Nephrology
`
`American Journal of
`
` Original Report: Patient-Oriented, Translational Research
`
` Am J Nephrol 2005;25:400–410
` DOI: 10.1159/000087212
`
` Received: March 18, 2005
` Accepted: June 13, 2005
` Published online: July 28, 2005
`
` Pharmacokinetic Study of Ferumoxytol:
`A New Iron Replacement Therapy in Normal
`Subjects and Hemodialysis Patients
`
` a,
`
` Robert Landry
` a
`W. Kline Bolton
`
`
`
`
`
`d Paula M. Jacobs b Robert Davis a Magdy Shenouda c
`
`
`
`
`
`
`
` a Division of Nephrology, University of Virginia Health System, Charlottesville, Va. ; b Advanced Magnetics, Inc.,
`
`
`
`
` Cambridge, Mass. ; c Jersey Shore Medical Center, Neptune, N.J. , and d Renal Associates of Baton Rouge,
` Baton Rouge, La. , USA
`
`
`
`
`
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` Key Words
` Intravenous iron ⴢ Ferumoxytol ⴢ Iron pharmacokinetics ⴢ
`Renal anemia ⴢ Chronic kidney disease
`
` Abstract
` Background: Currently available intravenous iron prepa-
`rations are not ideal, either because of safety concerns
`or dose limitations. We investigated the safety and phar-
`macokinetics of ferumoxytol, a new iron replacement
`therapy, in normal subjects and hemodialysis patients.
` Methods: In a randomized, double-blind, ascending-
`dose study in normal volunteers (n = 41), 6 subjects re-
`ceived placebo, and 8 subjects each received ferumoxy-
`tol, at 1, 2 or 4 mg iron/kg, injected at 60 mg iron/min.
`The remaining subjects received 4 mg iron/kg at injection
`rates of 90 (n = 3), 180 (n = 3) or 1,800 mg iron/min (n =
`5). In the second, open-label, ascending-dose study,
`20 hemodialysis patients received 125 or 250 mg of iron
`over 5 min. Results: In normal subjects, the blood half-
`life of ferumoxytol increased with increasing dose from
`
` This work was performed at the University of Virginia Health Sys-
`tem and at Jersey Shore Medical Center.
`
`9.3 to 14.5 h (p ! 0.05) but not with increasing rate of in-
`jection. The drug half-life in hemodialysis patients was
`similar to normal subjects. Ferumoxytol was not re-
`moved with hemodialysis. Serum iron (p ! 0.001), trans-
`ferrin saturation (p ! 0.001) and ferritin increased in both
`populations. No serious adverse events were attribut-
`able to ferumoxytol. Conclusion: Ferumoxytol was well
`tolerated in this study. Its pharmacokinetic properties
`and simplicity of administration suggest that it will be an
`attractive form of iron replacement therapy.
` Copyright © 2005 S. Karger AG, Basel
`
` Introduction
`
` Normocytic, normochromic anemia is a common and
`treatable complication of chronic kidney disease (CKD)
`and end-stage renal disease (ESRD). According to the
`USRDS 2001 annual data report, there is a signifi cant
`increase in the relative risk of cardiac, infectious, and all-
`cause mortality in ESRD patients with hematocrits ! 33%
` [1] and an even greater risk in patients with hematocrits
` ! 30%. Although multiple factors contribute to the ane-
`mia of CKD, the primary cause is insuffi cient production
`of endogenous erythropoietin (EPO). Effective treatment
`
` © 2005 S. Karger AG, Basel
`0250–8095/05/0254–0400$22.00/0
`
`Fax +41 61 306 12 34
`E-Mail karger@karger.ch
`www.karger.com
`
` Accessible online at:
`www.karger.com/ajn
`
` W. Kline Bolton, MD
`Division of Nephrology, Box 800133
`University of Virginia Health System
`Charlottesville, VA 22908-0133 (USA)
`Tel. +1 434 924 5125, Fax +1 434 924 5848, E-Mail wkb5s@virginia.edu
`
`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
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`of this anemia is associated with improved survival, de-
`creased morbidity, and increased quality of life. Higher
`hematocrits have also been associated with marked im-
`provements in various physiological parameters includ-
`ing oxygen utilization, muscle strength and function, car-
`diac function, possible regression of left ventricular hy-
`pertrophy, improvement in exercise tolerance and
`exercise-induced ST segment depression, cognitive and
`sexual function [2–7] .
