Clinical and Experimental Pharmacology and Physiology (2005) 32, 1020-1026
`
`EFFECTS OF INTRA VENOUS ABT-870 (IRON (111)-HYDROXIDE
`OLIGOSACCHARIDE) ON MEAN ARTERIAL PRESSURE AND HEART
`RATE IN THE ANAESTHETIZED BEAGLE: COMPARISON WITH
`OTHER IRON-CONTAINING HAEMATINIC AGENTS
`
`Lee C Preusser,* Ryan M Fryer,* Armin Gerhardt,* Yanhui Hu,t Leticia Delgado-Herrera,*
`Joel Z Melnick,* Laura A Williams,* Bryan F Cox* and Glenn A Reinhart*
`
`*Integrative Pharmacology, tNon-Clinical Statistics and +Renal Disease, Global Pharmaceutical Research and
`Development, Abbott Laboratories, Abbott Park, Illinois, USA
`
`SUMMARY
`
`1. Iron-deficiency anaemia, a complication of end-stage
`renal disease (ESRD), is often treated with parenteral iron
`therapies that have been shown to produce dose-limiting
`hypotension
`in patients. ABT-870
`(iron-(III)-hydroxide(cid:173)
`oligosaccharide) is comprised of elemental iron complexed
`with oligosaccharide, a composition that we hypothesised
`would allow the hypotensive effects of parenteral iron therapy
`to be overcome, thus allowing a rapid rate of infusion to be well
`tolerated.
`2. Mean arterial pressure (MAP) and heart rate (HR) were
`monitored in anaesthetized dogs following the infusion of
`ABT-870 and iron sucrose administered at doses of 7.1 and
`21.3 mg/kg using a rapid 30 s infusion. ABT-870 and iron
`sucrose were also monitored at doses of 7.1, 21.3 and 50 mg/kg
`administered over a 10 min period. Sodium ferric gluconate
`complex (SFGC) was administered in an identical fashion at
`doses of 12.5 and 31.2 mg/kg.
`3. A 30 s rapid infusion of ABT-870 at doses of 7.1 and
`14.3 mg/kg or a 10 min infusion of ABT-870 at doses of7.1 and
`21.3 mg/kg produced little effect on MAP and HR. Infusion of
`the highest dose of ABT-870 (50 mg/kg) produced no consistent
`hypotension, but did produce an increase in HR (maximal
`increase 35 ± 9 b.p.m. ), an effect that lasted only 15 min. A 30 s
`rapid infusion of iron sucrose at 7.1 mg/kg produced modest
`increases in MAP and HR (5 ± 1 mmHg and 5 ± 2 b.p.m.,
`respectively). However, rapid infusion of iron sucrose at
`14.3 mg/kg produced hypotension (to -8 ± 1 mmHg below
`baseline) and exerted variable, biphasic effects on HR ranging
`from -16 to +50 b.p.m. Although 10 min infusion of iron
`sucrose at 7.1 mg/kg exerted little effect on MAP and HR,
`at doses of 21.3 and 50 mg/kg iron sucrose elicited a
`profound dose-dependent decrease in MAP (-34 ± 11 and
`-83 ± 5 mmHg, respectively) and a pronounced increase in
`HR ranging from 32 to 49 b.p.m. above baseline. A 10 min
`
`Correspondence: Lee C Preusser, Integrative Pharmacology, Abbott
`Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6119, USA.
`Email: lee.preusser@abbott.com; ryan.fryer@abbott.com
`Received 29 March 2005; revision 27 May 2005; accepted 5 June 2005.
`© 2005 Blackwell Publishing Asia Pty Ltd
`
`infusion of SFGC at doses of 12.5 and 31.2 mg/kg
`produced a dose-dependent decrease in MAP (-28 ± 18 and
`-67 ± 12 mmHg below baseline) and a marked increase in HR
`(26 ± 11 and 94 ± 15 b.p.m. above baseline).
