
`
`Presently, there are several PK studies ongoing
`with higher doses of iron isomaltoside 1000 in differ-
`ent patient populations (ClinicalTrial.gov: NCT01213979,
`NCT01280240, NCT01213992, NCT01469078, and
`NCT01213680).
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`Iron isomaltoside 1000: a new high dose option for parenteral iron therapy
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`Table I
`
`Geometric mean (CV in %) for PK parameters of IBI, TI, and TBI
`Isomaltoside-bound iron
`Treatment
`
`Endpoint
`
`Total iron
`Treatment
`
`Transferrin-bound iron
`Treatment
`
`auc0-end (h*μg/ml)
`auc0-inf (h*μg/ml)
`cmax (μg/ml)
`c0 (μg/ml)
`ke (1/h)
`t1/2 (h)
`vD based on c0 (l)
`
`
`
`100 mg
`809 (24)
`888 (22)
`35.6 (39)
`28.3(32)
`0.033 (12)
`20.8 (12)
`3.5 (32)
`
`200 mg
`1885 (20)
`2141 (23)
`68.6 (26)
`64.5 (29)
`0.031 (24)
`22.5 (24)
`3.1 (30)
`
`100 mg
`894 (21)
`1010 (19)
`37.3 (38)
`28.9 (32)
`0.030 (15)
`23.2 (15)
`3.5 (32)
`
`200 mg
`2017 (19)
`2319 (21)
`71.1 (26)
`66.8 (28)
`0.029 (23)
`23.5 (23)
`3.0 (28)
`
`100 mg
`83 (19)
`163 (67)
`2.1 (30)
`1.7 (37)
`0.011 (85)
`62.2 (85)
`60.6 (36)
`
`200 mg
`129 (15)
`228 (51)
`3.0 (16)
`2.9 (37)
`0.013 (87)
`53.9 (87)
`68.3 (37)
`
` (cid:132)
` EFFICACY AND SAFETY PROFILE
`OF IRON ISOMALTOSIDE 1000
`
`In the recent past, the efficacy and safety of iron
`isomaltoside 1000 in the treatment of IDA has been
`investigated in two phase III clinical studies in
`patients with either chronic kidney disease (CKD) or
`chronic heart failure (CHF)19,20. The primary endpoint
`of these studies was to establish the safety profile
`of iron isomaltoside 1000, whereas efficacy was the
`secondary endpoint. Both were open-label, non-
`comparative, multi-centre studies where the patients
`attended six visits during a study period of eight
`weeks. At the investigator’s discretion, iron isomalto-
`side 1000 was administered either as four repeated
`intravenous (IV) bolus injections with 100-200 mg
`iron per dose administered at baseline and at week
`1, 2, and 4 (the last dose could be administered as
`total remaining dose if the total calculated iron
`requirement exceeded 800 mg) or as a high single
`iron correction dose (total dose infusion (TDI)) at
`baseline. If the TDI requirement exceeded 20 mg
`iron/kg the dose was divided into two and these
`given at an interval of one week. No test dose was
`given. The total calculated iron requirement and
`administered cumulative dose in each patient were
`based on a target Hb of 130 g/L and utilising the
`Ganzoni formula that reflects body weight, the dif-
`ference between actual haemoglobin and target hae-
`moglobin, and the desired level of iron stores (com-
`monly 500 mg)21. The safety assessments consisted
`of type and frequency of adverse events (AEs) and
`SAEs, changes in vital signs (including electrocardio-
`gram (ECG)), and clinical laboratory analyses (bio-
`chemistry: s-sodium, s-potassium, s-creatinine,
`s-albumin, s-urea, s-bilirubin, and alanine aminotrans-
`ferase (ALAT), haematology: leucocytes, complete
`
`blood cell count with differentials, and platelets) 1,
`2, 4, and 8 weeks after baseline. The efficacy assess-
`ments consisted of laboratory monitoring of treat-
`ment effect on haemoglobin (Hb), transferrin satura-
`tion (TSAT), and s-ferritin levels 1, 2, 4, and 8 weeks
`after baseline. In addition, the CHF study included
`s-iron, which was monitored at the same time points,
`and a linear analogue scale assessment (LASA) qual-
`ity of life (QoL) questionnaire measuring QoL 4 and
`8 weeks after baseline. The LASA is a validated QoL
`assessment consisting of 100-mm linear analogue
`scales that measured the patient’s energy level, abil-
`ity to do daily activities, and overall QoL.
