Pharmacokinetics, safety and tolerability of ...

Ferric Carboxymaltose

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Pharmacokinetics, safety and tolerability of intravenous ferric carboxymaltose: a dose-escalation study in volunteers with mild iron-deficiency anaemia Peter Geisser1, José Banké-Bochita2 1 2

Vifor (International) Inc., St. Gallen, Switzerland Institute of Clinical Pharmacology, Parexel GmbH, Berlin, Germany

Correspondence to: Peter Geisser, PhD, Vifor (International) Inc., CH-9001 St. Gallen, Switzerland; e-mail: [email protected]

Abstract Iron-deficiency anaemia (IDA) represents a major burden to public health worldwide. The therapeutic aim for patients with IDA is to return iron stores and haemoglobin (Hb) levels to within the normal range using supplemental iron therapy and erythropoiesis-stimulating agents. Oral and previous intravenous (i. v.) iron formulations have a number of disadvantages, including immunogenic reactions, oxidative stress, low dosages, long administration times and the requirement for a test dose. Ferric carboxymaltose (FCM, Ferinject.) is a novel, next-generation i. v. iron formulation with the potential to overcome these limitations. In this single-centre, randomized, double-blind, placebo-controlled study, the pharmacokinetics (PK), pharmacodynamics (PD), safety and tolerability of single, escalating doses of FCM were investigated.

Key words n n n

n n

Anaemia Ferinject. Ferric carboxymaltose, pharmacodynamics, pharmacokinetics Intravenous iron Iron deficiency

Arzneimittelforschung 2010;60(6 a):362–372

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Four ascending doses were investigated in a total of 24 patients with mild IDA (defined as serum ferritin < 20 lg/l and transferrin saturation [TfS] < 16 %): 100 mg iron as FCM given as an i. v. bolus injection, and 500, 800 and 1000 mg iron as FCM given as an i. v. infusion over 15 min. At each dose level six patients received FCM and two received placebo. The decision to escalate to the next dose was based on evaluation of safety and tolerability data from the previous dose. The maximum duration of the study was 5 weeks from screening to final assessment. Assessments were made of PK ironstatus parameters up to 168 h post-dose. Safety assessments included incidence of adverse events (AEs), clinical laboratory parameters and vital signs. PK and PD parameters were analysed using descriptive statistics. All analyses were performed on the safety population, which included all patients who received ‡ 1 dose of study medication. Seventy-seven patients were screened and, of these, 32 male and female patients with pre-study Hb between 9.2 and 11.9 g/dl and serum ferritin < 20 lg/l were included in the study. Two patients had TfS > 16 % (19.2 % and 17.2 %); both patients were considered by the investigator to be eligible for inclusion. Compared with placebo, a rapid, dose-dependent increase in total serum iron was observed across all dose groups. Mean (standard deviation) maximum total serum iron levels ranged between 36.9 (4.4) and 317.9 (42.3) lg/ml in the 100 and 1000 mg groups. Concentration–time curves of total serum iron continuously declined for up to 24 and 72 h post-dose in the 100

Geisser and Banké-Bochita – Ferric carboxymaltose

and 500 – 1000 mg groups, respectively. Non-compartmental analysis of PK parameters was truncated at 24 h (100 mg) and 72 h (500 – 1000 mg doses). A dosedependent, but not dose-linear, increase in serum ferritin was seen in all treatment groups compared with placebo, with peak levels of a 23 – 210-fold increase above baseline occurring 48 – 120 h postdose. Iron-binding capacity was transiently almost fully utilized after doses of 500, 800 and 1000 mg (TfS > 95 %). No meaningful changes in serum transferrin or serum transferrin receptor concentrations were observed during this study. The elimination pattern for FCM appeared to be mono-exponential; FCM was cleared from serum with a terminal halflife of approximately 7.4 – 12.1 h. The percentage of FCM excreted in urine was negligible (0.0005 %). FCM was well tolerated; a total of 19 AEs were reported by 8/32 patients (25 %), of which three were considered by the investigator to be related to FCM: nausea and vomiting (one patient [100 mg]), and headache (one patient [1000 mg]). The incidence of AEs did not increase with dose. No severe or serious AEs, or deaths occurred. FCM had no significant effect on laboratory safety parameters or vital signs. This study satisfactorily characterized the PK/PD parameters of single doses of 100, 500, 800 and 1000 mg iron as FCM. The majority of FCM was utilized or eliminated within 24 h of administration of a 100 mg dose and within 72 h of a 500 – 1000 mg dose. FCM was generally well tolerated across all doses in patients with mild IDA.

Arzneimittelforschung 2010;60(6 a):362–372 © ECV · Editio Cantor Verlag, Aulendorf (Germany)


