Use of ferric trimaltol in treating or preventing iron deficiency

Abstract

The invention relates to the use of ferric trimaltol for treating or preventing iron deficiency in human patients, with or without anaemia, by oral administration together with solid and / or liquid foo

Description

This invention relates to ferric trimaltol for use in treating or preventing iron deficiency in a human patient with or without anaemia, wherein the ferric trimaltol is administered orally in combination with food and / or a beverage. WO 2015 / 101971 (Iron Therapeutics Holdings AG.) discloses a dosage regimen of ferric trimaltol for the treatment of patients suffering from iron deficiency with or without anaemia. Specifically the disclosure relates to the treatment of patients with 30 mg ferric equivalent of ferric trimaltol twice daily. In the associated clinical, 128 patients suffering from iron deficiency anaemia were randomised. Of this group 67 were suffering from Crohn's disease and 53 were suffering from ulcerative colitis. All had mild to moderate disease activity and anaemia associated with inflammatory bowel disease, which was measured according to low haemoglobin levels (9.5 -12d / dL for women and 13g / dL(male), and were intolerant of ferrous iron. 60 patients were treated with ferric trimaltol capsules at a 30 mg ferric equivalent dose twice daily before breakfast and prior to sleep on an empty stomach for a period of 12 weeks. 60 patients received a matched placebo capsule and were treated in the same way for the same period. The results for the ferric trimaltol group showed a mean improvement of 2.25 g / dL (p <0.0001) representing the change from baseline for the ferric trimaltol group compared to the placebo group at week 12. More than 65 % of subjects treated with ferric trimaltol experienced normalised haemoglobin levels by week 12. WO 2016 / 063228 (Iron Therapeutics Holdings AG.) discloses a dosage regimen between 40 and 90 mg ferric iron equivalent twice daily of ferric trimaltol for use in the treatment of patients suffering from iron deficiency with orwithout anaemia. In the Example, subjects with iron deficiency having active inflammatory disease or acute chronic inflammation were administered 30, 60 or 90 mg ferric iron equivalent twice daily morning and evening of ferric trimaltol for seven days and a single 30, 60 or 90 mg ferric iron equivalent of ferric trimaltol on the morning of day eight. The patients fasted before being administered ferric trimaltol. Average values of 32.3, 49.1 and 48.7 micromol / L of blood serum total iron were measured for 30, 60 and 90 mg ferric iron equivalent dose groups on day 1 respectively. Similar values for obtained on day 8. Serum ferritin, an intracellular protein that stores iron in a soluble and non-toxic form and can be found in blood serum as an iron carrier, was higher for the 60 and 90 mg ferric iron equivalent dose groups than for the 30 mg ferric iron equivalent dose group suggesting that the higher dose is more effective at correcting iron deficiency. Harvey et al. (Aliment. Pharmacol. Ther., 12, 845 (1998)) discloses a study on the administration of 30 mg ferric iron equivalent twice daily morning and evening of before breakfast and the evening meal of ferric trimaltol to patients with iron deficiency anaemia and severe intolerance to ferrous preparations recruited from gastroenterology clinics for three months. Exclusion criteria included active inflammatory disease at entry into the clinical. Of the 23 patients, thirteen had Crohn's disease and two ulcerative colitis. Afterthree months, there was a significant increase in haemoglobin and ferritin from pre-treatment levels, and no serious adverse events were reported by the patients. According to the UK Electronic Medicines Compendium (EMC) issued Summary of Product Characteristics for FeraccruR™ (Norgine Limited - ferric trimaltol), treatment of iron deficiency anaemia with ferric trimaltol without food in adult subjects with chronic kidney disease (CKD) was studied in a phase III randomised placebo-controlled clinical study. 167 patients (age range 30-90 years; 50 males and 117 females) were randomized 2:1 to receive either ferric trimaltol 30 mg ferric equivalent capsules twice daily or placebo twice daily for a treatment period of 16 weeks. The patients had an estimated glomerular filtration rate (eGFR) of >15 mL / min / 1.73m2 (up to severe loss of kidney function) and <60 mL / min / 1.73m2 (at least mild to moderate loss of kidney function), a baseline haemoglobin (Hb) >8.0 g / dL and <11.0 g / dL, and a serum ferritin concentration of <250 ng / mL with a transferrin saturation (TSAT) <25 %, or a serum ferritin concentration of <500 ng / mL with a TSAT of <15 %. After the 16 week treatment had finished, treatment with ferric trimaltol only was continued for up to 36 weeks under an open-label. Administration of ferric trimaltol resulted in clinically and statistically significant increases in Hb compared to the placebo during the double-blind 16-week treatment period. The least squares mean (LSM) change in Hb concentration from baseline to Week 16 was 0.50 g / dL for the ferric trimaltol group and -0.02 g / dL for the placebo group, with a statistically significant LSM difference of 0.52 (p = 0.0149). The LSM change in ferritin concentration from baseline to Week 16 with Last Observation Carried Forward (LOCF) was 25.42 pg / L for the ferric trimaltol group and -7.23 pg / L for the placebo group, with a statistically significant LSM difference of 32.65 (p = 0.0007). The administration of ferric trimaltol for use in treating or preventing iron deficiency in a human patient with or without anaemia is carried out under fasted conditions because it was previously thought that there would be significant interference in ferric iron uptake in the presence of food through complexing or chelating effects. One general problem with taking any medication under fasted conditions is that this can sometimes lead to higher incidences of unwanted side effects, which can be reduced by administration with food. The inventors have surprisingly observed that, in practice, there is no significant difference in the level of up-take of ferric ions into blood serum between human patients who have fasted or are fed, i.e., area under the curve values are similar. This can offer users the advantage of greater flexibility when taking the treatment and therefore greater compliance. Summary of the invention In a first aspect of the invention, ferric trimaltol for use in treating or preventing iron deficiency in a human patient with or without anaemia, wherein the ferric trimaltol is administered orally in combination with solid and / or liquid food is provided. By the term 'treating iron deficiency' is meant eliminating or reducing iron deficiency. By the term 'ferric trimaltol is administered orally in combination with solid and / or liquid food' or 'ferric trimaltol is subsequently administered, ..., with ... solid and / or liquid food' is meant that solid and / or liquid food is taken by the human patient up to 4, 3, 2, 1, 0.5 hours before or after or simultaneously with administration of the ferric trimaltol. In a second aspect of the invention, use of ferric trimaltol for the manufacture of a medicament for treating or preventing iron deficiency in a human patient with or without anaemia is provided, wherein the ferric trimaltol is administered orally in combination with solid and / or liquid food. In a third aspect of the invention, a method for treating or preventing iron deficiency in a human patient with or without anaemia is provided, wherein an effective amount of ferric trimaltol is administered orally in combination with solid and / or liquid food. Brief description of the figures The invention is further described with reference to: Figure 1 which illustrates a clinical study design schematic (subjects were hospitalized from Period 1, Day -1 and discharged from Period 4, following the 24 hours post-dose sampling; safety blood sampling took place at Period 4 following the 24 hours post-dose sampling and 3 to 7 days post-dose subjects had a telephone safety