` EPO use in hemodialysis patients has led to the suc-
`cessful treatment of anemia in most ESRD patients [8] .
`However, several factors can decrease the effectiveness
`of EPO including aluminum toxicity, hyperparathyroid-
`ism, infection, infl ammatory conditions, malignancy,
`and, most importantly, iron defi ciency [9] . Absolute iron
`defi ciency in hemodialysis patients occurs for a variety of
`reasons, including blood retention in the dialysis mem-
`branes and connecting tubing system [9], occult gastroin-
`testinal blood loss [10, 11], blood loss during surgery, fre-
`quent blood sampling [12], and increased erythropoiesis
`from the use of EPO [12] . Functional iron defi ciency also
`occurs where adequate tissue iron stores are present but
`unavailable for erythropoiesis.
` The estimated prevalence of iron defi ciency in hemo-
`dialysis patients during EPO therapy is around 43–90%
` [9, 13, 14] . According to the National Kidney Founda-
`tion-Kidney Disease Outcomes Quality Initiative (KDO-
`QI) anemia guidelines [2] , patients should have suffi cient
`iron to achieve and maintain a hemoglobin of 11–12 g/dl
`and a hematocrit of 33–36%. To accomplish this, the
`guidelines suggest administering suffi cient iron to a main-
`tain transferrin saturation (TSAT) of 6 20% and a serum
`ferritin 6 100 ng/ml [2] . Many studies have shown that
`oral iron is generally ineffective in maintaining adequate
`stores in most dialysis patients [3, 15, 16] , as well as in
`patients not yet on dialysis [3, 16, 17] . Consequently, in-
`travenous iron is commonly used to achieve and main-
`tain adequate iron levels. Although intravenous iron re-
`placement can be given over 10 min (125 mg iron gluco-
`nate) or 5 min (100 mg iron sucrose), it is generally given
`over 15–60 min, which requires signifi cant expense for
`supplies such as tubing and infusion supplies, costly nurs-
`ing time, multiple administrations, and may be inconve-
`nient for the patient.
` Until 1999, iron dextran was the only intravenous iron
`preparation available in the USA. Since then, iron gluco-
`nate and iron sucrose have become available for intrave-
`nous use. Although serious and life-threatening reactions
`occur most frequently with iron dextran [18] , they do oc-
`cur rarely with iron gluconate and iron sucrose [19, 20] .
`
`In addition, non-life-threatening reactions such as hypo-
`tension, back pain, vomiting, vertigo, and pruritus also
`occur with the gluconate and sucrose formulations and
`may be related to the rate of administration [20, 21] .
`These reactions, although not life-threatening, will some-
`times preclude further dosing and therefore iron repletion
` [19, 22–24] . Finally, there is concern regarding the poten-
`tial deleterious effects of parenteral iron in increasing ox-
`idative stress and infection, and accelerating cardiovas-
`cular disease.
` We examined the safety and pharmacokinetics of a
`new compound for iron replacement therapy, ferumoxy-
`tol, administered as an intravenous bolus, fi rst in 41
`healthy volunteers in a placebo-controlled, dose and in-
`jection rate escalation study, and then in 20 chronic he-
`modialysis patients receiving EPO therapy.
`
` Materials and Methods
`
` Ferumoxytol
` The study drug, ferumoxytol (Advanced Magnetics, Inc., Cam-
`bridge, Mass., USA), is an ultrasmall superparamagnetic iron oxide
`(magnetite) nanoparticle coated with a semisynthetic carbohydrate
`designed to minimize immunological sensitivity. The drug has an
`average colloidal particle size of 30 nm by light scattering and a
`molecular weight of 750 kDa. Ferumoxytol is a sterile, isotonic,
`neutral pH liquid formulated to contain 30 mg/ml of elemental iron
`and 44 mg/ml of mannitol. Because of its magnetic properties, feru-
`moxytol can also be used as a magnetic resonance contrast agent.
`
` Study Designs
` Both trials were approved by Institutional Review Boards and
`conducted in accordance with the guidelines proposed in the Dec-
`laration of Helsinki, under an Investigational New Drug Exemp-
`tion. All patients gave written informed consent to be in the
`study.