`
` (cid:132)
` IRON ISOMALTOSIDE 1000
`ADMINISTERED TO PATIENTS
`WITH CHRONIC KIDNEY DISEASE
`
`The study was conducted at 15 centres in three
`European countries (six in Denmark, seven in Sweden,
`and two in the United Kingdom). A total of 182 CKD
`patients (128 men/54 women) receiving dialysis (n =
`161) or pre-dialysis care (n = 21) were included. The
`vast majority of patients were receiving haemodialysis.
`The patients were generally on ESA treatment (n = 82
`%), and the dosage of ESA was kept constant during
`the study. Patients were either switched from an exist-
`ing parenteral iron maintenance therapy (n = 144) or
`were not currently treated with parenteral iron (n =
`38). The mean ± SD age was 63.3 ± 13.8 years (range:
`21-91 years). Patients not receiving parenteral iron
`treatment when entering the study had a baseline Hb
`of 99.1 ± 9.0 g/L and a s-ferritin of 231 ± 154 μg/L,
`and patients who switched from a parenteral iron
`maintenance regimen had a baseline Hb of 114.9 ±
`
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`Philip A. Kalra, Klaus Bock, Morten Meldal
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`CMYKP
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`10.3 g/L and a s-ferritin of 380 ± 195 μg/L. The mean
`± SD total cumulative dose of iron per patient was
`529 ± 283 mg19. In total, 584 treatments were given
`(523 IV bolus 100 mg, 17 IV bolus 100-200 mg and
`44 TDIs) with single doses as high as 1800 mg22.
`
`Nineteen reported AEs were possibly or probably
`related to the study drug. There was no difference in
`the AE frequencies observed in patients treated with
`bolus doses or TDI. Three subjects (1.6 %) had more
`than one AE related to the study drug: one patient
`had two events of nausea, another patient had diar-
`rhoea, influenza, hyperhidrosis, low s-ferritin, and
`arthralgia, and a third patient had a haemorrhagic
`cyst in the right kidney and pruritus. Two of the AEs
`which were determined by the attending physician to
`be possibly treatment-related, fulfilled the criteria for
`SAEs. The events were sepsis with Staphylococcus
`aureus and unstable angina. Two deaths (one reported
`as due to an unknown cause and the other pneumonia)
`occurred, but these were both considered unrelated
`to the study drug. No acute anaphylactoid/anaphylactic
`or delayed allergic reactions were reported. There
`were no clinically significant changes in vital signs or
`routine safety clinical laboratory tests.
`
`Hb increased from 99.2 ± 9.0 g/L at baseline to
`111.2 g/L ± 14.7 at week 8 in patients not having
`received parenteral iron (p < 0.001) and remained stable
`in patients receiving maintenance iron therapy (114.9
`± 10.3 g/L at baseline, 117.5 ± 11.7 g/L at week 8; p =
`0.05). The mean ± SD maximal increase in Hb in the
`overall mixed CKD population was 7.9 ± 9.9 g/L (p <
`0.001). TSAT and s-ferritin also increased significantly
`from baseline to week 8 (p < 0.001). It was concluded
`that iron isomaltoside 1000 administered to CKD
`patients as repeated bolus injections or TDI without
`a test dose, was safe and well-tolerated and resulted
`in improved markers of iron status and anaemia19.
`
`mean age was 75 years (range: 61-88 years). Baseline
`Hb was 108.2 ± 7.6 g/L and s-ferritin was 180 ± 184
`μg/L. All 20 patients received a high single dose
`infusion with a mean infusion time of 59.8 minutes
`(range: 50-67 minutes) with a mean dose of 868 mg
`(range: 650-1000 mg).
`
`No study drug related AEs were reported, no
`deaths occurred, and no acute anaphylactic/anaphy-
`lactoid or delayed allergic reactions were observed.
`There were no clinically significant changes in routine
`clinical safety laboratory tests or vital signs. New
`clinically significant ECG abnormalities were observed
`on 13 occasions, but these did not indicate any new
`disease or progression of disease and could all be
`explained by the patients’ medical history.
`
`Haemoglobin was increased at every visit com-
`pared to baseline; however, the increase was non-
`significant due to the small patient population. As
`compared with baseline value, s-ferritin was signifi-
`cantly increased at all visits, while a statistical
`increase in s-iron and TSAT were observed one week
`after baseline. All QoL assessments increased sig-
`nificantly four weeks after baseline. The empirical
`mean for “energy level” increased by 49 %, “ability
`to do daily activities” increased by 38 %, and “overall
`QoL” increased by 23 %. Eight weeks after baseline,
`the scores were increased by 34 %, 20 %, and 13
`%, for each of these QoL parameters, respectively,
`but statistical significance was only reached for
`“energy level”. The authors concluded that, despite
`the uncontrolled study design and small sample size,
`iron isomaltoside 1000 was well-tolerated and
`improved QoL in patients with CHF20.