`4. In conclusion, unlike iron sucrose and SFGC, high doses
`of ABT-870 failed to exert consistent hypotensive effects. These
`data demonstrate that ABT-870 may have a substantial
`therapeutic window and considerable clinical potential for
`iron-replacement therapy.
`Key words: ABT-870, blood pressure, cardiovascular, end(cid:173)
`stage renal disease, heart rate, intravenous iron administration,
`iron replacement therapy, iron sucrose, sodium ferric gluco(cid:173)
`nate complex.
`
`INTRODUCTION
`
`The prevalence of end-stage renal disease (ESRD) in 2002 was
`estimated at 1435 per million population, a 56% increase from 10
`years earlier that was likely due to an increasing incidence of
`underlying disease factors and a decreasing mortality rate for
`ESRD patients. 1 Iron-deficiency anaemia is a common complic(cid:173)
`ation associated with ESRD; surgery, inflammatory responses,
`decreased dietary intake (owing to dietary restrictions) and
`decreased gastrointestinal absorption of iron (owing to prescribed
`phosphate binders and chronic uraemia itself) can deplete iron
`stores. In addition, haemodialysis often results in a blood loss
`leading to further iron depletion. Moreover, because patients with
`renal impairment do not produce enough natural erythropoietin to
`maintain an adequate supply of red blood cells, ESRD patients
`often
`receive erythropoietic
`therapy' with drugs
`such as
`recombinant human erythropoietin. 1 Erythropoietin boosts red
`blood cell production, which, in tum, may significantly increase
`the physiological demand for iron. Indeed, dialysis patients being
`treated with recombinant human erythropoietin therapy require
`rapid mobilization of iron reserves in order to meet the demands of
`new red blood cell production. The demands of this therapy can
`outstrip the body's ability to mobilize iron stores and functional
`iron deficiency can result. 2--4
`Iron is critical for normal haemoglobin synthesis to maintain
`oxygen transport and is necessary for metabolism and various
`enzymatic processes. Although iron replacement can be accom(cid:173)
`plished either by the oral or parental route, studies have demon-
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1068 - Page 1
`
`

`

`Haemodynamic effects of ABT-870
`
`1021
`
`strated that oral treatment has limited efficacy and tolerability
`compared with intravenous iron therapy in the ESRD patient
`population.5- 11 Intravenous iron therapy has emerged as a standard
`of care and the Kidney/Dialysis Outcomes Quality Initiative
`(K/DOQI) Anemia Clinical Practice Guidelines state that most
`erythropoietin-treated patients will require i.v. iron to maintain
`adequate iron stores. 12 In the US, parental iron therapy is available
`as a sodium ferric gluconate complex (SFGC; Ferrlecit®; Aventis
`Pharma, Dagenham, Essex, England), iron dextran (Infect®; Watson
`Pharma, Inc, Morristown, NJ, USA) and iron sucrose (Venofer®;
`American Reagent Laboratories, Shirley, NY, USA). These three
`preparations are thought to be equally efficacious in treating iron(cid:173)
`deficiency anaemia in haemodialysis patients, but differ with
`respect to potential toxicity, side-effects and dose recommen(cid:173)
`dations.13-18 The more recently approved parental iron compounds
`(iron sucrose and SFGC) have also been associated with potential
`oversaturation reactions,
`including hypotension and flushing,
`which may be a result of the accumulation of bioactive or labile
`iron in the circulation. 19-20 Importantly, iron sucrose has been
`associated with dose-limiting hypotension in the clinic.21 ·22
`ABT-870 (iron (ill)-hydroxide oligosaccharide) is in clinical
`development for the treatment of iron deficiency in haemodialysis
`patients. ABT-870 is composed of a low molecular weight
`protective carbohydrate coating surrounding an iron core of a stable
`ferric hydroxide structure, with a negligible amount of free iron in
`iron and,
`the _slow release of unbound
`solution, ensuring
`potentially, allowing for i.v. bolus administration, thus minimizing
`the concern for free iron toxicity. The low molecular weight
`protective carbohydrate coating is the same moiety used in
`Promit® (Taylor Pharmaceuticals, Decatur, IL, USA), which
`conforms
`to
`the European Pharmacopeia standard
`(http://
`www.pharmacosmos.com/lndex.asp?p=l, September 2005) for
`dextran 1 and has well-established clinical use.23
`Most patients will require a minimum cumulative dose of 1.0 g
`elemental iron, administered over JO sequential dialysis sessions,
`
`to achieve a favourable haemoglobin or haematocrit response.