follow-up; subjects who discontinued early and did not withdraw their consent, needed to attend a safety follow-up 3 to 7 days after drug discontinuation); Figure 2 which is a plot of Mean Serum Iron Concentration (pg / dL) by Formulation / Condition Group on Linear Scale and Semi-Log Scale - FAS Population (FAS = Full Analysis Set; log = logarithmic); Figure 3 which is a plot of Mean Baseline Corrected Serum Iron Concentration (pg / dL) by Formulation / Condition Group on Linear Scale and Semi-Log Scale - FAS Population (values of 0 or below for baseline corrected serum iron were excluded from this analysis; FAS = Full Analysis Set; log = logarithmic); Figure 4 which is a plot of Mean Plasma Maltol Glucuronide Concentration (ng / mL) by Formulation / Condition Group on Linear Scale and Semi-Log Scale - FAS Population (Note: Lower limit of quantification = 125 ng / mL.; FAS = Full Analysis Set; log = logarithmic); and Figure 5 which is a plot of Mean TSAT (%) by Formulation / Condition Group on Linear Scale and Semi-Log Scale - FAS Population (FAS = Full Analysis Set; log = logarithmic; TSAT = transferrin saturation). Detailed description of the invention In a first aspect of the invention, ferric trimaltol for use in treating or preventing iron deficiency in a human patient with or without anaemia, wherein the ferric trimaltol is administered orally in combination with solid and / or liquid food is provided. Ferric trimaltol or ferric maltol is a chemically stable complex formed between ferric iron (Fe3+) and maltol (3-hydroxy-2-methyl-4-pyrone) according to the chemical structure below: The molar ratio of iron to hydroxypyrone is 1:3. Maltol is a naturally occurring sugar derivative and is used in the food industry as a flavour enhancer. Ferric trimaltol may be administered in the form of a capsule or a liquid suspension composition. When ferric trimaltol is administered in the form of a capsule or tablet, the capsule or tablet dosage is typically 30 mg ferric iron equivalent (which equivalent to 231.5 mg ferric trimaltol). Ferric trimaltol in capsule or tablet format is preferably admixed with varying amounts of other excipients such as one or more pharmaceutically acceptable carrier, diluent, or excipient such as a binder, lubricant or disintegrator. Examples of such include, for example, lactose monohydrate, sodium lauryl sulphate, crospovidone, colloidal silicon dioxide, colloidal silicon dioxide, magnesium stearate. Examples of suitable carriers include lactose, gelatin, agar, starch, sucrose, glucose, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and microcrystalline cellulose. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn starch, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, povidone, carboxymethylcellulose, polyethylene glycol and waxes. Lubricants used in these dosage forms may include sodium oleate, sodium stearate, sodium benzoate, sodium acetate, sodium chloride, stearic acid, sodium stearyl fumarate, and talc. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, croscarmellose sodium, and sodium starch glycolate. One embodiment of a 30 mg ferric trimaltol preparation encased in, for example, a gelatine capsule comprises: 231.5mg ferric trimaltol 91.5mg lactose monohydrate 3.0mg sodium lauryl sulphate 9.0mg crospovidone 0.6mg colloidal silicon dioxide 3.0mg magnesium stearate Preferably, the ferric trimaltol is administered orally in the form of a liquid composition or liquid suspension composition. The ferric trimaltol may be in the form of a liquid composition or a liquid suspension composition. The term 'liquid composition' includes a solution of ferric trimaltol in a solvent, such as water, an oil and / or an alcohol, or other pharmaceutically acceptable liquid. The term 'liquid composition' can also encompass emulsions such as oil-in-water liquid emulsions, water-in-oil liquid emulsions, or multiple emulsions. The term 'liquid composition' also encompasses a semi-fluid composition or a semisolid composition. A semisolid composition typically does not hold its shape like a solid but does not flow like a liquid. Examples of semisolid compositions outside the scope of the invention include, for example, foodstuffs such as yoghurt or mayonnaise. The term 'liquid suspension composition' means a composition which comprises a suspension of ferric trimaltol in a liquid medium, for example an aqueous or non-aqueous liquid such as an oil and / or an alcohol, or other pharmaceutically acceptable liquid. The liquid suspension composition may also comprise dissolved ferric trimaltol. The ferric trimaltol may be visible as suspended particles. In one embodiment of the invention, the pH of the liquid composition or liquid suspension composition is controlled to, for example, stabilize the ferric trimaltol. For example, the composition may include an acidity regulator, such as a buffer. For example, the pH of the liquid composition or liquid suspension composition may advantageously be about 6 to about 8, for example from about 6.5 to about 7.5. In another embodiment of the invention, where the pH of the liquid composition or liquid suspension composition is less than about 7, such as when buffered by citric acid / Na citrate, then the addition of further maltol will reduce disproportionation and ensure that the ferric trimaltol in the composition is mainly a 1:3 chelate. The ferric trimaltol may be present in the liquid composition or liquid suspension composition at a concentration of from about 0.6 to about 60, from about 0.3 to about 20, from about 1 to about 10, preferably about 6 mg / ml ferric iron equivalent. In one embodiment of the invention, the liquid composition or liquid suspension composition comprises a sweetening agent. The sweetening agent may be a saccharide or non-saccharide sweetening agent. Suitable sweetening agents include, for example, one or more of aspartame, stevia-based sweetener extract, saccharin, refined sugar, sucralose, neohesperidine dihydrochalcone and hesperidine dihydrochalcone 4'-beta-D-glucoside, or mixtures thereof. The sweetening agent may be present in the liquid composition or liquid suspension composition in an amount of from about 0.1 to about 70 percent (w / v), or from about 1 to about 60 percent (w / v), such as from about 5 to about 40 percent (w / v) or from about 5 to about 20 percent (w / v) or from about 5 to about 10 percent (w / v) based on the total volume of the liquid composition or liquid suspension composition. In one embodiment of the invention, the liquid composition or liquid suspension composition comprises a sweetness enhancer. One example of a suitable sweetness enhancer is a maltol. This may be added separately from the ferric trimaltol. The sweetness enhancer preferably comprises maltol or ethyl maltol, or combinations thereof. The sweetness enhancer may be present in the liquid composition or liquid suspension composition in an amount of from about 0.1 to about 15 percent (w / v), or from about 0.2 to about 10 percent (w / v) or from about 1 to about 5 percent (w / v) based on the total volume of the liquid composition or liquid suspension composition. In another embodiment of the invention, the liquid composition or liquid suspension composition further comprises a flavouring agent. The flavour may be any suitable flavour. The flavour may, for example, be selected from the group consisting of apple, blackcurrant, orange, lemon, grape, maple, raspberry, cherry, menthol, peppermint, spearmint, vanilla, chocolate, strawberry and combinations thereof. The amount of the flavouring agent may be from about 0.01 to about 15 percent (w / v), or from about 0.02 to about 10 percent (w / v) or from about 0.1 to about 5 percent (w / v) based on the total volume of the liquid composition or liquid suspension composition. In another embodiment of the invention, the liquid composition or liquid suspension composition further comprises a preservative. The flavour may, for example, be selected from the group consisting of potassium nitrate, erythorbic acid, benzoic acid, sodium benzoate, potassium sorbate, calcium sorbate and combinations thereof. The amount of the flavouring