1. Introduction



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Worldwide, iron deficiency is the most frequently occurring nutritional deficiency [1]. The liabilities associated with tissue iron deficiency represent a major burden to public health authorities, and are often a greater burden than those associated with the most common manifestation of iron deficiency – anaemia [2]. Tissue iron deficiency without anaemia can impair psychomotor development and cognitive function in children and adolescents, adversely affect work capacity in adults, increase the frequency of low birth weight, premature birth and perinatal mortality, result in a decline in the endurance capacity of aerobic training in previously untrained women, and increase morbidity from infectious diseases [1 – 3]. Approximately 60 % of the body’s iron is present as haemoglobin (Hb) in circulating red blood cells. Iron is transported around the body in plasma bound to transferrin, the only iron-binding protein involved in transport; serum iron is delivered to the cells by the transferrin receptor. Transferrin-bound iron represents less than 0.2 % of total body iron, whereas 15 – 30 % of total iron is bound to the storage protein ferritin, primarily in the cytoplasm of cells in the liver, spleen and bone marrow [4]. Currently, serum ferritin levels provide the best indication of a patient’s iron status. In a healthy individual, serum ferritin levels correlate with the person’s iron stores [4]. Low serum ferritin levels are indicative of impaired delivery of iron for erythropoiesis. Although new blood parameters for iron storage are being developed, none are widely used at this time [5 – 7]. The concentration of transferrin is less affected by changes in iron metabolism; however, the level of serum iron may be expressed as a percentage of transferrin saturation (TfS) and a TfS of below 15 % has been associated with iron deficiency [4]. Iron deficiency can be functional or absolute [6, 8, 9]. Functional iron deficiency occurs when the mobilization of iron from stores to the labile iron pool is compromised and ferritin concentrations appear normal (above 40 lg/l) [10] or elevated (over 300 lg/l). Absolute iron deficiency develops when a patient’s iron status is reduced to such a low level that no iron is available for the production of Hb, and serum ferritin levels are less than 20 lg/l; more severe stages of iron deficiency may become associated with anaemia [3]. Anaemia results when the rate of erythropoiesis fails to match the rate of red blood cell destruction, for whatever reason, leading to a reduction in Hb levels [11]. This causation is common across all chronic indications of anaemia. With iron depletion, anaemia develops as a result of iron-deficient erythropoiesis, and the normocytic, normochromic red blood cells are gradually replaced by microcytic cells with a low Hb concentration [4]. Should Hb levels fall below two standard deviations of the distribution mean for Hb in a normal population of the same gender and age living at the same altitude, a diagnosis of iron-deficiency anaemia (IDA) can be

made. IDA is currently estimated to affect 700 – 800 million people worldwide [3]. Anaemia can have a significant negative impact on quality of life; for patients with cancer, fatigue has a greater impact on their daily life than pain [12, 13]. Untreated, anaemia can also have an impact on economic productivity, which in turn will affect patients’ families [11]. A relationship between reduced work capacity and iron deficiency has been demonstrated in agricultural and industrial workers from around the world. It has also been shown that this relationship can be reversed rapidly following iron supplementation, with work capacity and productivity levels quickly returning to normal [3]. Iron therapy and/or erythropoiesis-stimulating agents are the standard of care for IDA [9]. The aim of treatment is to return both iron stores and Hb to within the normal range (at least 100 lg/l serum ferritin and an Hb level of at least 11.0 g/dl) [9]. However, one major challenge in the treatment of IDA is to develop an effective and safe method of delivering large quantities of iron to patients. The effectiveness, safety and low cost of oral iron therapy has, to date, made it the treatment of choice for the majority of patients [4]. Most patients tolerate oral iron therapy without difficulty, but 10 – 40 % of patients treated have side-effects that can be attributed to iron replacement. Gastrointestinal events, drug–drug interactions and increases in oxidative stress as a consequence of the build up of non-transferrin-bound iron in plasma are adverse events (AEs) commonly associated with oral iron therapy, and can result in reduced patient compliance [2, 4, 14, 15]. For these reasons, oral iron supplementation is only suitable for brief periods of need and has limited efficacy in treating chronic IDA [2, 11, 14, 15]. Intravenous (i. v.) iron substitution is indicated in patients who must rapidly reverse their shortfall in iron requirements, have poor iron absorption, have an intolerance to or poor compliance with oral iron, or in whom blood transfusions should be avoided [4, 16 – 18]. Previous i. v. iron therapies have some disadvantages in terms of the risk of AEs such as anaphylactoid reactions to dextran antibodies [19]; in addition, it has been demonstrated that there is a possible increase in the risk of cardiovascular disease and bacterial infection [19]. The potential for these adverse reactions is related to the presence of non-transferrin-bound free iron in the circulation and the reactive free-oxygen species that can result. Furthermore, administration times can be long, dosages low [19] and test dosing may be necessary prior to the delivery of a higher dose. Iron(III)-hydroxide polymaltose complex (ferric carboxymaltose, FCM; Ferinject., Vifor (International) Inc., St Gallen, Switzerland) is a novel, next-generation i. v. iron formulation, developed to overcome the limitations of previous i. v. iron preparations [4, 20]. FCM is a Type I polynuclear iron(III)-hydroxide carbohydrate complex designed to mimic the physiologically occurring protein ferritin [4] with a molecular mass of approximately 150,000 Daltons and a very low toxicity [21, 22].



A Phase I study investigating the pharmacokinetics (PK) and red blood cell utilization of a single i. v. injection of 100 mg iron as FCM, labelled with 52Fe/59Fe, in six patients with IDA, demonstrated that iron as FCM is rapidly distributed to the bone marrow, liver and spleen [23]. In addition, there was high red blood cell utilization of the iron in these patients, ranging from 61 % to 99 %. Moreover, as a reflection of the safety of polysaccharide iron complexes, despite the much higher uptake of the injected dose by the bone marrow relative to the liver and spleen, there was non-saturation of the transport system to the bone marrow at this 100 mg dose. This suggests that the iron complex is rapidly transported from the plasma to the interstitium, and from there to an interstitial pool of transferrin, which can be the source of cellular iron uptake [23]. To investigate whether iron as FCM can be administered as a single infusion at much higher doses (up to 1000 mg iron over 15 min) than those currently administered for other i. v. iron formulations, we conducted a Phase I, single-centre, randomized, double-blind, placebo-controlled, single-dose, dose-escalating study in patients with mild IDA. Here, we present the PK and pharmacodynamics (PD) results of this trial, along with safety and tolerability data of FCM; this is the second trial of FCM conducted in human volunteers.