`Indeed, current clinical practice is limited to repeated dosing of i.v.
`iron both for repletion and maintenance of iron stores in haemo(cid:173)
`dialysis patients.24 Thus, to maximize the clinical usefulness of
`these agents, it may be desirable to administer these drugs less
`frequently and at higher doses per dialysis session.24·25 Therefore,
`because parental iron therapy can be associated with dose-limiting
`hypotension, the aim of the present study was to effectively
`characterize the effects of ABT-870 compared with iron sucrose
`and SFGC on mean arterial pressure (MAP) and heart rate (HR) in
`the anaesthetized beagle dog in separate studies using either a 30 s
`bolus infusion or a 10 min infusion paradigm.
`
`METHODS
`Male beagle dogs, weighing 10.3 ::': 0.2 kg (n = 5-6 per group; 14 groups),
`were anaesthetized with pentobarbital (35.0 mg/kg, i.v.) and immediately
`placed on a constant intravenous infusion of pentobarbital (6.0 mg/kg per
`h). Animals were intubated with a cuffed endotracheal tube and ventilated
`with room air by means of a mechanical respiration pump (Model 613;
`Harvard Apparatus, Millis, MA, USA). Expiratory CO2 was monitored with
`an end-tidal CO2 monitor (Model POET TE; Criticare Systems, Waukasha,
`WI, USA) and maintained at 4-5%. Polyethylene catheters were inserted
`into the right femoral vein for infusion of ABT-870, iron sucrose, SFGC, or
`Promit and a polyethylene catheter was inserted into the right femoral artery
`and connected to a pressure transducer (Transpac II; Abbott Laboratories)
`for the measurement of arterial blood pressure. Mean arterial pressure and
`HR were computed using commercial software and a signal processing
`workstation (Ponemah; Gould Instrument Systems, Valley View, OH,
`USA).
`The haemodynamic effects of ABT-870 (iron (lll)-hydroxide oligo(cid:173)
`saccharide; Abbott Laboratories) were characterized in separate studies in
`the anaesthetized beagle dog administered either as a 30 s rapid infusion or
`a 10 min infusion. During rapid infusion, ABT-870 was administered at a
`total dose of 7 .1 or 14.3 mg/kg, doses equivalent to 0.5 and 1.0 g, respec(cid:173)
`tively, for a 70 kg human. During the IO min infusion studies, ABT-870 was
`administered at 7.1 and 21.3 mg/kg or as a total dose of 500 mg (approxi(cid:173)
`mately 50 mg/kg). These doses are equivalent to 0.5, 1.5 and 3.5 g,
`
`Table 1 Haemodynamic response to rapid infusion (30 s) of dextran 1 and doses of 7. I or 14.3 mg/kg ABT-870 or iron sucrose
`
`Mean positive
`change
`
`Time to peak
`positive response
`from start of
`infusion (min)
`
`Mean negative
`change
`
`Time to peak
`negative response
`from start of
`infusion (min)
`
`Maximum range
`within group
`
`Dextran I
`MAP(mmHg)
`HR(b.p.m.)
`
`ABT-870 (7.1 mg/kg)
`MAP(mmHg)
`HR (b.p.m.)
`
`ABT-870 (14.3 mg/kg)
`MAP(mmHg)
`HR (b.p.m.)
`
`Iron sucrose (7 .1 mg/kg)
`MAP(mmHg)
`HR(b.p.m.)