`
` (cid:132)
` HIGH DOSING OF IRON
`ISOMALTOSIDE 1000
`
` (cid:132)
` IRON ISOMALTOSIDE 1000
`ADMINISTERED TO PATIENTS
`WITH CHRONIC HEART FAILURE
`
`The study was conducted at seven centres in two
`European countries (four centres in Denmark and
`three centres in Sweden). A total of 20 CHF patients
`(10 men/10 women) with mild anaemia were included.
`None of the patients received ESA treatment. The
`
`As discussed, iron isomaltoside 1000 can be
`administered in high doses without a test dose due
`to its low immunological activity and low risk of free
`iron related toxicity. Three sub-analyses of safety
`and efficacy parameters of the patients in the CKD
`and CHF studies, who were treated with high dose
`infusion, were performed23-25.
`
`The first analysis included 19 haemodialysis patients
`with CKD and anaemia. All 19 patients received a
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`CMYKP
`
`Iron isomaltoside 1000: a new high dose option for parenteral iron therapy
`
`high single dose infusion, with a mean dosage of
`986 mg (range: 463-1800 mg) over 30-60 minutes.
`A total of 19 AEs were reported in 9 patients (47 %),
`but none of them was considered to be related to
`the study drug by the investigator. No acute anaphy-
`lactoid/anaphylactic or delayed allergic reactions were
`observed, and there were no significant changes in
`safety clinical laboratory tests or vital signs. Efficacy
`markers of IDA improved significantly23.
`
`The second analysis included 21 pre-dialysis
`patients with CKD and anaemia. One SAE that was
`considered to be treatment related was observed.
`The event was angina pectoris in an 80-year-old CKD
`patient with a medical history of angina. It occurred
`10-11 days after the patient had received 1400 mg
`iron isomaltoside 1000. The medical history of the
`patient and the time delay in the occurrence of the
`event made the relationship of the SAE to iron
`isomaltoside 1000 quite unlikely. No acute anaphy-
`lactoid/anaphylactic or delayed allergic reactions were
`observed, and there were no significant changes in
`safety clinical laboratory tests or vital signs. Efficacy
`markers of IDA improved significantly25.
`
`The third analysis consisted of the above 40 CKD
`patients aggregated with the 20 CHF patients. A total
`of 58 out of 60 patients had one single high dose
`infusion, and only two CKD patients required two
`divided doses in order to fulfil their iron needs. The
`mean dosage was 975 mg (range: 462-1800 mg) in
`the CKD patients and 868 mg (range: 650-1000 mg)
`in the CHF patients. One treatment related SAE was
`observed, which was the event of angina pectoris
`discussed above. No acute anaphylactoid/anaphy-
`lactic or delayed allergic reactions were observed,
`and there were no significant changes in safety clini-
`cal laboratory tests or vital signs. Efficacy markers
`of IDA improved significantly24.
`
`In conclusion, iron isomaltoside 1000 administered
`as high doses to CKD and CHF patients was safe, well
`tolerated, and effective in improving markers of IDA.
`
` (cid:132)
` IRON ISOMALTOSIDE 1000
`AND NEPHROTOXICITY
`
`It has been suggested that parenteral iron may
`have a direct toxic effect on renal tubular cells which
`
`could cause renal phosphate wasting26,27. In 2004,
`Zager and colleagues reported a study comparing
`the nephrotoxicity of iron sucrose, iron gluconate,
`iron dextran, and iron isomaltoside 1000 over a broad
`dosage range (0, 30 to 1000 μg iron/mL)28. The iron
`preparations were added to isolated mouse proximal
`tubule segments and cultured proximal tubular
`human kidney cells. Cell injury was assessed by
`lactate dehydrogenase release, adenosine triphos-
`phate reductions, cell cytochrome c efflux, and/or
`electron microscopy. The iron preparations evoked
`in vitro toxicity and up to 30-fold differences in
`severity were observed. The highest toxicity was
`observed in iron sucrose and the lowest in iron
`dextran and iron isomaltoside 1000 (iron sucrose >
`iron gluconate >> iron dextran = iron isomaltoside
`1000). The large differences may be explained by
`the difference in capacities of the irons to gain intra-
`cellular access. According to transmission electron
`microscopy (TEM) studies, the nanostructure of iron
`dextran and iron isomaltoside 1000 are similarly large
`and globular while iron sucrose and iron gluconate,
`in addition to being more soluble formulations, differ
`significantly in structure and display elongated and
`smaller nanostructures15.
`
`Similar data was found with in vivo correlates of
`iron toxicity which included increases in renal malon-
`dialdehyde, renal ferritin, and heme oxygenase-1
`expression in mice. These changes also appeared to
`parallel in vivo glomerular iron uptake (seen with
`iron sucrose and iron gluconate, but not with iron
`dextran and iron isomaltoside 1000)28.