2. Patients and methods 2.1 Patients Thirty-two patients aged between 18 and 45 years of age of Caucasian race with mild IDA were selected from a pool of volunteers recruited by Parexel GmbH (Institute of Clinical Pharmacology, Berlin, Germany). Mild IDA was defined as an Hb level of between 9.0 and 12.0 g/dl in women, or 9.0 and 13.0 g/dl in men, a serum ferritin level of less than 20 lg/l and a transferrin saturation (TfS) of less than 16 % as measured between 0800 and 0900 h. Patients had a normal body mass index, ranging from 18 to 28 kg/m2, were in good general health, and had normal clinical and laboratory safety assessments, including negative HIV-1/2 antibodies, hepatitis B surface antigen and hepatitis C-antibody screening tests. Inclusion criteria included negative alcohol breath tests and urine drug screening, and drinking no more than five cups of xanthine-containing beverages per day. Female patients of childbearing age had

to be using adequate contraception. Exclusion criteria comprised any history or clinical findings of iron storage diseases; iron utilization disorders or anaemia not attributable to iron deficiency; general allergic predispositions and elevated serum transaminases to more than three times the upper limit of normal. Any patient receiving any investigational medication within the 3 months prior to the start of the study, any medication within the 2 weeks prior to the first dose, any non-study drug while in the Clinical Performance Unit (CPU), or any other investigational drug during the course of the study were also excluded. Patients with a history of chronic drug or alcohol abuse, or a history of more than moderate alcohol consumption (i. e. more than 200 g alcohol per week) could not participate. All patients provided written, informed consent under the provisions of the Declaration of Helsinki before enrolment to the trial.

2.2 Study design The study was approved by the local ethics committee, and was conducted in compliance with Good Clinical Practice and Good Manufacturing Practice, and in accordance with applicable national laws and regulations. Four single ascending doses of i. v. iron as FCM were administered: 100 mg iron as FCM given as an i. v. bolus injection, and 500, 800 and 1000 mg iron given as i. v. infusions over 15 min (Table 1). At each dose level, six patients received FCM and two received placebo. The dosage levels in this study were determined from toxicity studies conducted in rats and dogs. Consequently, the maximum total iron dose allowed was 1000 mg iron and a single dose was considered sufficient for the PK analyses [24]. At each dose level, six patients were randomized to receive treatment with FCM and two to receive placebo, according to a randomization code prepared by Parexel Department of Biostatistics. Treatment was administered in the morning to each patient in the fasted state. Patients were assigned to dose levels according to their Hb level at screening and their potential individual iron requirement as calculated using the Ganzoni formula [25], according to which the individual potential iron requirement is a function of the patient’s Hb level and body weight (Table 2): Iron deficit [mg] = body weight [kg] · (target Hb1) – actual Hb) [g/l] · 0.242) + depot iron3) [mg]

1) 2)

3)

Target Hb, 150 g/l. Factor 0.24 = 0.0034 (iron content Hb = 0.34 %) · 0.07 (blood volume = 7 % of body weight · 1000 (conversion g to mg). Depot iron, 500 mg (above 35 kg body weight).

Table 1: Dose groups, infusion solutions and method of administration. Dose group (mg iron as FCM)

Study drug infusion: six patients per group

Placebo infusion: two patients per group

Method of administration: FCM or placebo

100

1 ampoule (2 ml) FCM

2 ml 0.9 % NaCl

2 ml (100 mg)/1 min

500

5 ampoules (10 ml) FCM + 240 ml 0.9 % NaCl

250 ml 0.9 % NaCl

250 ml (500 mg)/15 min

800


250 ml 0.9 % NaCl

250 ml (800 mg)/15 min

1000


250 ml 0.9 % NaCl

250 ml (1000 mg)/15 min

FCM, ferric carboxymaltose.

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Table 2: Assignment of patients to dose levels according to their Hb level at screening and their individual iron requirement. Hb level (g/dl)

Potential iron requirement (mg)

Assigned dose level

9.0 – 13.0 (males) 9.0 – 12.0 (females)

740 – 1796

100 to 800 mg iron or placebo

9.0 – 13.0 (males) 9.0 – 12.0 (females)

980* – 1796

1000 mg iron or placebo

Hb, haemoglobin. *Potential iron requirement had to be ‡ 980 mg for inclusion at the 1000 mg (or placebo) dose level. Calculation according to the Ganzoni formula [25].

2.3 Assessments Pre-study screening was performed before study drug administration between Days – 28 and – 4. Patients stayed in the CPU from Day – 1 to Day 4. Patients then returned on Day 8 for a follow-up examination, 7 days post-dose. After each dose level, relevant safety and tolerability data, including routine safety