`
`Baseline
`
`117.0 ::': 6.0
`119.0 ::': 4.0
`
`125.0 ::': 4.0
`110.0 ± 6.8
`
`119.0 ::': 6.6
`107.0 ::': 6.6
`
`121.0 ::': 6.2
`111.0 ::': 5.4
`
`4.0 ::': 1.2
`5.0 ::': I.I
`
`3.0 ::': 1.2
`7.9 ± 1.0
`
`3.0 ::': 0.2
`9.0 ± 1.9
`
`5.0 ::': 1.2
`6.0 ± 1.5
`
`8.5 ± 3.1
`5.3 ::': 1.8
`
`7.9 ::': 1.0
`4.3 ::': 2.2
`
`4.5 ::': 22.2
`1.6 ± 0.7
`
`6.6 ::': 2.3
`3.3 ± 1.8
`
`6.0 ± 1.7
`1.9 ± 0.9
`
`-5.0 ::': 9.6
`-6.0 ::': 1.9
`
`-2.0 ::': 0.3
`-5 ::': 2
`
`-3.0 ::': 0.7
`-4.0 ± 0.8
`
`-1.0 ± 0.0
`-5.0 ± 1.5
`
`-8.0 ± 1.2
`-8.0 ::': 2.0
`
`9.6 ± 3.2
`5.6 ::': 2.2
`
`1.6 ± 0.7
`8.9 ::': 3.0
`
`4.6 ::': 2.6
`4.0 ± 1.2
`
`0.3 ::': 01
`8.1 ::': 1.1
`
`-12.0to+7.0
`-14.0 to +9.0
`
`-3.0 to +9.0
`-12.0 to +13.0
`
`-5.0 to +6.0
`-6.0 to +17.0
`
`-1.0 to +10.0
`-9.0 to +I 1.0
`
`1.9 ::': 0.7
`4.9 ::': 1.4
`
`-20.0 to +5.0
`-16.0 to +50.0
`
`Iron sucrose (I 4.3 mg/kg)
`5.0 ± 1.3
`119.0 ::': 5.1
`MAP(mmHg)
`HR (b.p.m.)
`118.0 ± 6.2
`23.0 ::': 7.8*
`Data are the mean::':SEM (n = 6). *P < 0.05 compared with baseline.
`MAP, mean arterial pressure; HR, heart rate.
`
`© 2005 Blackwell Publishing Asia Pty Ltd
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1068 - Page 2
`
`

`

`1022
`
`LC Preusser et al.
`
`respectively, for a 70 kg human. Iron sucrose (Venofer®) was investigated
`as a comparator agent to ABT-870 and was administered at identical doses,
`but in a slightly higher volume, than ABT-870 because iron sucrose is
`commercially available at a lower concentration. Because SFGC is
`available commercially at a much lower concentration than ABT-870,
`SFGC (Ferrlecit®) was administered at identical volumes but at lower doses
`than ABT-870 (12.5 and 31.2 mg/kg, corresponding to 0.85 and 2.1 g,
`
`200
`
`(a)
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`
`Infusion
`
`Infusion
`
`-5
`
`0
`
`5
`Time (min)
`
`10
`
`15
`
`Fig. 1 Effect of a 10 min infusion of dextran 1 (Promit®; Taylor
`Pharmaceuticals, Decatur, IL, USA) on (a) mean arterial pressure (MAP)
`and (b) heart rate (HR) in the anaesthetized dog. Data are the mean±SEM
`(11 = 6). *P < 0.05 compared with baseline.
`
`200
`
`(a)
`
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`:::c::
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`
`Infusion
`
`respectively, for a 70 kg human). Dextran 1 (Promit®; J 50 mg/mL; NaCl,
`6 mg/mL) was administered as a 30 s rapid infusion or 10 min infusion at
`a volume comparable to that administered to ABT-870-treated animals in
`order to assess the haemodynamic effects of the dextran component of
`ABT-870 in the absence of iron.