agent may be from about 0.01 to about 5 percent (w / v), or from about 0.02 to about 2 percent (w / v) or from about 0.1 to about 1 percent (w / v) based on the total volume of the liquid composition or liquid suspension composition. In another embodiment of the invention, the liquid composition or liquid suspension composition further comprises a surfactant. The surfactant may, for example, be selected from the group consisting of alkyl glycosides, carrageenan (carbohydrate), cholesterol, lanolin, lecithin, monoglycerides (fatty acid), phytosterols, proteins, Polysorbate 80, tea saponin extract and combinations thereof. The amount of the surfactant may be from about 0.01 to about 5 percent (w / v), or from about 0.02 to about 2 percent (w / v) or from about 0.1 to about 1 percent (w / v) based on the total volume of the liquid composition or liquid suspension composition. In another embodiment of the invention, the liquid composition or liquid suspension composition further comprises a viscosity modifier such as xanthum gum. These tend to often be the same as suspending agents as described hereinbelow and are used at similar concentrations. In another embodiment of the invention when the composition is or comprises a liquid suspension composition, the liquid suspension composition further comprises a suspending agent. A suspending agent helps to reduce the sedimentation rate of particles in suspension. Suitable examples of suspending agents include methylcellulose, polyvinylpyrrolidone, carboxymethyl cellulose, sodium alginate or povidone and combinations thereof. The amount of the suspending agent may be from about 0.01 to about 15 percent (w / v), or from about 0.02 to about 10 percent (w / v) or from about 0.1 to about 5 percent (w / v), or from about 0.1 to about 2 percent (w / v) based on the total volume of the liquid suspension composition. In one embodiment of the invention, the method of forming the liquid composition or the liquid suspension composition comprises combining ferric trimaltol and other dry ingredients, preferably in a solid or dry form, such as a powder, with a liquid. Alternatively, the ferric trimaltol and other dry ingredients may be combined separately with the liquid, such as water or an oil. One example of a ferric trimaltol oral liquid suspension composition containing 30 mg elemental ferric iron, in the form of 231.5 mg ferric trimaltol in 5 ml liquid suspension composition (6 mg ferric iron equivalent per ml) consists of: 4.69 % w / v ferric trimaltol; 30.60 % w / v viscosity modifier; 0.50 % w / v surfactant; 0.20 % w / v preservative; 5.00 % w / v suspending agent; 0.30 % w / v flavouring agent; 0.20 % w / v sweetening agent; 2.61 % w / v pH regulator; and q.s. diluent. In one embodiment, the iron deficiency is iron deficiency with or without anaemia resulting from one or more of the group consisting of nutritional deficiency, kidney disease, coeliac disease and other malabsorption disorders, inflammatory bowel disease (IBD), menorrhagia, cancer, pregnancy, heart disease and bariatric surgery. In one embodiment, the inflammatory bowel disease is Crohn's disease. Preferably the Crohn's disease is not active, that is to say the human patient has a Crohn's Disease Activity Index of <220. In another embodiment, the inflammatory bowel disease is ulcerative colitis. Preferably the ulcerative colitis is not active, that is to say the human patient has a Simple Clinical Colitis Activity Index (SCCAI) value of <4. In yet another embodiment, when the iron deficiency is iron deficiency with or without anaemia resulting from kidney disease, kidney disease does not include chronic renal disease with an estimated Glomerular Filtration Rate (eGFR) <about 60 mL / min / m2. Preferably the ferric trimaltol is administered in the form of a 30-90, 60-90,15, 30, 60, 90 mg ferric iron equivalent dose once or twice a day where the human patient is an adult, or 15-30 mg ferric iron equivalent dose twice a day where the human patient is 10-17 years old, or 15 mg ferric iron equivalent dose twice a day where the human patient is 2-9 years old. Preferably when the ferric trimaltol is administered twice daily, the ferric trimaltol being administered once in the morning and once during the evening. Furthermore, it is preferred if the ferric trimaltol is administered for at least 24, 20,16,15,14,13,12, 8, 4 weeks. In addition, one option is to continue administering ferric trimaltol subsequent to the expiry of the time period for initial administration set forth hereinabove in the range 15-120 mg ferric iron equivalent once or twice daily, or every two, three, four, five, six or seven days where the human patient is an adult, or 15-30 mg ferric iron equivalent twice a day where the human patient is 10-17 years old, or 15 mg ferric iron equivalent twice a day where the human patient is 2-9 years old, with or without solid and / or liquid food, optionally the ferric trimaltol is administered indefinitely as a maintenance dose. In a second aspect of the invention, use of ferric trimaltol for the manufacture of a medicament for treating or preventing iron deficiency in a human patient with or without anaemia is provided, wherein the ferric trimaltol is administered orally in combination with solid and / or liquid food. In a third aspect of the invention, a method for treating or preventing iron deficiency in a human patient with or without anaemia is provided, wherein an effective amount of ferric trimaltol is administered orally in combination with solid and / or liquid food. The various embodiments, options, and preferred features of the first aspect of the inventions set forth hereinabove are equally applicable to the second and third aspects of the invention. Example A Randomized, Open-Label, Single Dose, 4-Way Crossover, Phase 1 Study to Compare the Pharmacokinetics of Oral Administration of Ferric Trimaltol Capsules and a Liquid Suspension Composition Under Fasted and Fed Conditions in Adult Healthy Volunteers Study Objectives: The primary objectives were to evaluate the pharmacokinetics (PK) of iron absorption after a single 30 mg ferric iron equivalent dose of ferric trimaltol administered as a capsule or liquid suspension (fasted and fed conditions) via primary parameters, maximum observed concentration (Cmax) and area under the plasma concentration curve from 0 up to the last measurable concentration (non-below) quantification limit after dosing (AUCiast). The secondary objectives were to evaluate the PK after a single 30 mg ferric iron equivalent dose of ferric trimaltol administered as a capsule or liquid suspension (fasted and fed conditions) through measurements of transferrin saturation (TSAT), baseline corrected serum iron, transferrin, total iron binding capacity (TIBC), unsaturated iron binding capacity (UIBC), and plasma maltol and maltol glucuronide; and to assess the safety and tolerability of ferric trimaltol after a single dose of 30 mg ferric iron equivalent administered as a capsule or liquid suspension (fasted and fed conditions) based on vital signs, adverse events (AEs), concomitant medications, and routine clinical laboratory safety blood tests. Ferric trimaltol capsules: 30 mg ferric iron equivalent comprising 231.5 mg ferric trimaltol; 91.5 mg lactose monohydrate; 3.0 mg sodium lauryl sulphate; 9.0 mg crospovidone; 0.6 mg colloidal silicon dioxide; and 3.0 mg magnesium stearate. Ferric trimaltol liquid suspension composition (6 mg / ml) comprising 4.69 % w / v ferric trimaltol; 30.60 % w / v viscosity modifier; 0.50 % w / v surfactant; 0.20 % w / v preservative; 5.00 % w / v suspending agent; 0.30 % w / v flavouring agent; 0.20 % w / v sweetening agent; 2.61 % w / v pH regulator; and q.s. diluent. Methodology: This was a Phase 1, randomized, open-label, single dose, 4-way crossover study, to compare the PK of iron and maltol absorption from ferric trimaltol capsules and a ferric trimaltol oral liquid suspension composition under fasted and fed conditions in adult healthy volunteers. The study was comprised of the following stages: Screening: Up to 14 days; Randomized treatment: A treatment period of 4 days with at least a 48-hour