Table 3: Assessments made during the treatment period. Assessment

Treatment period Screening

Study day Drug administration

– 28 to – 4

Treatment –1

1

1

Post-study

2

3

4

5–7

8

X

X

X

X

Blood sampling (PK/PD)2

X

X

X

X

Urine sampling (PK)3

X

X

X

X

X X

X X

X X

X X

X X

X X

X X

X X

X X

X X

X X

X

X

X

X

X

–X–

–X X

Clinical safety laboratory – chemistry – haematology – serology

X X X

Vital signs – blood pressure, heart rate4 – oral body temperature5

X X

12-lead ECG6

X

48-h telemetry ECG7 AE reporting

–X– X

X

In-house nights In-house days

X

X

X

X

X

X

X

X

X

X

X

X

1

100 mg dose: start of i. v. bolus injection at time 0 over 1 min; 500, 800 and 1000 mg doses: start of I. V. infusion at time 0 over 15 min. Assessments were made of serum iron, total serum iron, ferritin, transferrin, TfS, UIBC at 0800, 1200, 1600, 2000 and 2400 h on Day – 1 (iron profile), pre-dose and 5, 15, 30 and 45 min and at 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120, 144 and 168 h post-dose; TfS was assessed at 0800 and 2000 h on Day – 1 and pre-dose. UIBC was evaluated at 5, 15 and 30 min and 1, 2, 3, 6, 12, 24, 48, 72, 96, 120, 144 and 168 h post-dose. 3 Total iron concentration was determined 24 h before time 0 and collection intervals 0 – 4, 4 – 8, 8 – 12, 12 – 24, 24 – 48 and 48 – 72 h postdose. 4 At screening, within the 20 min before time 0, and at 5, 15 and 30 min, 1, 2, 3, 4, 6, 12, 24, 36, 48 and 72 h post-dose. 5 At screening, within the 20 min before time 0, and at 30 min, 4, 12, 24, 36, 48 and 72 h post-dose. 6 At screening, within the 20 min before time 0, and at 15 min, and 1, 3, 6, 12, 24, 36, 48 and 72 h post-dose. 7 From the morning of Day – 1 until time 0 and from time 0 until 24 h post-dose. AE, adverse event; ECG, electrocardiogram; PD, pharmacodynamics; PK, pharmacokinetics; TfS, transferrin saturation; UIBC, unsaturated iron binding capacity. 2



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The test drug was an injection solution (5 % w/v iron containing 50 mg iron per ml as FCM) packaged as 2 ml ampoules containing 100 mg of iron (batch no. 291100; manufactured by Vifor (International) Inc.). No concomitant medication was permitted during in-house study periods; however, up to 1000 mg of paracetamol could be given as needed, if approved by the Principal Investigator or study physician.

laboratory parameters, vital signs measurements and AEs, were sent to the sponsor. This formed the basis of the decision for the patient to proceed to the next dose. In all dose groups, the start of i. v. dose administration was considered as time 0. In the 500, 800 and 1000 mg dose groups, i. v. infusion of iron as FCM was stopped 15 min after time 0. Post-infusion blood and urine assessments were made at 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, 72, 96, 120, 144 and 168 h for all dose groups (Table 3). Blood samples were taken to determine concentrations of serum iron (pre-dose) or total serum iron (post-dose), ferritin, transferrin, TfS (pre-dose) and unsaturated iron binding capacity (UIBC; post-dose). Urine samples were evaluated for total iron concentration. Total iron in serum and in urine samples were determined using Inductively Coupled Plasma Optical Emission Spectrometry applying validated assay methods. A validated enzyme-immunoassay on an Abbot Axsym instrument using Assay kits was used to assay serum ferritin, whereas transferrin was assayed by a validated immuno-turbimetric assay method on a Roche Hitachi Modular instrument using Roche Hitachi assay kits. Pre-dose serum TfS was calculated from serum iron and transferrin concentrations, and was calculated from UIBC and transferrin concentrations post-dose. UIBC in serum was determined by a validated analytical method developed by Farmovs-Parexel (Bloemfontein, South Africa). Based on the post-dose concentration data of total serum iron, model-independent PK parameters were determined for all patients treated at the different dose levels. These parameters included the maximum serum concentration (Cmax), time



Fig. 1: Flow of patients through the study. PD, pharmacodynamics; PK, pharmacokinetics.

to maximum serum concentration (Tmax), area under the serum concentration–time curve over a certain time (AUC0 – t, AUC0 – 24, AUC0 – 72 [subscript denotes the time interval]), terminal elimination half-life (t1/2), total body clearance (CL), volume of distribution during elimination, volume of distribution at steady state and mean residence time (MRT) for total serum iron. Parameters were derived from post-treatment baselineadjusted individual concentration profiles, respecting the new equilibrium between transferrin-bound iron and the iron deposits. Urine PK analyses were performed to obtain estimates for total renal clearance of iron and total iron in urine (Ae) from baseline-adjusted parameters. PK parameters were truncated after 24 h in the 100 mg group and after 72 h in the 500, 800 and 1000 mg groups, to exclude a new post-treatment baseline that arises after replenishment of the iron stores. PD parameters included serum concentrations of ferritin, transferrin, TfS and UIBC. In addition, Hb levels, reticulocyte count and serum transferrin receptor concentration were evaluated.

Safety measurements included routine serology, haematology and clinical chemistry laboratory parameters. Vital signs, 12-lead electrocardiogram (ECG) monitoring and 48-h continuous ECG monitoring by telemetry ECG (Apex S recorder, GE Medical Systems, Freiburg, Germany) were performed, and the incidence of AEs recorded.

2.4 Statistical analyses The sample size was determined by following empirical considerations for a PK dose-finding study. The population analysed was the safety population, which included all patients who had received at least one dose of study medication. PK and PD parameters were analysed using descriptive statistics. The dose linearity of FCM was assessed by calculating the dose-perbody-weight adjusted total iron PK parameters AUC0 – 1, AUC0 – t and Cmax. These adjusted parameters were then logtransformed prior to analysis by means of a one-way analysis of variance with “dose level” as a factor.