`Data are expressed as the group mean±SEM. For the 10 min infusion
`protocol, statistical analysis was performed for each parameter at each
`dosing regimen using repeated-measures ANOVA (Prism 4.0 software;
`GraphPad Software, San Diego, CA USA); Dunnett's t-test was used to
`compare changes from baseline within each group at 30 s intervals during
`compound infusion (20 time points). For the 30 s infusion protocol, a t-test
`was used to compare the baseline values with mean positive and mean
`negative changes from baseline for each compound and haemodynamic
`parameter. Statistical significance was determined at P < 0.05.
`
`RESULTS
`
`In the anaesthetized beagle, dextran 1 (Promit®), the dextran
`structural component used in ABT-870, when infused at volumes
`and rates equivalent to those used for ABT-870, produced only
`negligible effects on MAP and HR (Table 1; Fig. 1 ).
`Infusion of SFGC for 10 min at 12.5 mg/kg produced a modest
`increase in MAP (to 6 ::!:: 1 mmHg above baseline) during the latter
`one-third of compound infusion (Fig. 2). During the post-treatment
`period, SFGC produced highly variable reductions in MAP. Indeed,
`in two of six animals, SFGC produced profound decreases in MAP
`(to -39 and -90 mmHg below baseline), whereas the remaining
`animals remained unresponsive. In the two animals in which
`arterial pressure fell, SFGC also elicited large increases in HR
`(maximal increase 76 and 35 b.p.m. above baseline, respectively).
`Infusion of SFGC for 10 min at 31.2 mg/kg (Fig. 2) produced a
`marked and consistent decrease in MAP (to -67 ::!:: 12 mmHg
`below baseline), with the maximum response occurring approxi(cid:173)
`mately 6 min into the infusion; MAP then climbed steadily towards
`
`200
`
`(b)
`
`150
`
`100
`
`50
`
`0
`
`200
`
`(d)
`
`150
`
`100
`
`50
`
`0
`
`Infusion
`
`-5
`
`0
`
`5
`
`10
`
`15
`-5
`Time (min)
`
`0
`
`5
`
`10
`
`15
`
`Fig. 2 Effect of a IO min infusion of sodium ferric gluconate complex (Ferrlecit®; Aventis Pharma, Dagenham, Essex, England) at doses of (a,c) 12.5 and
`(b,d) 31.2 mg/kg on mean arterial pressure (MAP; a,b) and heart rate (HR; c,d) in anaesthetized dogs. Data are the mean±SEM (11 = 6). *P < 0.05 compared
`with baseline.
`
`© 2005 Blackwell Publishing Asia Pty Ltd
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1068 - Page 3
`
`

`

`Haemodynamic effects of ABT-870
`
`1023
`
`baseline values. Heart rate increased to 61 ::': 19 b.p.m. above
`baseline during SFGC infusion and remained elevated into the
`post-treatment period. The substantial hypotensive response
`observed following administration of SFGC at 31.2 mg/kg
`precluded treatment at higher doses.
`
`Rapid infusion (30 s) of ABT-870 at 7. 1 and 14.3 mg/kg
`produced no statistically significant haemodynamic effects and
`rapid infusion of iron sucrose at 7.1 mg/kg produced no statistically
`significant effects on blood pressure or HR (Table 1). However,
`rapid infusion of iron sucrose at 14.3 mg/kg produced highly
`
`200
`
`(a)
`
`200
`
`(b)
`
`oi 150
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`c..
`~ 50
`
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`
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`
`0
`
`200
`
`(c)
`
`150
`
`E
`ci. 100 Bill
`e
`a:'.