washout period between each dose administration. During the crossover PK phase, subjects were randomized in a 1:1:1:1 ratio to receive 1 of the following treatment sequences. Eight subjects were randomized to each sequence: Sequence A: Period 1; single dose of 30 mg ferric trimaltol capsule in a fed condition; Period 2; single dose of 30 mg (5 mL) ferric trimaltol liquid suspension composition in a fed condition; Period 3; single dose of 30 mg ferric trimaltol capsule in a fasted condition; and Period 4; single dose of 30 mg (5 mL) ferric trimaltol liquid suspension composition in a fasted condition. Sequence B: Period 1; single dose of 30 mg (5 mL) ferric trimaltol liquid suspension composition in a fasted condition; Period 2; single dose of 30 mg ferric trimaltol capsule in a fed condition; Period 3; single dose of 30 mg (5 mL) ferric trimaltol liquid suspension composition in a fed condition; and Period 4; single dose of 30 mg ferric trimaltol capsule in a fasted condition. Sequence C: Period 1; single dose of 30 mg ferric trimaltol capsule in a fasted condition; Period 2; single dose of 30 mg (5 mL) ferric trimaltol liquid suspension composition in a fasted condition; Period 3; single dose of 30 mg ferric trimaltol capsule in a fed condition; and Period 4; single dose of 30 mg (5 mL) ferric trimaltol liquid suspension composition in a fed condition. Sequence D: Period 1; single dose of 30 mg (5 mL) ferric trimaltol liquid suspension composition in a fed condition; Period 2; single dose of 30 mg ferric trimaltol capsule in a fasted condition; Period 3; single dose of 30 mg (5 mL) ferric trimaltol liquid suspension composition in a fasted condition; and Period 4; single dose of 30 mg ferric trimaltol capsule in a fed condition. After at least 10 hours of overnight fasting at the Clinical Unit, subjects were randomized to 1 of the 4 treatment sequences. PK samples were collected pre-dose and up to 24 hours postdose during each period (11 times) for the measurements of serum iron, TSAT, TIBC, UIBC, transferrin, and plasma maltol and maltol glucuronide. On Day -1, subjects received standardized meals as well. Figure 1 illustrates a schematic of the study design. Ferric trimaltol capsule and liquid suspension composition fasted conditions Prior to the first treatment period, subjects arrived at the Clinical Unit on Day -1 at least 13 hours before dosing. Eligibility was checked again before randomization and subjects were dosed after the O-hour baseline blood sample according to their randomized sequence. Capsules were taken with 240 mL potable tap water, must have been swallowed whole, and must not have been chewed, divided, or crushed. A 5 mL liquid suspension composition was measured out by using a 3 mL syringe, graduated up to 2.5 mL. Subjects could take the liquid suspension composition with 240 mL potable tap water if needed. Water was allowed during the 10 hours of fasting but was not allowed for 1 hour before and 2 hours post-dose (except for study drug administration). No food was allowed for at least 4 hours post dose. Within 30 minutes following the 4 hours post-dose blood samples, subjects received a standardized meal. Blood samples were taken at 11 additional times after dosing; post-dose PK sample times were 15 minutes ± 2 minutes, 30 minutes ± 2 minutes, 45 minutes ± 5 minutes, 1 hour ± 5 minutes, 1.5 hours ± 5 minutes, 2 hours ± 5 minutes, 3 hours ± 5 minutes, 4 hours ± 5 minutes, 6 hours ± 10 minutes, 10 hours ± 15 minutes, and 24 hours ± 15 minutes. Standard meals were provided to the subjects at 4, 8, and 12 hours after study drug administration in the morning. Meals were identical in each treatment period. Iron content and time of consumption of each meal was recorded during the hospitalization. Subjects stayed in the Clinical Unit throughout the study period. During the washout, subjects stayed at the Clinical Unit and received standard meals. Iron content of the meals was measured. Ferric trimaltol capsule and liquid suspension composition fed conditions Prior to the first treatment period, subjects arrived at the Clinical Unit on Day -1 at least 13 hours before dosing. Eligibility was checked again before randomization. Subjects then had their baseline blood samples taken and received a test meal 30 minutes prior to administration of ferric trimaltol. Subjects finished their meal in 30 minutes or less; however, ferric trimaltol was administered 30 minutes after start of the meal. Capsules were taken with 240 mL potable tap water. Liquid suspension composition was taken with 240 mL potable tap water if needed. Water was allowed during the 10 hours fasting but not allowed for 1 hour before and 2 hours post dose (except for study drug administration). No food was allowed for at least 4 hours post dose. Within 30 minutes following the 4 hours post-dose blood samples, subjects received a standardized meal. Blood samples were taken at 11 additional times after dosing; post-dose PK sample times were 15 minutes ± 2 minutes, 30 minutes ± 2 minutes, 45 minutes ± 5 minutes, 1 hour ± 5 minutes, 1.5 hours ± 5 minutes, 2 hours ± 5 minutes, 3 hours ± 5 minutes, 4 hours ± 5 minutes, 6 hours ± 10 minutes, 10 hours ± 15 minutes, and 24 hours ± 15 minutes. Standard meals were provided to the subjects at 4, 8, and 12 hours after study drug administration in the morning. Meals were identical in each treatment period. Iron content and time of consumption of each meal were recorded during the hospitalization. The test meal consisted of 164, 192, and 576 calories from protein, carbohydrates, and fat, respectively. This meal included the following: 2 eggs fried in butter, 4 strips of bacon, / 2 cup of hash browns, 2 pieces of white toast with 2 tablespoons of butter, and 8 ounces of water. Substitutions in this meal could be made as long as the meal provided a similar amount of calories from protein, carbohydrates, and fat and had comparable meal volume and viscosity. Subjects stayed in the Clinical Unit throughout the study period. During the washout, subjects stayed at the Clinical Unit and received standard meals. Iron content of the meals was measured. Number of Subjects: Completed: 32 subjects completed Discontinued: 0 subjects discontinued from the study Diagnosis and Main Criteria for Inclusion: The population for the study included healthy adult subjects, 18 to 55 years of age. The subject must have had a body mass index of 18 to 32 kg / m2. Exclusion Criteria: A subject who met any of the following criteria was not eligible for participation in the study: 1. Presence or history of any other condition (including surgery) known to interfere with the absorption, distribution, metabolism, or excretion of medicines; 2. Donation or loss of 550 mL or more blood volume or receipt of a transfusions of any blood product within 8 weeks prior to study drug administration and 14 days for plasma donation unless medically inadvisable; 3. Use of any over-the-counter (OTC) medications, including herbal product within 7 days prior to Screening until study completion. Except for ordinary pain (eg, headache), some analgesics (mainly paracetamol), and contraception which had no drug interactions with the study drug given; 4. Has received within 28 days prior to Screening intramuscular or IV injection or administration of depot iron preparation; 5. Had received oral iron supplementation within 7 days prior to Screening; and 6. Had concomitant disease that would significantly compromise iron absorption or absorbed iron utilization such as swallowing disorders, gastric pH-disturbance, and / or extensive small bowel resection. Concomitant Therapy Not permitted 1. Treatment with other oral iron preparations (prescription and non-prescription) within 7 days prior to Screening and throughout the study period; 2. Treatment with parenteral iron preparations within 28 days prior to Screening and throughout the study period; 3. Oral antibiotics, which were prohibited at Screening and during the study; 4. Blood transfusions within 12 weeks before Screening and during the study; 5. Erythropoiesis stimulating agents within 28 days before Screening and during the study; 6. Multivitamins