` Normal Subjects. This phase I safety and pharmacokinetic study
`was a randomized, double-blind, placebo-controlled, ascending-
`dose study in adult male and female volunteers (n = 41). Subjects
`were 18–60 years old, not anemic, and in good general health. Eight
`subjects each received ferumoxytol at doses of 1, 2 and 4 mg iron/
`kg at injection rate of 60 mg iron/min (2 ml/min). Six subjects re-
`ceived saline as a placebo. The remaining 11 subjects received feru-
`moxytol at 4 mg iron/kg at an injection rate of 90 (n = 3), 180 (n =
`3) or 1,800 mg iron/min (n = 5).
` For pharmacokinetic analysis, serial blood samples were taken
`pre-dose, 5, 10, 15, 30 min, and 1, 4, 8, 12, 24, 48, 72 and 168 h
`post-dosing. For safety assessment, blood and urine samples were
`taken at screening, 48 and 24 h pre-dosing, at 8, 24, 48 and 72 h,
`and 7 days post-dosing. Evaluations included a complete blood
`count, biochemistry panel, iron metabolism panel (serum iron, per-
`cent TSAT, transferrin, and ferritin) and clotting function tests.
`Resting 12-lead electrocardiograms were obtained at screening, and
`48 h pre-dosing, at 15 min, 1, 4, 8, and 24 h, and 7 days post-dos-
`
` Ferumoxytol Iron Therapy
`
` Am J Nephrol 2005;25:400–410
`
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`ing. Vital signs were obtained at the same time points and addition-
`ally at 1, 5, 10, 30, 45 min, and 2, 4, 48 and 72 h.
` Hemodialysis Patients. The study in hemodialysis patients was
`an open-label, dose escalation study to assess the safety and phar-
`macokinetics of two doses of ferumoxytol in non-anemic chronic
`hemodialysis patients (n = 20) receiving EPO therapy for anemia.
`Subjects were at least 18 years old, currently undergoing outpatient
`hemodialysis three times a week and receiving EPO therapy; he-
`moglobin 6 11 g/dl and/or hematocrit 6 33% was required. Pa-
`tients had not received oral or parenteral iron therapy for at least
`2 weeks prior to entry; nor did they receive it for the duration of
`the study.
` Two doses of ferumoxytol, containing 125 and 250 mg of ele-
`mental iron, were evaluated, given as an intravenous injection over
`5 min, with the safety of the fi rst dose established before proceed-
`ing to the higher dose. The fi rst 10 patients were given a single dose
`of 4.2 ml of ferumoxytol (125 mg iron, 25 mg iron/min) and the
`second group of 10 patients was given a single dose of 8.4 ml of
`ferumoxytol (250 mg iron, 50 mg iron/min). Ferumoxytol was ad-
`ministered within 30 min of starting dialysis in all patients. No test
`dose was given.
` Laboratory tests including complete blood count, electrolytes,
`comprehensive chemistry, hepatic function, iron metabolism pan-
`el and clotting function panel were drawn 1 week pre-dose, and at
`48 h, 2 weeks, and 4 weeks following dosing. A panel consisting of
`complement levels (CH 50 and C3) and a complete blood count with
`differential was drawn immediately pre-dose and at 60 and 180 min
`post-dose to assess complement activation.
` Blood clearance samples were drawn immediately pre-dose and
`post-dose at 5, 10, 15, 30, 60, 120, 180 min, 48 h, and 96 h. Patients
`were evaluated for evidence of adverse reactions during and after
`the drug administration and at 48 and 96 h following drug admin-
`istration.
`
` Drug Concentration Quantifi cation
` Because ferumoxytol has strong magnetic properties (T1 relax-
`ivity of 38 mmol s –1 and T2 relaxivity of 83 mmol s –1 ) the intact,
`unmetabolized drug can be quantifi ed by magnetic resonance spec-
`trometer measurements [25] , independent of serum iron, which has
`very low magnetic properties. The T1 spin-spin magnetic resonance
`relaxation time of the serum samples, standards, and controls were
`measured at 39.5 ° C using a Brucker PC-120 nuclear magnetic res-
`onance spectrometer with an applied fi eld of 0.47 T (20 MHz) using
`an inversion-recovery pulse sequence. The limit of detection of the
`assay was 3 ␮ g/ml of ferumoxytol iron.