`I
`
`50
`
`0
`
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`
`-5
`
`0
`
`5
`
`10
`
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`
`Infusion
`
`150
`
`100
`
`50
`
`0
`
`200
`
`(d)
`
`150
`
`Jhi 1oo l t f± / : f -
`
`50
`
`0
`
`15
`-5
`Time (min)
`
`Infusion
`
`0
`
`5
`
`10
`
`15
`
`Fig. 3 Effect of a 10 min infusion of (a,c) ABT-870 or (b,d) iron sucrose (Venofer®; American Reagent Laboratories, Shirley, NY, USA) at doses of
`7.1 mg/kg on mean arterial pressure (MAP; a,b) and heart rate (HR; c,d) in anaesthetized dogs. Data are the mean±SEM (11 = 6). *P < 0.05 compared with
`-
`baseline.
`
`200
`
`(a)
`
`oi 150
`I
`E .s 100
`c..
`<(
`::!=
`
`50
`
`0
`
`200
`
`(c)
`
`******
`
`Infusion
`
`150
`
`E
`ci. e 100
`
`a:'.
`I
`
`Infusion
`
`50
`
`0
`
`200
`
`(b)
`
`150
`
`100
`
`50
`
`0
`
`200
`
`(d)
`
`150
`
`100
`
`50
`
`0
`
`*
`
`Infusion
`
`***
`
`Infusion
`
`-5
`
`0
`
`5
`
`10
`
`15
`
`-5
`Time (min)
`Fig.4 Effect of a 10 min infusion of (a,c) ABT-870 or (b,d) iron sucrose (Venofer®; American Reagent Laboratories, Shirley, NY, USA) at doses of
`21.3 mg/kg on mean arterial pressure (MAP; a,b) and heart rate (HR; c,d) in anaesthetized dogs. Data are the mean±SEM (11 = 6). *P < 0.05 compared with
`baseline.
`
`0
`
`5
`
`10
`
`15
`
`© 200S Blackwell Publishing Asia Pty Ltd
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1068 - Page 4
`
`

`

`1024
`
`LC Preusser et al.
`
`variable effects on MAP (range from -20 mmHg below baseline to
`5 mmHg above baseline) and HR (from-16 b.p.m. below baseline
`to 50 b.p.m. above baseline). Increases in HR following iron
`sucrose at 14.3 mg/kg were statistically elevated relative to baseline
`(23 ::':: 7.8 b.p.m.).
`Infusion of ABT-87O or iron sucrose for JO min at 7.1 mg/kg
`(Fig. 3) did not produce any physiologically relevant effects on
`MAP or HR.
`Infusion of ABT-87O for IO min at 21 .3 mg/kg (Fig. 4) produced
`no physiologically relevant effects on HR and only a modest
`increase in MAP (to 6 ::':: 2 mmHg above baseline at the end of
`infusion). The JO min infusion of iron sucrose at 21.3 mg/kg
`produced a decrease in MAP to -34 ::':: 6 mmHg below baseline at
`the end of compound infusion. This reduction in MAP was
`followed by a
`transient
`increase
`in blood pressure
`(to
`13 ::':: 5 mmHg) during the postinfusion period. At 21 .3 mg/kg, iron
`sucrose also produced tachycardia; HR increased to 56 ::':: 13 b.p.m.
`above baseline near the end of iron sucrose infusion and remained
`elevated for part of the postinfusion period.
`Infusion of ABT-87O for IO min at 50 mg/kg (Fig. 5) produced
`an increase in MAP to 22 ::':: 2 mmHg above baseline. Heart rate
`increased in a similar fashion to MAP, reaching 28 ::':: 8 b.p.m.
`above baseline at the end of compound administration. Both
`MAP and HR decreased during the post-treatment period (to
`13 ::':: 2 mmHg and 16 ::':: 4 b.p.m. above baseline, respectively) by
`15 min postinfusion. Infusion of iron sucrose for IO min at
`in MAP (to
`50 mg/kg (Fig. 5) produced a rapid decline
`-83 ::':: 5 mmHg below baseline); MAP then climbed steadily
`towards baseline values. Heart rate increased to 57 ::':: 9 b.p.m.
`above baseline, concomitant with the fall in blood pressure.