Table 4: Patient demographics and pre-dose characteristics. Treatment (N = 32)

Age, years Women, % Height, cm Weight, kg Haemoglobin,* g/dl Serum ferritin,{ lg/l Transferrin,{ g/l Transferrin saturation,{ % UIBC,* lmol/l

Placebo (N = 8)

100 mg (N = 6)

500 mg (N = 6)

800 mg (N = 6)

1000 mg (N = 6)

28.8 (7.4) 8 (100) 173.9 (7.3) 63.0 (6.1) 11.4 (1.1) 5.8 (6.0) 3.1 (0.2) 31.7 (5.5) 53.5 (7.6)

37.5 (3.8) 5 (83.3) 163.2 (4.2) 61.2 (9.6) 10.3 (0.7) 2.1 (1.5) 3.4 (0.5) 25.3 (5.8) 64.2 (10.9)

29.8 (10.7) 6 (100) 175.2 (4.7) 68.2 (9.4) 11.2 (1.2) 5.2 (6.6) 3.4 (0.5) 25.0 (7.6) 64.0 (12.6)

25.7 (8.5) 5 (83.3) 170.3 (6.6) 64.9 (6.5) 11.7 (0.7) 4.0 (2.5) 3.5 (0.4) 38.0 (6.9) 53.9 (6.9)

34.2 (7.1) 6 (100) 172.0 (8.3) 65.5 (5.5) 11.3 (0.4) 3.1 (2.0) 3.4 (0.2) 27.3 (5.6) 61.5 (6.3)

All data are mean (standard deviation) unless stated otherwise. *Day –1; {Pre-dose values.

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(a)


(b)

Fig. 2: Analyses of pharmacokinetic and pharmacodynamic blood sampling parameters: (a) mean total serum iron (lg/ml) by treatment over time; (b) mean serum ferritin concentrations by treatment over time. A: 08.00 Day – 1; B: 12.00 Day – 1; C: 16.00 Day – 1; D: 20.00 Day – 1; E: 24.00 Day – 1.

3. Results

3.2 PK and PD analyses

3.1 Patients

A rapid dose-dependent increase in total serum iron concentrations was seen after the administration of FCM compared with placebo (Fig. 2a). The highest serum concentrations were reached immediately after the bolus injection of 100 mg iron as FCM, or shortly after the cessation of infusion of 500 mg (15 min), and 800 and 1000 mg iron (30 min). The mean (SD) maximum concentrations of total serum iron ranged from 36.9 (4.4) lg/ml with 100 mg iron to 317.9 (42.3) lg/ml following the 1000 mg iron dose. After an initial plateau-

Seventy-seven patients with mild IDA were screened for inclusion in the study. Of these, 32 patients were included and completed the trial; there were no withdrawals (Fig. 1). The safety population and the PK/PD population were identical. There were no relevant differences between dose groups in either patient demographics or baseline characteristics (Table 4). Only two of the patients participating in the study were male (6 %), and all patients were of Caucasian origin. Arzneimittelforschung 2010;60(6 a):362–372 © ECV · Editio Cantor Verlag, Aulendorf (Germany)


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Table 5: PK parameters of total serum iron truncated at 72 h post-dose (non-compartmental analysis).


Treatment (N = 32)

Cmax, lg/ml Tmax, h (mean [SD]) AUC0 – t, lg · h/ml AUC0 – 24, lg · h/ml AUC0 – 72, lg · h/ml T1/2, h CL, ml/min Vd,area, ml Vd,ss, ml MRT, h

100 mg (n = 6)

500 mg (n = 6)

800 mg (n = 6)

1000 mg (n = 6)

37 (1.10) 0.3 (0.29) 333 (1.21) 333 (1.21) –* 7.4 (1.09) 4.3 (1.22) 2774 (1.15) 2879 (1.18) 11.2 (1.11)

156 (1.12) 0.3 (0.12) 2346 (1.15) 1838 (1.14) 2345 (1.15) 12.1 (1.20) 3.5 (1.15) 3637 (1.27) 3421 (1.21) 16.6 (1.18)

319 (1.23) 1.0 (0.62) 5171 (1.21) 3958 (1.20) 5171 (1.21) 10.3 (1.13) 2.6 (1.21) 2269 (1.26) 2442 (1.20) 16.1 (1.07)

331 (1.13) 1.2 (0.56) 6277 (1.25) 4699 (1.18) 6277 (1.25) 9.4 (1.20) 2.6 (1.25) 2148 (1.35) 2576 (1.14) 16.5 (1.16)

All data are geometric mean (GSD) unless stated otherwise. *PK profile was truncated at 24 h post-dose. AUC, area under the serum concentration–time curve, subscripts denote the time interval; CL, total clearance; Cmax, maximum total serum iron concentration measured; GSD, geometric standard deviation; MRT, mean residence time; T1/2, apparent half-life of elimination; Tmax time to reach maximum serum concentration; Vd,area, volume of distribution during elimination; Vd,ss, volume of distribution at equilibrium.