`
` Safety Evaluation
` Vital signs (blood pressure, heart rate, respiration rate and tem-
`perature) were evaluated at multiple time points before and after
`the drug administration in both studies. In addition, for the hemo-
`dialysis patients, the change in blood pressure recorded for each
`patient on the day of ferumoxytol injection was compared to the
`intradialytic blood pressure measurements recorded for that pa-
`tient during the dialysis session 1 week prior to drug administra-
`tion. Hypotension was considered an adverse event if the decrease
`in blood pressure was clinically signifi cant based on the opinion of
`the investigator, regardless of the degree or absolute value.
` Adverse events were identifi ed by direct questioning and obser-
`vation during drug administration, the post-administration obser-
`vation period, and at later time points up to a week for the normal
`
`subjects and a month for the hemodialysis patients. A serious ad-
`verse event was defi ned as one which constitutes a defi nite hazard
`and/or results in a handicap to the patient, including but not lim-
`ited to: death; a life-threatening adverse drug experience; inpatient
`hospitalization or prolongation of existing hospitalization; a persis-
`tent or signifi cant disability/incapacity; chest pain, dyspnea or oth-
`er evidence of anaphylaxis.
`
` Statistical Analysis
` Data are presented as mean 8 SD. Two-way analysis of vari-
`ance (ANOVA) with between-groups repeated measures was used
`to evaluate differences in laboratory measures and pharmacoki-
`netic parameters between groups. The pharmacokinetic parameters
`were calculated assuming a fi rst order process in a single compart-
`ment model, with a fi rst order elimination rate constant (K el ), area
`under the curve (AUC) calculated by trapezoidal rule (t 0h –t 48h ),
`maximum concentration (C max ) estimated as the instantaneous
`concentration at t = 0 and clearance calculated as volume of distri-
`bution (V d ) ! K el . Parameters were calculated using PK Solutions
`2.0 (Summit Research Services, Pharmacokinetics and Metabolism
`Software, Montrose, Colo., USA).
`
` Other Analyses
` Although these were not effi cacy trials, and neither volunteers
`nor hemodialysis patients were anemic, changes in hematologic
`parameters including serum iron, serum ferritin, TSAT, hemoglo-
`bin, hematocrit, and reticulocyte count were evaluated for evidence
`of iron utilization.
`
` Results
`
` Demographics
` Normal Subjects. The study population was comprised
`of comparable numbers of men and women, and was pre-
`dominantly black (63%), with an average age of 33.5 8
`7.7 years ( table 1 ). Seven of these patients had ferritin
`levels ! 12 ng/ml; none had hemoglobin values ! 10.8 g/dl.
`The four treatment groups did not differ signifi cantly
`with respect to gender, race, age, height, and weight.
` Hemodialysis Patients. The study population included
`20 patients (age 34–77 years; 10 women, 10 men, 70%
`black, see table 1 ) currently undergoing hemodialysis
`three times weekly at an outpatient dialysis unit. The fi rst
`10 patients recruited were assigned to the low-dose group
`(125 mg iron). After this dose was found to be well toler-
`ated in this patient population, 10 additional patients
`were recruited to the high-dose group (250 mg iron).
`
` Pharmacokinetics
` Normal Subjects. The pharmacokinetic summary data
`including V d , K el , AUC, C max , half-life, and clearance for
`the dose escalation arm of the trial are shown in table 2 .