`
`DISCUSSION
`
`Parental iron therapy is used to replenish body iron stores in
`patients with iron deficiency on chronic haemodialysis and
`receiving erythropoietin. In
`these patients,
`iron stores are
`frequently low owing to a combination of factors, such as
`decreased iron intake and reduced gastrointestinal absorption,
`blood loss during the dialysis procedure and increased erythro(cid:173)
`poiesis.26 Despite the necessity of i.v. iron infusion for ESRD
`patients, it has been demonstrated that iron therapy can produce
`hypotension in the clinic. 19-21 ·27 In the present study, we demon(cid:173)
`strate that ABT-87O, at doses as high as 50 mg/kg, unlike iron
`sucrose and SFGC, produced no uniform hypotensive effects in the
`pentobarbital-anaesthetized beagle.
`We speculate that i.v. iron administration in the form of iron
`(III)-hydroxide oligosaccharide (ABT-87O), which contains an iron
`core of a stable ferric hydroxide structure that is surrounded by a
`low molecular weight protective carbohydrate coating, ensures the
`slow release of unbound iron and, therefore, produces limited to no
`hypotension when administered during a rapid infusion and at
`high doses. In addition, Promit®, which makes up the dextran
`component of ABT-870, produced no physiologically relevant
`haemodynamic changes when administered during a rapid infusion
`or when infused over IO min. However, hypotension was observed
`in animals receiving i.v. iron in the form of iron sucrose and SFGC.
`In agreement with the present study, the more recently approved
`parental iron compounds (iron sucrose and SFGC) have been
`associated with potential oversaturation reactions in humans,
`including hypotension and flushing. 19·20·27 These effects may be a
`result of the accumulation of bioactive iron in the circulation and
`
`200
`
`(a)
`
`200
`
`(b)
`
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`Fig. 5 Effect of a 10 min infusion of (a,c) ABT-870 (n = 6) or iron sucrose (Venofer®; American Reagent Laboratories, Shirley, NY, USA; n = 5) at doses
`of 50 mg/kg mean arterial pressure (MAP; a,b) and heart rate (HR; c,d) in anaesthetized dogs. Data are the mean±SEM. *P < 0.05 compared with baseline.
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`© 2005 Blackwell Publishing Asia Pty Ltd
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1068 - Page 5
`
`

`

`Haemodynamic effects of ABT-870
`
`1025
`
`could, potentially, be exacerbated in patients with low transferrin
`levels (<180 mg/dL). 28•29 In clinical trials, of 231 dialysis patients
`with chronic renal failure who were administered 100 mg, i.v., iron
`as iron sucrose, 36% experienced hypotension;20 in separate single(cid:173)
`and multiple-dose safety studies, postadministration hypotensive
`events were also observed in 2 and 4% of patients, respectively,
`following sodium SFGC administration. 19·27 These results are
`consistent with the present study in the anaesthetized beagle,
`supporting the clinical relevance of this model to assess the
`potential haemodynamic effects of iron-containing haematinic
`agents. We demonstrate that both iron sucrose and SFGC, at
`clinically relevant doses, produced highly variable effects on MAP
`(including hypotension) and HR in individual animals at low doses
`and severe hypotension and tachycardia at higher doses (up to
`50 mg/kg and 31.2 mg for iron sucrose and SFGC, respectively).
`To maximize the clinical usefulness of these agents, it may be
`desirable to administer these drugs less frequently and at higher
`doses per dialysis session.25 However, neither iron sucrose nor
`SFGC have been approved for 'total dose' infusions. 25 In the
`present study, we demonstrated that ABT-870, at both therapeutic
`and supratherapeutic doses, produced no consistent hypotensive
`effects when administered over IO min to the anaesthetized beagle
`dog. In addition, when ABT-870 was administered as a rapid
`infusion (over 30 s), ABT-870 produced no hypotensive effect at
`the highest dose tested. These data are in sharp contrast with the
`profound haemodynamic effects produced by iron sucrose or
`SFGC in the same model.