within 7 days prior to Screening and throughout the study period; and 7. Other prescription or OTC medications, including herbal products, from Screening until study completion. Primary endpoint: 1. PK analysis of total serum iron concentration; Cmax and AUCiast in fasted and fed conditions. Secondary endpoints: 1. PK analysis of total serum iron concentration; area under the plasma concentration curve for 0 to infinity (AUCinf) in fasted and fed conditions; 2. PK analysis of baseline corrected serum iron concentration; Cmax, AUCiast, and AUCinf in fasted and fed conditions; 3. PK analysis of maltol and maltol glucuronide in plasma; Cmax and AUCiast in fasted and fed conditions; 4. PK analysis of TSAT, TIBC, UIBC, and transferrin; Cmax and AUCiast in fasted and fed conditions; 5. Treatment-emergent adverse events (TEAEs); 6. Serious adverse events (SAEs); 7. TEAEs leading to premature discontinuation of study drug / PK assessments; 8. Clinical laboratory safety blood results; 9. Changes in vital signs; and 10. Concomitant medications. Statistical Methods: Analysis day was calculated from the date of first dose of study drug. The day of the first dose of study drug was Day 1, and the day immediately before Day 1 was Day -1. There was no Day 0. Baseline was defined as readings or measurements at Day 1 prior to study drug administration of each period. If the reading at Day 1 pre-dose was missing, the last reading before first dosing was set as baseline. All subjects who had at least 1 dose of study drug and 1 subsequent contact with the Investigator were analyzed for safety. All subjects who had at least 1 dose of study drug and 1 evaluable post-dose PK sample were included in the Full Analysis Set (FAS) Population. This population was utilized for the PK analysis. To compare the PK of ferric trimaltol capsules and liquid liquid suspension under fasted and fed conditions, a subject must have had a calculable PK parameter for both formulations under fasted and fed conditions. An analysis of variance model was performed on the In-transformed PK parameters (Cmax, AUCiast, and AUCinf) of the 2 formulations including terms for sequence (treatment sequence), treatment (formulation / condition), period as fixed effects, and subjects nested within a sequence as a random effect. The estimates were back-transformed into original scale. The point estimates for ratios and the corresponding 90 % Cis (confidence intervals) are provided. Pharmacokinetics: PK samples were collected on Day 1 to Day 8, pre-dose, and post-dose according to the PK Sample Schedule Group that the subject was assigned to. On all 4 PK study days, all subjects had baseline PK blood samples collected immediately prior to Ferric trimaltol dosing (0 hours). Subjects then had further PK blood samples collected at 11 additional times after dosing; the post-dose PK sample times were 15 minutes ±2 minutes, 30 minutes ±2 minutes, 45 minutes ±5 minutes, 1 hour ±5 minutes, 1.5 hours ±5 minutes, 2 hours ±5 minutes, 3 hours ±5 minutes, 4 hours ±5 minutes, 6 hours ±10 minutes, 10 hours ±15 minutes, and 24 hours ±15 minutes. For each individual subject, the post-dose PK blood sampling schedule was the same on all 4 PK days. PK blood samples on the PK days were serum iron, TIBC, UIBC, transferrin, TSAT, maltol, and maltol glucuronide. The actual collection times were used for the calculation of PK parameters. The Linear Up Log Down method (equivalent to the Linear Up / Log Down option in WinNonlin® Professional) was used in the computation of AUG, if applicable. Parameters are listed by treatment sequence group for each individual subject and summarized by formulation / condition using the following descriptive statistics: the number of subjects, arithmetic mean, SD, geometric mean, geometric coefficient of variation, median, minimum, and maximum. To compare the PKof ferric trimaltol capsules and oral liquid suspension under fasted and fed conditions, a subject must have had a calculable PK parameter for both formulations under fasted and fed conditions. An analysis of variance model was performed on the In-transformed PK parameters (Cmax, AUCiast, and AUCinf) of the two formulations including terms for sequence (treatment sequence), treatment (formulation / condition), period as fixed effects, and subjects nested within a sequence as a random effect. The estimates were back-transformed into original scale. The point estimates for ratios and the corresponding 90% confidence intervals (Cis) are provided. The PK parameters analyses were based on the FAS Population. Safety: Safety analyses were performed based on the Safety Population. Safety was evaluated through assessments of AEs, TEAEs, electrocardiograms (ECGs), vital signs, physical examinations, and clinical laboratory tests. Summary of Results: Pharmacokinetics The primary objective of this study was to evaluate the PK of iron absorption after a single 30 mg dose of ferric trimaltol administered as a capsule or oral liquid suspension (fasted and fed conditions) via primary parameters Cmax and AUCiast. Of note, the ferric trimaltol capsule / fasted formulation is the current administration in adults recommended by the package insert of the approved product. Overall, the mean Cmax and AUCiast of serum iron was higher for the ferric trimaltol capsule administered in the fasted condition compared to all other treatments. Additionally, as might be expected, Tmax of serum iron was slightly delayed in both capsule and liquid suspension formulations when a high fat meal was consumed 30 minutes prior to administration of ferric trimaltol compared to the fasted condition. For the fasted condition, the ratios of Cmax, AUCiast, and AUCinf geometric LS means (90% Cl) for serum iron were 69.94% (61.75, 79.23), 77.54% (70.38, 85.42), and 78.16% (65.64, 93.06), respectively, comparing the liquid suspension versus capsule. The geometric LS mean of Cmax in the ferric trimaltol liquid suspension / fasted group was lower than that in the ferric trimaltol capsule / fasted group and the 90% Cl was below 80%. These findings indicate that, in the fasted condition, ferric trimaltol capsule and liquid suspension composition had different PK with respect to Cmax but a definitive difference in PK was not observed with respect to AUCiast and AUCinf. For the capsule formulation, the ratios of Cmax, AUCiast, and AUCinf geometric LS means (90% Cl) were 147.27% (130.01, 166.81), 134.25% (121.86, 147.91), and 137.53% (114.45, 165.26), respectively, comparing fasted versus fed conditions. These findings indicate that a food effect was observed for ferric trimaltol capsule with respect to Cmax but a definitive food effect was not observed with respect to AUCiast and AUCinf as they were considered statistically equivalent (values within 80 and 125 % are assumed equivalent and as the lower Cl for these two values were <125 % no definitive effect was observed). For the liquid suspension formulation, the ratios of Cmax, AUCiast, and AUCinf geometric LS means (90% Cl) were 103.93% (91.75, 117.72), 107.32% (97.41, 118.24), and 96.10% (76.45, 120.79), respectively, comparing fasted versus fed conditions. These findings indicate that the ferric trimaltol liquid suspension composition had similar PK when administered in fasted or fed conditions with respect to Cmax and AUCiast as they were considered statistically equivalent. For the fed condition, the ratios of Cmax, AUCiast, and AUCinf geometric LS means (90% Cl) for serum iron were 99.11% (87.50, 112.27), 96.99% (88.04, 106.86), and 111.86% (87.36, 143.23), respectively, comparing the liquid suspension composition versus capsule. These findings indicate that, in the fed condition, ferric trimaltol capsule and liquid suspension composition had similar PK with respect to Cmax and AUCiast and a definitive difference in PK was not observed for AUCinf. The secondary endpoint iron parameters, baseline corrected serum iron and TSAT, were consistent with the primary endpoint findings, although the formulation effect and capsule food effect differences were more marked with baseline corrected serum iron. No formulation or food effects were recorded for any of