`The AUC and C max increased signifi cantly with dose, as
`
`402
`
` Am J Nephrol 2005;25:400–410
`
` Landry /Jacobs /Davis /Shenouda /Bolton
`
`
`
`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
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`Table 1. Subject characteristics
`
`Number
`Age
`Gender, m/f
`Race, B/W/H/O
`Weight, kg
`Height, cm
`Hemoglobin, g/dl
`Transferrin saturation, %
`Serum iron, ␮g/ml
`Ferritin, ng/ml
`
`Normal subjects
`
`Hemodialysis patients
`
`41
`33.587.7 (20–58)
`22/19
`26/8/7/0
`79.6815.1 (46.5–115.0)
`171.289.8 (153.0–189.0)
`13.081.2 (10.8–16.0)
`21.487.6 (7.4–40.2)
`69.0820.7 (20–107)
`41.0832.5 (4–109)
`
`20
`60.7811.8 (34–77)
`10/10
`14/5/0/1
`84.2814.5 (55–107)
`168.487.8 (157–183)
`12.481.0 (10.7–12.9)
`29.689.7 (14–47)
`58.8819.8 (32–99)
`2598154 (86–677)
`
`Table 2. Pharmacokinetic parameters at
`increasing dose, constant injection ratea
`
`Parameter
`
`Rate, ml/min
`Rate, mg iron/min
`Number
`Mean dose, mg
`Kel, h–1b
`Half-life, hb
`Cmax, ␮g iron/mlb
`AUC, ␮g ironⴢh/mlb
`Vd, l
`Vd, ml/kg
`Cl, ml/hb
`Cl, ml/(hⴢkg)c
`
`Dose group
`
`1 mg Fe/kg
`
`2
`60
`8
`85817
`0.07680.010
`9.381.1
`26.387.0
`3968122
`3.180.8
`36.3810.0
`235.8891.8
`2.8281.21
`
`2 mg Fe/kg
`
`4 mg Fe/kg
`
`2
`60
`8
`152830
`0.06980.010
`10.281.5
`62.0811.6
`9978320
`2.480.7
`31.187.4
`162.9852.4
`2.1780.63
`
`2
`60
`8
`321871
`0.04980.007
`14.582.4
`126.0832.6
`2,7718624
`2.480.6d
`31.688.5
`115.7815.1
`1.5180.33
`
`a Values are mean 8 SD. Kel = First order rate constant; AUC = area under the curve;
`Cmax = maximum plasma concentration of intact drug; half-life = elimination half-life; Cl =
`clearance; Vd = volume of distribution.
`b Signifi cant by dose, p < 0.001.
`c Signifi cant by dose, p < 0.02.
`d Signifi cant by gender, p < 0.01 (see text).
`
`did the half-life, while clearance decreased (p ! 0.001).
`The elimination half-life increased from 9.3 to 14.5 h
`from 1 to 4 mg of iron/kg. The high-dose group showed a
`statistically signifi cant difference in V d by gender, also
`observed in all groups but not at statistically signifi cant
`levels. This difference is attributable to a lower body
`weight in the females, since total blood volume is propor-
`tional to body weight. The V d per kilogram was not sig-
`nifi cantly different.
` The pharmacokinetic results from the injection rate
`escalation are shown in table 3 . There were no signifi cant
`differences in the pharmacokinetic parameters with in-
`creasing administration rates. Including all subjects who
`
`received the dose of 4 mg iron/kg, a mean dose of 316 mg
`of iron in this study, the mean half-life is 14.7 h. The high-
`est individual dose administered in this study was 420 mg
`of iron.
` The concentration of ferumoxytol with time is shown
`in fi gure 1 . The concentrations are dose-dependent (p !
`0.001), and 90% of the highest dose is cleared from the
`blood by 48 h, approximately 3 half-lives.
` Hemodialysis Patients. The pharmacokinetic summa-
`ry data including V d , K el , AUC, C max , half-life, and clear-
`ance are presented in table 4 . The plasma pharmacoki-
`netic parameters were similar to those observed in normal
`subjects. The half-life was different by dose (p ! 0.01) as
`
` Ferumoxytol Iron Therapy
`
` Am J Nephrol 2005;25:400–410
`
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`
` Fig. 1. Serum concentration of ferumoxytol
`with time in normal subjects by dose. ` =
`Placebo; d = 1 mg/kg; + = 2 mg/kg; I =
`4 mg/kg. Concentration of ferumoxytol was
`dose-dependent (p ! 0.001). The values are
`for intact drug and do not include serum
`iron.