shaped phase, the concentration–time curves continuously declined. This decline appeared to be mono-exponential in the majority of patients for up to 24 h in the 100 mg group and until 72 h post-dose in the 500, 800 and 1000 mg dose groups. The total serum iron levels were below the limit of quantification in the majority of patients within 60 – 96 h post-dose. A dose-dependent, but not dose-linear, increase in serum ferritin concentrations was observed in all FCM treatment groups compared with placebo (Fig. 2b). At baseline (Day – 1), mean (SD) serum ferritin concentrations were between 2.1 (1.5) and 5.8 (6.0) mg/l across the different treatment groups. Ferritin levels began to rise between 6 and 12 h after dosing in all FCM treatment groups, with peak serum ferritin concentrations of a 23- to 210-fold increase above baseline occurring between 48 h (100 mg iron) and 120 h (800 and 1000 mg iron) after dosing. In contrast, mean (SD) ferritin levels remained approximately unchanged from baseline at 6.8 (4.4) lg/l in the placebo group. The increase in serum ferritin concentrations is indicative of the replenishment of depleted iron stores after treatment with iron as FCM. Treatment with different doses of FCM generally had no clinically meaningful impact on serum transferrin levels or serum transferrin receptor concentrations over the observation period. Although a trend towards lower concentrations in transferrin levels was observed after the i. v. administration of FCM, the overall decline was small and similar across both FCM and placebo treatment groups. The i. v. administration of FCM led to a steep decline in UIBC, particularly following the 800 and 1000 mg doses. At the end of the observation period, the UIBC remained lower than pre-dose values in the 500, 800 and 1000 mg treatment groups. Before dosing with FCM, the mean (SD) TfS ranged between 25 % (8 %) in the 500 mg FCM group and 38 % (7 %) in the 800 mg

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iron group. After dosing there was a clear treatment-related increase in TfS in the FCM groups compared with placebo. At the point of maximum mean change from baseline, TfS was > 95 % in the 500, 800 and 1000 mg treatment groups. Following 100 mg iron, approximately 86 % of transferrin was saturated at the maximum point of effect. At the end of the observation period, the proportion of the protein still utilized for iron binding ranged from approximately 33 % (500 mg iron) to 55 % (800 and 1000 mg iron) TfS, which is nearly within the normal range. The non-compartmental analysis of PK parameters of total serum iron was truncated 72 h post-dose (or 24 h for the 100 mg dose) as this served better to characterize the PK profile of total serum iron following i. v. injection or infusion. After replenishment of the iron stores, there is a “new” post-treatment baseline, which is typified by a higher (normal) level of serum iron and normalized kinetic processes between protein-bound iron and the organs of utilization. Using this cut-off point, the average serum exposure was very similar across all treatment groups when compared with the values generated by censored data (data that were censored after the first value was below the limit of quantification), indicating that the PK profile of FCM was sufficiently characterized by these truncated values (Table 5). It is of note that injection of the 800 mg dose of iron deviated slightly from a dose-linear increase in Cmax, although the maximum levels after 1000 mg were approximately double those achieved with the 500 mg dose. Following the i. v. bolus injection of 100 mg iron, the median Tmax was reached after approximately 5 min, coinciding with the end of the injection period. In the treatment groups for which FCM was administered by i. v. infusion over 15 min, Tmax was reached either within the end of infusion in the 500 mg dose group, or much later in the 800 mg (53 min) and 1000 mg (1 h 16 min) dose groups. The increase in AUC0 – t with incremental doses of FCM was higher than expected for dose-proportional increases. Arzneimittelforschung 2010;60(6 a):362–372 © ECV · Editio Cantor Verlag, Aulendorf (Germany)



Fig. 3: Linear logistical regression of individual patient values for (a) Cmax (lg/ml) versus 100, 500, 800 and 1000 mg iron as FCM (r2 = 0.90; p < 0.001) and (b) AUC0 – t (h · lg/ml) versus 100, 500, 800 and 1000 mg iron as FCM (r2 = 0.80; p < 0.001). Individual patient values are represented by the different symbols. AUC, area under the serum concentration–time curve, subscripts denote the time interval; Cmax, maximum total serum iron concentration measured.

3.3 Safety Generally FCM was well tolerated in this population of 24 patients with mild IDA. Overall, the numbers of AEs were low across all treatment groups. A total of 19 AEs were reported in eight patients. Three AEs in two patients were considered to be related to the study medication, these were nausea and vomiting in one patient in the 100 mg dose group, and headache observed in one patient in the 1000 mg group. The other 16 AEs were unlikely to be related or were unrelated to study drug and comprised headache (five patients), dizziness (two patients), nausea (two patients), and affecting one patient each, eczema, loose stools, flatulence, nasopharyngitis, abdominal pain, general discomfort and syncope. There was no increase in the occurrence of AEs with higher doses of FCM. There were no severe or serious AEs and no deaths occurred. All AEs were resolved without sequelae. Paracetamol was administered for moderate headache in three patients who received 800 to 1000 mg iron as FCM. The study drug was found to have no significant effect on any of the assessed laboratory parameters and no clinically significant effects of FCM were seen on vital signs. In particular, liver enzyme activity, renal parameters, electrolytes and metabolic status were normal in all patients, with only minor, clinically insignificant exceptions apparent before and after dosing. Geisser and Banké-Bochita – Ferric carboxymaltose