the other secondary iron parameters (i.e., TIBC, UIBC, and transferrin). For the fasted condition, the ratios of Cmax, AUCiast, and AUCinf geometric LS means (90% Cl) for maltol glucuronide were 156.74% (139.27, 176.39), 116.62% (110.72, 122.83), and 114.00% (109.81, 118.35) comparing the liquid suspension versus capsule formulations. These findings indicate that, in the fasted condition, there was a formulation effect with respect to Cmax showing higher concentrations in the liquid suspension composition group, but ferric trimaltol had similar PK when administered as a liquid suspension or capsule with respect to AUCiast and AUCinf. For the capsule formulation, the ratios of Cmax, AUCiast, and AUCinf geometric LS means (90% Cl) for maltol glucuronide were 144.94% (128.79, 163.12), 124.33% (118.04, 130.96), and 112.21% (106.89, 117.78), respectively, comparing fasted versus fed conditions. These findings indicate that a food effect was observed for ferric trimaltol capsule with respect to Cmax but a definite food effect was not observed with respect to AUCiast or AUCinf. For the liquid suspension formulation, the ratios of Cmax, AUCiast, and AUCinf geometric LS means (90% Cl) for maltol glucuronide were 229.18% (203.65, 257.92), 136.15% (129.26, 143.40), and 131.07% (126.25,136.08) comparing fasted versus fed conditions. These findings indicate that a food effect was observed for ferric trimaltol liquid suspension composition with respect to Cmax, AUCiast, and AUCinf. It is noted that the overall exposure of maltol and maltol glucuronide are less influenced by physiological iron status compared to the iron PK parameters. Safety Overall, 8 (25.0%) subjects experienced TEAEs: 3 (9.4%) subjects each in the ferric trimaltol liquid suspension composition / fed and ferric trimaltol liquid suspension composition / fasted treatment periods and 2 (6.3%) subjects in the ferric trimaltol capsule / fasted treatment period. All TEAEs were mild in severity. There were no study drug-related TEAEs. There were no SAEs, serious TEAEs, or TEAEs leading to discontinuation of study drug, discontinuation from the study, or death. The most commonly reported TEAE was headache (3 [9.4%] subjects): 1 (3.1%) subject in the ferric trimaltol capsule / fasted treatment period and 2 (6.3%) subjects in the ferric trimaltol liquid suspension composition / fasted treatment period. There was a single Gl TEAE: 1 (3.1%) subject in the ferric trimaltol liquid suspension composition / fasted treatment period experienced hypoesthesia oral. There were no clinically significant changes from baseline in laboratory parameters during the study. There were no clinically significant changes from baseline in vital signs or physical examinations. There were no clinically significant, abnormal 12-lead ECG parameters at Screening. Ferric trimaltol was safe and well-tolerated after a single dose of 30 mg administered as a capsule or oral liquid suspension in fasted and fed conditions in healthy adult subjects. There were no apparent differences between the formulations (liquid suspension versus capsule) in the number of AEs and no study drug-related TEAEs for either formulation. Conclusions: Both capsule and liquid suspension composition of ferric trimaltol in fasted and fed conditions were readily absorbed with mean serum iron concentrations returning to baseline or slightly below at 24 hours. The mean Cmax and AUCiast of serum iron was higher for the ferric trimaltol capsule administered in the fasted condition compared to all other treatments. Additionally, as expected, Tmax was delayed in both capsule and liquid suspension formulations when a high fat meal was consumed 30 minutes prior to administration of ferric trimaltol compared to the fasted condition. In the fasted condition, ferric trimaltol capsule and liquid suspension composition had different serum iron PK with respect to Cmax but a definitive difference in PK was not observed with respect to AUCiast and AUCinf. In the fed condition, ferric trimaltol capsule and liquid suspension composition had similar PK with respect to Cmax and AUCiast. A food effect was observed for ferric trimaltol capsule with respect to Cmax but a definitive food effect was not observed with respect to AUCiast and AUCinf. Ferric trimaltol liquid suspension composition had similar serum iron PK when administered in fasted or fed conditions with respect to Cmax and AUCiast. The Cmax data suggest that there might be a formulation effect in the fasted state in favor of the capsule with respect to serum iron levels but this was not definitively supported by AUCiast and AUCinf comparisons, nor was this supported by the maltol and maltol glucuronide PK. Overall, 8 (25.0%) subjects experienced TEAEs: 3 (9.4%) subjects each in the ferric trimaltol liquid suspension composition / fed and ferric trimaltol liquid suspension composition / fasted treatment periods and 2 (6.3%) subjects in the ferric trimaltol capsule / fasted treatment period. All TEAEs were mild in severity. There were no study drug-related TEAEs. There were no SAEs, serious TEAEs, or TEAEs leading to discontinuation of study drug, discontinuation from the study, or death. The most commonly reported TEAE was headache (3 [9.4%] subjects): 1 (3.1%) subject in the ferric trimaltol capsule / fasted treatment period and 2 (6.3%) subjects in the ferric trimaltol liquid liquid suspension / fasted treatment period. There were no clinically significant changes from baseline in laboratory parameters during the study. There were no clinically significant changes from baseline in vital signs or physical examinations. There were no clinically significant, abnormal 12-lead ECG parameters at Screening. Ferric trimaltol was safe and well-tolerated after a single dose of 30 mg administered as a capsule or oral liquid suspension in fasted and fed conditions in healthy adult subjects. There were no apparent differences between the formulations (liquid suspension versus capsule) in the number of AEs and no study drug-related TEAEs for either formulation. List of abbreviations and definition of terms: Az Apparent terminal elimination rate constant AE Adverse event AUC Area under the plasma concentration curve AUCinf Area under the plasma concentration curve for 0 to infinity AUCiast Area under the plasma concentration curve from 0 up to the last measurable concentration (non-below) quantification limit after dosing BID Twice daily BQL Below the quantifiable limit Cl Confidence interval CKD Chronic kidney disease Cmax Maximum observed concentration CRA Clinical Research Associate CV Coefficient of variation ECG Electrocardiogram FAS Full Analysis Set Gl Gastrointestinal Hb Hemoglobin IBD Inflammatory bowel disease ICF Informed consent form ID Iron deficiency IDA Iron deficiency anemia IRB Institutional Review Board IV Intravenous LLOQ Lower limit of quantification LS Least squares MedDRA Medical Dictionary for Regulatory Activities NCA Non-compartmental analysis NTBI Non-transferrin bound iron OFP Oral ferrous product PIP Pediatric Investigation Plan PK Pharmacokinetic(s) PT Preferred term RT-PCR Real-time reverse transcriptase-polymerase chain reaction SAE Serious adverse event SOC System organ class t1 / 2 Apparent terminal elimination half-life TEAE Treatment-emergent adverse event TIBC Total iron binding capacity Tlag Delay between the time of dosing and time of appearance of concentration in the sampling compartment Tmax Time to maximum plasma concentration TSAT Transferrin Saturation UIBC Unsaturated iron binding capacity Data: 5 Demographic and Other Baseline Characteristics Table 1 Table 1: Demographic and Baseline Characteristics by treatment sequence - Randomized Population summarizes demographic and baseline characteristics by treatment 10 sequence for the Randomized Population. The mean age of subjects in each treatment sequence ranged from 33.6 to 40.5 years and the mean BMI of subjects in each treatment sequence ranged from 23.51 to 28.55 kg / m2. Most subjects were Black or African American and the majority were not Hispanic or Latino. There were a similar number of male and female subjects in each treatment sequence. 