`
`Table 3. Pharmacokinetic parameters at increasing injection rate, constant dosea
`
`Parameter
`
`Administration rate group
`
`Dose, mg iron/kg
`Rate, ml/min
`Rate, mg iron/min
`Number
`Mean dose, mg Fe
`Kel, h–1
`Half-life, h
`Cmax, ␮g iron/ml
`AUC, ␮g ironⴢh/ml
`Vd, l
`Vd, ml/kg
`Cl, ml/h
`Cl, ml/(hⴢkg)
`
`4b
`2
`60
`8
`321871
`0.04980.007
`14.582.4
`126.0832.6
`2,7718624
`2.480.6
`31.688.5
`115.7815.1
`1.5180.33
`
`4
`3
`90
`3
`323869
`0.04980.008
`14.582.3
`124.7831.1
`2,8578336
`2.480.9
`29.686.3
`116.1840.0
`1.4180.18
`
`4
`6
`180
`3
`337845
`0.05180.005
`13.681.4
`141.4850.0
`2,9148984
`2.480.5
`29.089.3
`121.2827.1
`1.4780.43
`
`4
`60
`1,800
`3
`273881
`0.04380.006
`16.282.5
`134.5830.3
`3,3438963
`2.080.4
`29.185.7
`83.289.7
`1.2880.43
`
`4
`–
`–
`17
`316866
`0.04880.007
`14.782.2
`130.0832.5
`2,9128683
`2.380.6
`30.487.3
`111.0824.1
`1.4480.33
`
`a Values are mean 8 SD. Kel = First order rate constant; AUC = area under the curve; Cmax = maximum plas-
`ma concentration of intact drug; half-life = elimination half-life; Cl = clearance; Vd = volume of distribution.
`b Data in this group repeated from table 2, column 3, for comparison.
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`were C max , AUC, and clearance (p ! 0.001). The half-life
`was 10.7 h in the low-dose group and 16.2 h in the high-
`dose group, similar to that observed in normal subjects.
` The concentration of ferumoxytol remained stable
`during the dialysis procedure, indicating that ferumoxy-
`tol is not removed with hemodialysis ( fi g. 2 ).
`
` Laboratory Values
` Normal Subjects. As expected, serum iron and TSAT
`increased in a dose-dependent manner, peaking at 1-day
`post-dose, whereas serum ferritin peaked at day 3; all re-
`turned toward baseline at 7 days. The changes in all were
`statistically signifi cant (p ! 0.001). The serum iron, TSAT,
`and serum ferritin are shown in fi gure 3 .
`
`404
`
` Am J Nephrol 2005;25:400–410
`
` Landry /Jacobs /Davis /Shenouda /Bolton
`
`
`
`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
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`Luitpold Pharmaceuticals, Inc., Ex. 2040, P. 5
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`Table 4. Pharmacokinetic parameters in hemodialysis patientsa
`
`Parameter
`
`Dose group
`
`Rate, ml/min
`Number
`Mean dose, mg Fe/kg
`Kel, h–1b
`Half-life, hb
`Cmax, ␮g iron/mlc
`AUC, ␮g ironⴢh/mlc
`Vd, l
`Vd, ml/kg
`Cl, ml/h
`Cl, ml/(hⴢkg)
`
`125 mg iron
`
`250 mg iron
`
`24
`10
`1.580.2
`0.07380.029
`10.783.6
`44.3815.2
`1,1878484
`1.880.8
`20.687.5
`121.4847.0
`1.4380.57
`
`48
`10
`3.280.6
`0.04580.008
`16.283.3
`88.7826.1
`2,8318765
`2.381.0
`27.289.0
`95.4830.2
`1.1680.24
`
`a Values are mean 8 SD. Kel = First order rate constant;
`AUC = area under the curve; Cmax = maximum plasma concentra-
`tion of intact drug; half-life = elimination half-life; Cl = clearance;
`Vd = volume of distribution.
`b p < 0.01.
`c p < 0.001.
`
` Hemodialysis Patients. There were no acute changes
`in blood pressure after infusion of ferumoxytol. There
`was, however, a statistically signifi cant decrease in intra-
`dialytic systolic and diastolic blood pressures in both
`groups on the day of iron injection during the course of
`dialysis, p ! 0.05. To confi rm that the change in systolic
`and diastolic blood pressure over time was related to di-
`alysis and ultrafi ltration and not to administration of
`ferumoxytol, the change in systolic and diastolic blood
`pressure in this cohort during their dialysis treatments
`exactly 1 week prior to ferumoxytol administration was
`also evaluated. The results are shown in fi gure 5 . The pa-
`tients in both groups also experienced a signifi cant de-
`cline in intradialytic blood pressure 1 week prior to iron
`administration. The rate of decline for systolic and dia-
`stolic blood pressure during dialysis on the day of injec-
`tion was not signifi cantly different from the rate of decline
`1 week prior to injection.