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As the non-compartmental analysis of total serum iron for the 100 mg iron group was truncated at 24 h post dose, the AUC0 – 72 values for this dose are not available, however, at the other doses, the values of AUC0 – 72 were similar to those for AUC0 – t. Examining the data until 72 h post-dose (or 24 h postdose in the 100 mg iron group) resulted in the geometric mean (geometric standard deviation [GSD]) T1/2 ranging from 7.4 (1.09) to 12.1 (1.20) h and the MRT ranging from 11.2 (1.11) to 16.6 (1.18) h. Analysing data truncated at 72 h post-dose reflects more reliably the true terminal T1/2 and MRT of FCM, as they are not influenced by post-treatment baseline equilibrium of serum iron levels. The CL was low with the geometric mean (GSD) ranging between 2.6 (1.21) and 4.3 (1.22) ml/ min. This approach has therefore demonstrated that the majority of administered FCM was utilized or eliminated within 24 h of a 100 mg dose, and within 72 h of a 500 – 1000 mg dose. Hb levels showed no significant changes during the 8day observation period. Nevertheless, a clear treatment response was observed in the increase in reticulocyte counts at the post-study visit in those groups in which patients had received FCM. The dose linearity of FCM was evaluated using doseand body-weight-adjusted total iron PK parameters (based on non-compartmental analysis) calculated by dividing AUC0 – t and Cmax by dose per kg body weight. The increase in Cmax for the 100, 500 and 1000 mg iron as FCM dose groups was compatible with dose linearity, although Cmax had borderline significance (p = 0.077). This was mainly because of the results from the 800 mg group, in which some values were higher than expected from a dose-linear increase. For AUC0 – t, a significant outcome was obtained (p < 0.001) indicating that one or more dose levels deviated from unity for this parameter. The deviation was mainly caused by outlying patients in the 800 mg (n = 1) and 1000 mg (n = 2) dose groups (Fig. 3); the baseline characteristics of these patients do not offer an explanation for these outlying values. Nevertheless, over the whole dose range a good correlation between AUC0 – t and dose is demonstrated, as evidenced by the linear regression coefficient (r2 = 0.80; p < 0.001). The elimination pattern for FCM appeared to be mono-exponential. Two elimination phases, as required by the two-compartmental model, could not be separated when the post-treatment baseline was excluded from the analysis. The mono-exponential elimination characteristic indicates that iron as FCM is not deposited in a store in the body from where it could diffuse back to the serum. Concentrations of Ae were low and did not exceed 4.8 lg/ml in the small number of patients for whom concentrations could be detected. In all other patients, the percentage of FCM excreted in the urine was negligible (0.0005 %), falling below the detection limit of the assay.



4. Discussion The Type I iron complex FCM, represents the next generation of i. v. iron preparations indicated for the treatment of iron deficiency secondary to a number of diverse aetiologies, including renal failure, cardiology and gastrointestinal disorders. This Phase I, placebocontrolled, dose-escalation study is the second FCM trial conducted in humans to reliably determine the PK/PD and safety margin of FCM. The administration of iron as FCM in 24 patients as either a bolus injection of 100 mg, or a 15-min infusion of 500, 800 or 1000 mg, led to a rapid increase in total serum iron levels compared with placebo patients with mild IDA. Patients need sufficient stores of iron to achieve and maintain an Hb level of at least 11.0 g/dl. In order to do this in patients with IDA, supplemental iron needs to be administered to achieve normal serum ferritin levels of 100 lg/l [10]. In patients with chronic kidney disease, an optimal serum ferritin level of 200 – 500 lg/l is recommended [9]. The serum ferritin levels achieved in this study with the administration of 500 to 1000 mg iron as FCM, were within and beyond the optimal levels. However, patients receiving 100 mg iron as FCM did not achieve optimal serum ferritin levels. These increases in serum ferritin levels indicate that treatment with FCM is effective not only in replenishing depleted iron stores, but also in enabling patients to have immediate access to clinically required amounts of iron. Moreover, in comparison with oral ferrous supplements, FCM is injected or infused, and therefore there are no absorption issues to limit the uptake of iron; consequently, the entire dose of iron as FCM can be utilized by the body. The major sites for the storage of iron are the liver, spleen and bone marrow. These also seem to be part of the major pathway for the metabolism of injected iron polysaccharides [23, 26]. However, an inverse relationship exists between the occurrence of maximum iron levels and increasing FCM dose, perhaps arising from a rapid uptake of the iron complex by the reticuloendothelial system (RES) [23, 27]. In this study, the injection/infusion of FCM led to a rapid increase in total serum iron levels. However, with increasing doses of FCM, a shift in the time taken to achieve Tmax was observed and exceeded 1 hour or more at doses of 800 mg and 1000 mg iron as FCM. This time to Tmax was considerably longer than the end of infusion time of FCM, and may be partially explained by the redistribution of iron from the initial sites of uptake such as the liver, spleen and bone marrow. The average serum exposure to iron, as expressed by Cmax and AUC values, increased with ascending doses of iron in a higher than dose-proportional manner, in particular regarding AUC. Nevertheless, linear regression of Cmax and AUC values over the whole dose range of iron as FCM, demonstrates that there is a good correlation between dose and effect (Cmax, r2 = 0.90, p < 0.001; AUC, r2 = 0.80, p < 0.001). Differences in baseline char-