15 Table 1: Demographic and Baseline Characteristics by treatment sequence - Randomized Population Characteristic Statistic / Category Treatment sequence A Treatment sequence B Treatment sequence C Treatment sequence D n 8 8 8 8 Mean (SD) 38.1 (10.30) 34.0 (11.05) 33.6 (6.44) 40.5 (8.82) Sex, n (%) Male 5 (62.5) 5 (62.5) 4 (50.0) 3 (37.5) Female 3 (37.5) 3 (37.5) 4 (50.0) 5 (62.5) Childbearing potential, n (%) Yes 2 (66.7) 2 (66.7) 2 (50.0) 2 (40.0) No 1 (33.3) 1 (33.3) 2 (50.0) 3 (60.0) Race, n (%) Black or African American 8 (100.0) 6 (75.0) 5 (62.5) 5 (62.5) White 0 (0.0) 2 (25.0) 3 (37.5) 3 (37.5) Other 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Ethnicity, n (%) Hispanic or Latino 0 (0.0) 0 (0.0) 1 (12.5) 2 (25.0) Not Hispanic or Latino 8 (100.0) 8 (100.0) 7 (87.5) 6 (75.0) Height (cm) n 8 8 8 8 Mean (SD) 175.56 (13.518) 174.76 (8.065) 168.49 (7.776) 165.68 (11.042) Weight (kg) n 8 8 8 8 Mean (SD) 88.57 (16.774) 72.61 (16.878) 75.05 (14.306) 74.86 (11.920) BMU (kg / m2) n 8 8 8 8 Mean (SD) 28.55 (2.660) 23.51 (3.418) 26.37 (4.466) 27.15 (2.024) Serum iron concentrations The change from baseline serum iron after administration of ferric trimaltol is a measure of iron absorption from ferric trimaltol and is measured using standard clinical laboratory diagnostic tests (fully automated chemistry analyzers using a colorimetric reaction with ferrine or ferrozine as a chromogen to form a color complex with iron). Figure 2 presents the plot of mean serum iron concentration by formulation / condition group on linear scale and semi-log scale for the FAS Population. Both capsule and liquid suspension composition of ferric trimaltol in fasted and fed conditions were readily absorbed with mean serum iron concentrations returning to baseline or slightly below at 24 hours. After 2 hours post-dose, the mean serum iron concentration of the ferric trimaltol capsule / fasted condition was higher than all other treatments studied. Serum iron PK parameters Table 2 presents a summary of PK parameters for serum iron for the FAS Population. The mean range of Cmaxfor serum iron was 112.125 to 162.156 ng / mL with all treatments displaying an approximate mean serum Cmax of 115 ng / mL besides ferric trimaltol capsule / fasted, which had a mean Cmax of 162.156 ng / mL. The mean range of Az was 0.051 to 0.070 / hour and the mean range of t% was 15.836 to 19.039 hours across all treatments. The mean serum AUCiast in the ferric trimaltol capsule / fasted group was 2383.54 h*ng / mL, while the mean range for the other treatments was 1753.69 to 1876.68 h*ng / mL. The mean range 5 for AUCinf was 2922.46 to 3694.05 h*ng / mL and the highest AUCinf level was observed in the ferric trimaltol capsule / fasted group. The appearance of the Cmax for serum iron, noted as Tmax, was slightly delayed in both ferric trimaltol capsule and liquid suspension formulations in the fed condition compared to the 10 same formulations in the fasted condition. Table 2: Summary of PK Parameters for Serum Iron - FAS Population Formulation / Condition Statistic Cmax (ng / mL) Tmax (h) Az (1 / h) (h) AUCiast (h*ng / mL) AUCinf (h*ng / mL) Ferric trimaltol capsule / fed n 32 32 10 10 32 10 Mean 119.313 7.398 0.054 15.836 1831.74 2922.46 SD 69.0920 9.1629 0.0338 5.7522 718.965 1052.148 Median 100.000 3.500 0.044 16.139 1624.45 3008.12 Minimum 38.00 0.00 0.03 4.87 760.8 1064.5 Maximum 323.00 24.00 0.14 22.30 3410.3 4311.8 Geometric mean 104.634 5.444 0.048 14.574 1705.15 2711.73 Geometric CV% 53.9 177.1 50.1 50.1 40.1 46.0 Ferric trimaltol liquid suspension / fed n 32 32 10 10 32 10 Mean 113.656 5.461 0.070 18.655 1753.69 3330.98 SD 51.1043 7.4920 0.0436 24.1518 631.660 2128.861 Median 102.000 3.500 0.061 11.521 1653.13 2717.60 Minimum 41.00 0.00 0.01 4.56 817.9 1252.5 Maximum 258.00 24.00 0.15 86.04 3800.2 7799.7 Geometric mean 103.705 3.512 0.055 12.504 1653.90 2816.90 Geometric CV% 45.7 173.7 98.3 98.3 35.8 66.2 Ferric trimaltol capsule / fasted n 32 32 19 19 32 19 Mean 162.156 3.726 0.066 15.843 2383.54 3694.05 SD 49.6661 4.0687 0.0306 17.8875 661.742 1561.138 Median 162.000 2.000 0.059 11.848 2400.45 3306.39 Minimum 53.00 1.00 0.01 5.41 907.4 1505.6 Maximum 268.00 24.00 0.13 83.90 4016.8 8310.7 Geometric mean 154.090 2.868 0.057 12.055 2289.24 3424.80 Geometric CV% 35.0 71.5 71.0 71.0 30.5 41.4 Ferric trimaltol liquid suspension / fasted n 32 32 13 13 32 13 Mean 112.125 3.211 0.051 19.039 1876.68 3445.41 SD 31.7498 2.7534 0.0227 14.7037 642.360 2615.954 Median 111.500 2.000 0.054 12.879 1836.76 3025.50 Minimum 52.00 0.00 0.01 8.26 796.2 1146.1 Maximum 205.00 10.00 0.08 53.66 3936.4 10939.3 Geometric mean 107.778 2.326 0.044 15.601 1774.97 2818.88 Geometric CV% 29.6 108.3 66.5 66.5 35.4 70.1 The actual collection times were used for the calculation of PK parameters. The Linear Up Log Down method (equivalent to the Linear Up / Log Down option in WinNonlin’ Professional) was used in the computation of AUC, if applicable. The Az was presented for subjects who exhibited a terminal elimination phase in their concentration-time profiles. If Az was not assigned, the values of associated PK parameters (eg, Az, AUCinf, or t / ,) were not calculated. Az = apparent terminal elimination rate constant; AUC = area under the plasma concentration curve; AUCinf = area under the plasma concentration curve for 0 to infinity; AUCiast = area under the plasma concentration curve from 0 up to the last measurable concentration (non-below) quantification limit after dosing; Cmax = maximum plasma concentration; CV = coefficient of variation; FAS = Full Analysis Set; N / A = not applicable; PK = pharmacokinetic(s); SD = standard deviation; t / ,= apparent terminal elimination half-life; Tmax = time to maximum plasma concentration; h = hours Serum iron comparative analysis To assess the impact of formulation of ferric trimaltol on the PK of serum iron, an ANOVA model was performed on the In-transformed PK parameters (Cmax, AUCiast, and AUCinf) of the 5 2 formulations including terms for sequence (treatment sequence), treatment (formulation / condition), and period as fixed effects, and subjects nested within a sequence as a random effect. Table 3 presents an analysis of PK parameters for serum iron in the fasted condition for the FAS Population. For the fasted condition, the ratios of Cmax, AUCiast, and AUCinf geometric LS means (90% Cl) 5 for serum iron were 69.94% (61.75, 79.23), 77.54% (70.38, 85.42), and 78.16% (65.64, 93.06), respectively, comparing the liquid suspension composition versus capsule. The geometric LS mean of Cmax in the ferric trimaltol liquid suspension composition / fasted group was lower than in the ferric trimaltol capsule / fasted group and the 90% Cl was below 80%. These findings indicate that, in the fasted condition, ferric trimaltol capsule and liquid suspension 10 composition had different PK with respect to Cmax but a definitive difference in PK was not observed with respect to AUCiast and AUCinf. Table 3: Analysis of PK Parameters for Serum Iron in Fasted Condition - FAS Population Parameter Statistic Ferric Trimaltol Capsule / Fasted (N = 32) Ferric Trimaltol liquid suspension / Fasted (N = 32) Cmax (ng / mL) n 32 32 Geometric LS mean 154.09 107.78 Treatment comparison ferric trimaltol liquid suspension / fasted vs capsule / fasted Ratio of geometric LS mean (%) 69.94 90% Cl for ratio (%) (61.75, 79.23) AUCiast (h*ng / mL) n 32 32 Geometric LS mean 2289.24 1774.97 Treatment comparison ferric trimaltol liquid suspension / fasted vs capsule / fasted Ratio of geometric LS mean (%) 77.54 90% Cl for ratio (%) (70.38, 85.42) AUCmf (h*ng / mL) [1] n 19 13 Geometric LS mean 3854.96 3013.01 Treatment comparison ferric trimaltol liquid suspension / fasted vs capsule / fasted Ratio of geometric LS mean (%) 78.16 90% Cl for ratio (%) (65.64, 93.06) An ANOVA model was performed on the In-transformed PK parameters (Cmax, AUCiast, and AUCinf) of the 2 formulations including terms for sequence (treatment sequence), treatment (formulation / condition), and period as fixed effects, and subjects nested within a sequence as a random effect. The estimates were back-transformed into original scale. Ratios were defined as Cmax(liquid suspension) / Cmax(capsule) and AUCiast(liquid suspension) / AUCiast(capsule), AUCinf(liquid suspension) / AUCinf(capsule) in the fasted condition. 