` There were no serious adverse events recorded in the
`hemodialysis patients, no episodes of hypersensitivity or
`anaphylaxis, and no episodes of hypotension caused by
`administration of the study drug. Adverse events consid-
`ered remotely related to ferumoxytol administration in-
`cluded nausea and vomiting in 1 patient who reported
`nausea in the hours prior to starting dialysis and prior to
`receiving the study drug, and transient elevation of liver
`function tests in 1 patient.
`
` Fig. 2. Serum concentration of ferumoxytol with time in hemodi-
`alysis patients. + = 125 mg; d = 250 mg. Concentration of feru-
`moxytol was dose-dependent (p ! 0.001) and was constant during
`the hemodialysis session. The values are for intact drug and do not
`include serum iron.
`
` The TSAT rose signifi cantly (p ! 0.001) at day 1, but
`did not exceed 100%. The rise in ferritin was delayed,
`relative to the TSAT and demonstrated that the drug was
`being metabolized and added to the normal body iron
`stores in these non-anemic subjects.
` No changes were seen in hemoglobin or hematocrit, as
`expected. Reticulocytes increased from 1.1 to 1.3% by
`day 7 in the highest dose group but the changes did not
`reach statistical signifi cance.
` Hemodialysis Patients. No decrease in white blood cell
`count, platelet count, C3 or CH 50 was observed following
`administration of ferumoxytol showing a lack of comple-
`ment system activation (data not shown). No signifi cant
`changes in the chemistry values were observed except for
`1 patient who exhibited transient elevations of liver func-
`tion tests.
` There was a signifi cant increase in serum iron (p !
`0.001), TSAT (p ! 0.001), and ferritin (p ! 0.05 for the
`250-mg dose group only) at 48 h in both groups which
`returned toward baseline levels by the end of the study,
`as shown in fi gure 4 . There was no signifi cant change in
`hemoglobin or hematocrit from baseline in either group
`over time.
`
` Safety
` Normal Subjects. No consistent, clinically relevant, or
`unexpected changes were observed. Only one treatment-
`associated adverse event (metallic taste) was considered
`possibly related to ferumoxytol administration.
`
` Ferumoxytol Iron Therapy
`
` Am J Nephrol 2005;25:400–410
`
`405
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`
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` Fig. 3. Effect of ferumoxytol on serum iron ( a ), TSAT ( b ), and se-
`rum ferritin ( c ) in normal subjects. ` = Placebo; d = 1 mg/kg;
` + = 2 mg/kg; I = 4 mg/kg. The changes were signifi cant (p !
`0.001) for all doses.
`
` Fig. 4. Effect of ferumoxytol on serum iron ( a ), TSAT ( b ), and se-
`rum ferritin ( c ) in hemodialysis patients. d = 125 mg; + = 250 mg.
`There was an acute increase in serum iron (p ! 0.001), TSAT (p !
`0.001), and ferritin (p ! 0.05 for the 250-mg dose only) at 48 h after
`infusion of either dose of ferumoxytol which returned to or below
`baseline by the end of the observation period.
`
`406
`
` Am J Nephrol 2005;25:400–410
`
` Landry /Jacobs /Davis /Shenouda /Bolton
`
`
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`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
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`

`
` Fig. 5. Systolic and diastolic blood pres-
`sures in patients receiving ferumoxytol at
`both low and high doses decreased during
`dialysis (p ! 0.05) but there were no acute
`decrements in blood pressure and the de-
`crease during dialysis was comparable to
`that observed in a routine dialysis session
`the previous week. d = Drug administra-
`tion session; + = pre-administration ses-
`sion.
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` Discussion
`
` In this study, we demonstrated that the new intrave-
`nous iron drug ferumoxytol can safely be administered at
`rates as high as 1,800 mg of iron/min. The highest dose
`administered in these trials was 420 mg of iron to a nor-
`mal subject; in the high-dose group of normal volunteers,
`the mean dose was 316 mg. A total of 27 patients and
`subjects received a dose of at least 250 mg iron. The phar-
`macokinetic parameters were equivalent in normal sub-
`jects and in non-anemic hemodialysis patients. The drug
`was not removed by dialysis.