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acteristics of the patients do not provide a satisfactory explanation for this phenomena, although it is possible that the up to 10-fold doses of FCM administered in this study exceeded the capacity of the transport systems of primary iron distribution in these patients; however, as only one of these patients exhibiting exceedingly high serum iron levels had 100 % TfS, this is unlikely. One limitation of this study is that only a small number of patients were involved, which may represent problems in terms of skewing the analysis of results. Alternatively, as total serum iron is dependent on the distribution volume, there may have been differences in blood/serum volume that were independent of body weight. The MRT of iron complex particles was calculated to be less than 24 h on average. FCM was cleared from the serum with a terminal elimination half-life between 10 and 18 h, and the total body clearance ranged from 2.6 ml/min to 3.4 ml/min. The volumes of distribution at steady state and during elimination were similar (between 2.4 and 5.2 l); however, because of the supra-proportional increase in AUC with the higher doses of iron (if linear kinetics are assumed), these volumes may have been underestimated. Profiles of the PK parameters used in the optimal regression fit for the elimination phase were truncated at 24 h post-dose for the 100 mg group and 72 h post-dose in the 500, 800 and 1000 mg groups. This better characterized the PK profile of total serum iron after i. v. injection/infusion, as it respects the “new” post-treatment baseline that exists after the replenishment of the iron stores. The post-treatment baseline differs from the baseline measured before iron therapy in that it is characterized by different kinetic processes between protein-bound iron and organs of iron utilization. The post-treatment baseline therefore mainly represents the equilibrium between transferrin-bound iron and the organs of utilization after replenishment of the iron stores 24 – 72 h post-dose. Using this approach, the overall iron exposure was similar across all dose groups, although somewhat lower in the 100 mg dose group. Practically, this can be translated to mean that the majority of the administered iron complex was deposited, utilized and eliminated within 24 h after a 100 mg iron dose and within 72 h after higher doses of 500 – 1000 mg iron as FCM. The elimination pattern of FCM essentially appears to be mono-exponential. This suggests that in addition to there being no maximal saturation of transferrin immediately after injection or infusion of FCM, there is no store of the FCM complex within the body from which iron can diffuse back into the serum. Renal elimination of iron was negligibly small and did not contribute to the overall elimination of FCM. However, the assay methodology did not permit exact quantification of the low concentrations of total iron in urine; therefore the true amount of renal clearance could not be evaluated. Previous studies investigating the PK of iron sucrose, which is similar in structure to FCM, found that renal Arzneimittelforschung 2010;60(6 a):362–372 © ECV · Editio Cantor Verlag, Aulendorf (Germany)



Acknowledgements and disclosures The authors take full responsibility for the content of the paper, but thank Laura Giles, DPhil (Caudex Medical; supported by Vifor Pharmaceuticals), for her assistance in preparing the initial draft of the manuscript and collating the comments of authors and other named contributors.

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clearance did not play an important role in total body clearance (less than 5 %) [28]. Doses of 500, 800 and 1000 mg of iron as FCM transiently achieved almost full saturation of transferrin during or immediately after cessation of the iron transfusion, as indicated by a UIBC of less than 5 %, or a TfS of over 95 %. Data from previous studies indicate that, in contrast with the less stable oral iron complexes, there is no direct release of iron from iron polysaccharides into the circulation as non-transferrin-bound “free” iron [23, 26, 27]. Rather, Beshara et al. [23] suggested that the iron complex is transported from the circulation into the interstitium and into an interstitial pool of transferrin, before labile iron is mobilized from the complex. Therefore, the high saturation values of transferrin achieved with the administration of i. v. iron is indicative of the highly stable Type I FCM complex, ensuring that all available iron is bound to transferrin for transport to the RES and Hb synthesis. At the end of the observation period (Day 8), approximately one-third to one-half of transferrin was still being used for iron binding. PD analysis of reticulocyte counts clearly suggests that the haematopoietic system was activated in these patients with mild IDA after the administration of FCM. This indicates that the supplemental iron administered as FCM was being successfully utilized by the functional iron pool and had entered the haem synthesis pathway. Nevertheless, no significant change in Hb levels occurred during the 8-day observation period; this would be unexpected for this short time period and a longer follow-up period would be required to evaluate the effect of iron as FCM on Hb levels. The four single ascending doses of FCM were well tolerated in patients with mild IDA in this Phase I study. Overall, the incidence of drug-related AEs was low across all treatment groups, and in comparison with earlier i. v. iron treatments, there was a low rate of AEs with FCM. Safety laboratory assessments and vital signs did not reveal any clinically significant changes in any of the parameters. In addition, FCM does not contain dextran so it is unlikely that anti-dextran antibodies will arise from the administration of this form of supplemental iron. Consequently, there is a reduced risk of anaphylaxis with this therapy. All available pre-clinical and human PK/PD data support the use of FCM in the treatment of iron deficiency when administered as either a single transfusion of up to 1000 mg iron over 15 min once weekly, or as an injection of 100 mg iron given up to three times weekly. This study demonstrates that the good safety and PK profile of FCM provides patients with the full therapeutic benefit of a parenteral iron replacement treatment.



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[23] Beshara S, Sorensen J, Lubberink M, Tolmachev V, Langstrom B, Antoni G, et al. Pharmacokinetics and red cell utilization of 52Fe/59Fe-labelled iron polymaltose in anaemic patients using positron emission tomography. Br J Haematol. 2003 Mar;120(5):853 – 9. [24] Geisser P, Rumyantsev V. Pharmacodynamics and safety of ferric carboxymaltose: a mutiple-dose study in patients with iron-deficiency anaemia secondary to a gastrointestinal disorder. Arzneimittelforschung. 2010;60(6 a):373 – 385. [25] Ganzoni AM. [Intravenous iron-dextran: therapeutic and experimental possibilities]. Schweiz Med Wochenschr. 1970 Feb 14;100(7):301 – 3. [26] Finch CA, Deubelbeiss K, Cook JD, Eschbach JW, Harker LA, Funk DD, et al. Ferrokinetics in man. Medicine (Baltimore). 1970 Jan;49(1):17 – 53. [27] Beshara S, Lundqvist H, Sundin J, Lubberink M, Tolmachev V, Valind S, et al. 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. [28] Danielson BG, Salmonson T, Derendorf H, Geisser P. Pharmacokinetics of iron(III)-hydroxide sucrose complex after a single intravenous dose in healthy volunteers. Arzneimittelforschung. 1996 Jun;46(6):615 – 21.