`
` (cid:132)
` IRON ISOMALTOSIDE 1000
`AND S-PHOSPHATE
`
`As some parenteral iron therapies have been found
`to be associated with hypophosphataemia13,26,27,29-32,
`the effect of iron isomaltoside 1000 on s-phosphate
`is being measured in several ongoing clinical studies,
`and interim analyses of s-phosphate data have been
`performed as part of the protocols. At the current
`time, these interim analyses included 25 oncology
`patients and 50 patients with non-dialysis dependent
`chronic kidney disease (NDD-CKD) treated with iron
`isomaltoside 1000 (data on file, Pharmacosmos A/S,
`ClinicalTrial.gov: NCT01145638 (oncology study) and
`NCT01102413 (NDD-CKD study)).
`
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`
`

`
`Philip A. Kalra, Klaus Bock, Morten Meldal
`
`CMYKP
`
`The phosphate analyses are part of two phase III,
`prospective, open-label, randomised, comparative
`studies. A total of 350 patients with a diagnosis of
`non-myeloid cancer and 350 NDD-CDK patients with
`renal-related anaemia are being randomised 2:1 to
`either IV iron isomaltoside 1000 (group A) or oral
`iron sulphate (group B). The patients in group A are
`equally divided into two sub-groups (A1 and A2).
`Group A1 are treated with IV iron isomaltoside, where
`the full iron replacement dose is administered as
`infusions of maximum 1000 mg iron isomaltoside
`1000 over 15 minutes until full replacement dose is
`achieved. Group A2 are treated with IV bolus injec-
`tions of 500 mg iron isomaltoside 1000 over 2 min-
`utes, administered once per week until full replace-
`ment dose is achieved. Group B are treated with
`200 mg oral iron sulphate daily for 8-12 weeks. For
`the individual patient, the duration of the study is
`8-10 weeks in the NDD-CKD study and 24-26 weeks
`in the oncology study. S-phosphate is measured
`prior to iron administration and at every visit. At
`baseline in the oncology study, s-phosphate was 4.0
`
`± 0.9 mg/dL in group A1 and A2, and 3.6 ± 0.6 mg/
`dL in group B, and in the NDD-CKD study, s-phos-
`phate was 4.5 ± 0.9 mg/dL in group A1 and A2, and
`4.3 ± 0.9 mg/dL in group B.
`
`At interim analysis there was no significant
`change in the s-phosphate levels in any of the IV
`treatment groups in either the oncology or NDD-CKD
`patients. Mean (95 % CI) values of s-phosphate for
`the three treatment arms are shown in Fig. 3 (oncol-
`ogy study) and Fig. 4 (NDD-CKD study). In other
`studies, s-phosphate levels below 2 mg/dL have been
`considered an indicator for hypophosphatemia13,32.
`In the iron isomaltoside 1000 studies, 3 out of 75
`patients experienced a decrease in s-phosphate with
`a value slightly below 2 mg/dL post treatment. The
`first patient was a NDD-CKD patient treated with an
`infusion (1000 mg of iron isomaltoside 1000). The
`patient had a s-phosphate level of 1.8 mg/dL three
`weeks after baseline. The second patient was an oncol-
`ogy patient treated with an infusion (also 1000 mg).
`This patient had a s-phosphate level of 1.9 mg/dL at
`
`Figure 3
`
`Mean (95 % CI) phosphate values in oncology patients during the 24 week study period. Group A1 was treated with iron isomaltoside 1000 infusion, group A2
`was treated with iron isomaltoside 1000 bolus injection, and group B was treated with oral iron sulphate (data on file, Pharmacosmos A/S).
`
`20 Port J Nephrol Hypert 2012; 26(1): 13-24
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`
`

`
`CMYKP
`
`Iron isomaltoside 1000: a new high dose option for parenteral iron therapy
`
`Figure 4
`
`Mean (95 % CI) phosphate values in NDD-CKD patients during the 8 week study period. Group A1 was treated with iron isomaltoside 1000 infusion, group A2
`was treated with iron isomaltoside 1000 bolus injection, and group B was treated with oral iron sulphate (data on file, Pharmacosmos A/S).
`
`one and four weeks after baseline. The third patient
`was an oncology patient treated with two bolus injec-
`tions (500 mg + 250 mg of iron isomaltoside 1000).
`The patient already had a low s-phosphate level at
`the screening visit (2.0 mg/dL), and four weeks after
`baseline the s-phosphate level was 1.9 mg/dL. All
`three patients had a s-phosphate which normalised
`at the following visit. No adverse drug reaction was
`reported in the t