` Hemoglobin and hematocrit did not change after the
`administration of single doses of ferumoxytol in this
`study. Because these were not effi cacy trials, we enrolled
`normal subjects and patients who were at hemoglobin
`target by K/DOQI guidelines [2] . We did not expect an
`increase in hemoglobin with the regimen used in this
`study. The observed reticulocytosis in the high-dose nor-
`mal group suggests that an increase in erythropoiesis did
`occur because of iron administration. In addition, a sig-
`nifi cant increase in serum iron, TSAT, and serum ferritin
`in all groups was observed after administration of one
`dose of ferumoxytol, confi rming the bioavailability of the
`iron in ferumoxytol.
` Kidney disease is a substantial public health problem.
`The prevalence of decreased glomerular fi ltration rate in
`patients not on dialysis is estimated at approximately
`20 million with another 20 million at risk for CKD [26] .
`
`Iron defi ciency is present in 43–90% of hemodialysis pa-
`tients receiving EPO [5, 9, 14] . Many patients with de-
`creased glomerular fi ltration rate and those at risk for
`CKD will also require iron therapy to maintain an accept-
`able hematocrit.
` A safe, effective, and cost-effective agent to replete
`iron is imperative in this population given the large num-
`ber of individuals who will ultimately require it. Cur-
`rently available parenteral iron drugs, while effective at
`repleting iron stores, have risks associated with their use.
`Until recently, iron dextran was the only intravenous iron
`preparation available in the USA. Reactions have been
`reported in 4.7–43% of patients administered intrave-
`nous iron dextran [23, 27, 28] . Most of these reactions are
`mild, with 38% of patients given a total dose infusion [28]
`exhibiting delayed reactions of arthralgia, myalgia, and
`fever, but some patients experience anaphylactoid-type
`reactions (defi ned as any dyspnea, wheezing, chest pain,
`hypotension, urticaria, or angioedema) which can be seri-
`ous and life-threatening.
` The mechanism of allergic and anaphylactic reactions
`due to iron dextran is still poorly understood but is thought
`to be due to the dextran portion of the molecule which is
`known to be immunogenic [29] . Therefore, iron com-
`pounds such as sodium ferric gluconate complex in su-
`crose (Ferrlecit ® ) or iron sucrose (Venofer ® ) which do not
`contain dextran might be preferable. However, serious
`reactions also occur with these iron preparations.
`
` Ferumoxytol Iron Therapy
`
` Am J Nephrol 2005;25:400–410
`
`407
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`
` Faich and Strobos [30] found the rate of allergic and
`anaphylactic reactions for ferric gluconate was 3.3 per
`million doses compared to 8.7 per million doses for iron
`dextran. Pascual et al. [31] reported that 3 (5%) of 60 he-
`modialysis patients treated with ferric gluconate (125 mg)
`as a ‘slow injection’ had reactions severe enough to stop
`further treatment. Nissenson et al. [32] reported that 3 of
`88 (3.4%) patients given ferric gluconate had reactions
`severe enough to prevent further dosing. According to the
`drug package insert, 12 patients (0.8%) from a total of
`1,498 sodium ferric gluconate-treated patients experi-
`enced serious reactions which precluded further therapy
`with sodium ferric gluconate [19] . True allergic and/or
`anaphylactoid reactions with ferric gluconate, however,
`are exceedingly rare [33].
` Iron sucrose (Venofer ® ) has also been approved for use
`in the USA recently. In clinical trials of iron sucrose pri-
`or to FDA approval [24, 34] , no patients were discontin-
`ued due to adverse drug reactions and no anaphylactoid
`reactions were reported. In addition, only 27 anaphylac-
`toid reactions were reported among an estimated 450,000
`exposed patients between 1992 and 1999 from the spon-
`taneous reporting system [20] . However, adverse reac-
`tions including hypotension, back pain, vomiting, or ver-
`tigo have been reported in 0.9% of patients receiving 100-
`mg doses of iron sucrose and in 5.9% of patients receiving
`200-mg doses (non-approved dose) of iron sucrose [21] .
`In a study including even higher doses of iron sucrose,
`36% of the 22 patients given 500 mg of iron sucrose di-
`luted in 250 ml of saline as a 2-hour infusion had hypo-
`tension, 2 requiring hospitalization [35] . These reactions,
`especially hypotension, may be due to rate of administra-
`tion and total dose administered [20, 21] . These rate- and
`dose-related adverse reactions