`The haemodynamic effects of iron sucrose were more variable
`than ABT-870. Although neither ABT-870 nor iron sucrose
`produced consistent haemodynamic effects during a rapid 30 s
`rapid infusion at 7 .1 mg/kg, when iron sucrose was administered at
`14.3 mg/kg, variable and marked biphasic effects on both HR and
`MAP were observed in individual animals
`Neither ABT-870 nor iron sucrose produced any physiologically
`relevant effects on MAP and HR at 7.1 mg/kg infused over 10 min.
`However, when iron sucrose was administered at higher doses
`(21 .3 and 50 mg/kg) during a 10 min infusion, the compound
`produced highly variable haemodynamic effects, including marked
`hypotension and tachycardia. Because the increase in HR was
`associated with a steep reduction in MAP, the marked tachycardia
`observed with iron sucrose suggests a reflex-mediated compen(cid:173)
`satory response initiated by extensive systemic vasodilation. In
`with iron sucrose, ABT-870 produced no consistent hypotension at
`any dose tested. In fact, infusion of ABT-870 at 21.3 mg/kg
`produced a modest increase in MAP (4--13 mmHg above baseline)
`without any physiologically relevant effects on HR and, at
`50 mg/kg, ABT-870 produced increases in both HR and MAP
`that began to trend towards baseline within 5 min following
`infusion. Because MAP and HR increased simultaneously, these
`data may suggest that the increase in MAP produced by ABT-870
`is mediated by transient cardiac stimulation independent of marked
`reductions in vascular tone.
`In a recently published study performed in haemodialysis
`patients, there were no significant differences in postadministrative
`hypotensive events following a 10 min infusion of SFGC at 125 mg
`compared with placebo30 and, in a separate higher-dose study,
`when SFGC was administered at doses ;::c 250 mg over I h, no
`undesirable haemodynamic effects were reported. 24 However, the
`potential haemodynamic effects resulting from higher doses (as
`
`evaluated in the present study) or faster infusion rates of SFGC
`were not evaluated systematically in either clinical trial. We have
`demonstrated that the slow infusion of SFGC at a dose of
`12.5 mg/kg produces variable effects on MAP and HR. Indeed,
`following the 10 min infusion of SFGC, MAP fell to -79 and
`-90 mmHg below baseline in two of six animals, concomitant with
`increases in HR (to 76 and 35 b.p.m. above baseline, respectively).
`The effects of SFGC were exacerbated, and more consistent, at
`higher concentrations; at 31.2 mg/kg, SFGC produced a fall in
`MAP to -34 ±: 11 mmHg below baseline that was followed by an
`increase in HR (56 ±: 13 b.p.m.).
`Therefore, at doses deemed therapeutic and supratherapeutic (up
`to 50 mg/kg), ABT-870 produced no consistent hypotensive effects
`in the anaesthetized beagle. These data are in marked contrast with
`the haemodynamic effects, including hypotension and tachycardia,
`produced by iron sucrose and SFGC at similar or lower doses.
`Therefore, ABT-870 may have a substantially wider therapeutic
`index for iron-replacement therapy compared with other iron(cid:173)
`containing haematinic agents and may be able to be administered
`via a rapid infusion (30 s) at doses up to 14.3 mg or during a slower
`infusion (10 min) at doses up to 21.3 mg without producing any
`physiologically relevant changes in MAP or HR.
`
`ACKNOWLEDGEMENTS
`
`The authors gratefully acknowledge the insight of Dr Dheerendra
`R Kommala (Abbott Laboratories, Abbott Park, IL, USA) in the
`completion of this study. The authors also thank Pamela Rakestraw
`(Abbott Laboratories, Abbott Park, IL, USA) for carefully auditing
`the data to ensure the accuracy of the results.
`
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`© 2005 Blackwell Publishing Asia Pty Ltd
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`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1068 - Page 6
`
`

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