1. Serum iron Zz and its derived parameters were also calculated for profiles where AUCextrap >20% and were included in all analyses. For all other analytes, Zz and its derived parameters were not calculated for profiles with AUCextrap >20%. Az = apparent terminal elimination rate constant; ANOVA = analysis of variance; AUCextrap = area under the plasma concentration curve from 0 to infinity extrapolated; AUCinf = area under the plasma concentration curve from 0 to infinity; AUCiast = area under the plasma concentration curve from 0 up to the last measurable concentration (non-below) quantification limit after dosing; Cl = confidence interval; Cmax = maximum observed concentration; FAS = Full Analysis Set; In = natural logarithm; LS = least squares; PK = pharmacokinetic(s); vs = versus. Table 4 presents an analysis of PK parameters for serum iron in fed condition for the FAS Population. 5 For the fed condition, the ratios of Cmax, AUCiast, and AUCinf geometric LS means (90% Cl) for serum iron were 99.11% (87.50, 112.27), 96.99% (88.04, 106.86), and 111.86% (87.36, 143.23), respectively, comparing the liquid suspension composition versus capsule. These findings indicate that, in the fed condition, ferric trimaltol capsule and liquid suspension composition had similar PK with respect to Cmax and AUCiast and a definitive difference in PK 10 was not observed for AUCinf. Table 4: Analysis of PK Parameters for Serum Iron in Fed Condition - FAS Population Parameter Statistic Ferric Trimaltol Capsule / Fed (N = 32) Ferric Trimaltol Liquid suspension / Fed (N = 32) Cmax (ng / mL) n 32 32 Geometric LS mean 104.63 103.71 Treatment comparison ferric trimaltol liquid suspension / fed vs capsule fed Ratio of geometric LS mean (%) 99.11 90% Cl for ratio (%) (87.50, 112.27) AUCiast (h*ng / mL) n 32 32 Geometric LS mean 1705.15 1653.90 Treatment comparison ferric trimaltol liquid suspension / fed vs capsule / fed Ratio of geometric LS mean (%) 96.99 90% Cl for ratio (%) (88.04, 106.86) AUCmf (h*ng / mL) [1] n 10 10 Geometric LS mean 2803.03 3135.36 Treatment comparison ferric trimaltol liquid suspension / fed vs capsule / fed Ratio of geometric LS mean (%) 111.86 90% Cl for ratio (%) (87.36, 143.23) An ANOVA model was performed on the In-transformed PK parameters (Cmax, AUCiast, and AUCinf) of the 2 formulations including terms for sequence (treatment sequence), treatment (formulation / condition), and period as fixed effects, and subjects nested within a sequence as a random effect. The estimates were back-transformed into original scale. Ratios were defined as Cmax(liquid suspension) / Cmax(capsule) and AUCiast(liquid suspension) / AUCiast(capsule), AUCinf(liquid suspension) / AUCinf(capsule) in the fed condition. 1. Serum iron Az and its derived parameters were also calculated for profiles where AUCextrap >20% and were included in all analyses. For all other analytes, Az and its derived parameters were not calculated for profiles With AUCextrap >20%. Az = apparent terminal elimination rate constant; ANOVA = analysis of variance; AUCextrap = area under the plasma concentration curve from 0 to infinity extrapolated; AUCinf = area under the plasma concentration curve from 0 to infinity; AUCiast = area under the plasma concentration curve from 0 up to the last measurable concentration (non-below) quantification limit after dosing; Cl = confidence interval; Cmax = maximum observed concentration; FAS = Full Analysis Set; In = natural logarithm; LS = least squares; PK = pharmacokinetic(s); vs = versus. Serum iron food effect analysis Table 5Error! Reference source not found, presents an analysis of PK parameters for serum iron for fasted versus fed conditions by formulation for the FAS Population. To assess the impact of a high fat meal on the PK of ferric trimaltol, an ANOVA model was performed on the In-transformed PK parameters (Cmax, AUCiast, and AUCinf) of the 2 formulations including terms for sequence (treatment sequence), treatment (formulation / condition), and period as fixed effects, and subjects nested within a sequence as a random effect. For the capsule formulation, the ratios of Cmax, AUCiast, and AUCinf geometric LS means (90% 5 Cl) were 147.27% (130.01, 166.81), 134.25% (121.86, 147.91), and 137.53% (114.45, 165.26), respectively, comparing fasted versus fed conditions. These findings indicate that a food effect was observed for ferric trimaltol capsule with respect to Cmax but a definitive food effect was not observed with respect to AUCiast and AUCinf as they were considered statistically equivalent. 10 For the liquid suspension formulation, the ratios of Cmax, AUCiast, and AUCinf geometric LS means (90% Cl) were 103.93% (91.75, 117.72), 107.32% (97.41, 118.24), and 96.10% (76.45, 120.79), respectively, comparing fasted versus fed conditions. These findings indicate that the ferric trimaltol liquid suspension composition had similar PK when administered in fasted or 15 fed conditions with respect to Cmax and AUCiast as they were considered statistically equivalent (the AUCinf fell below 80 % therefore there is no definitive conclusion). Table 5: Analysis of PK Parameters for Serum Iron for Fasted vs Fed Condition by Formulation - FAS Population Formulation Parameter Statistic Ferric Trimaltol Fed (N = 32) Ferric Trimaltol Fasted (N =32) Capsule Cmax (ng / mL) n 32 32 Geometric LS mean 104.63 154.09 Treatment comparison ferric trimaltol fasted vs fed Ratio of geometric LS mean (%) 147.27 90% Cl for ratio (%) (130.01, 166.81) AUCiast (h*ng / mL) n 32 32 Geometric LS mean 1705.15 2289.24 Treatment comparison ferric trimaltol fasted vs fed Ratio of geometric LS mean (%) 134.25 90% Cl for ratio (%) (121.86, 147.91) AUCinf (h*ng / mL) [1] n 10 19 Geometric LS mean 2803.03 3854.96 Treatment comparison ferric trimaltol fasted vs fed Ratio of geometric LS mean (%) 137.53 90% Cl for ratio (%) (114.45, 165.26) Liquid suspension composition Cmax (ng / mL) n 32 32 Geometric LS mean 103.71 107.78 Treatment comparison ferric trimaltol fasted vs fed Ratio of Geometric LS Mean (%) 103.93 90% Cl for ratio (%) (91.75, 117.72) AUCiast (h*ng / mL) n 32 32 Geometric LS mean 1653.90 1774.97 Treatment comparison ferric trimaltol fasted vs fed Ratio of Geometric LS Mean (%) 107.32 90% Cl for ratio (%) (97.41, 118.24) AUClnf(h*ng / mL) [1] n 10 13 Geometric LS mean 3135.36 3013.01 Treatment comparison ferric trimaltol fasted vs fed Ratio of geometric LS mean (%) 96.10 90% Cl for ratio (%) (76.45, 120.79) An ANOVA model was performed on the In-transformed PK parameters (Cmax, AUCiast, and AUCinf) of the 2 formulations including terms for sequence (treatment sequence), treatment (formulation / condition), and period as fixed effects, and subjects nested within a sequence as a random effect. The estimates were back-transformed into original scale. Ratios were defined as Cmax(fasted) / Cmax(fed), AUCiast(fasted) / AUCiast(fed), and AUCinf(fasted) / AUCinf(fed). 1. Serum iron Az and its derived parameters were also calculated for profiles where AUCextrap >20% and were included in all analyses. For all other analytes, Az and its derived parameters were not calculated for profiles With AUCextrap >20%. Az = apparent terminal elimination rate constant; ANOVA = analysis of variance; AUCextrap = area under the plasma concentration curve from 0 to infinity extrapolated; AUCinf = area under the plasma concentration curve from 0 to infinity; AUCiast = area under the plasma concentration curve from 0 up to the last measurable concentration (non-below) quantification limit after dosing; Cl = confidence interval; Cmax = maximum observed concentration; FAS = Full Analysis Set; In = natural logarithm; LS = least squares; PK = pharmacokinetic(s); vs = versus. Secondary Pharmacokinetic Evaluations Baseline corrected serum iron Baseline corrected serum iron PK parameters 5 Figure 3Error! Reference source not found, presents a plot of mean baseline corrected serum iron concentration (pg / dL) by formulation / condition group on linear scale and semi-log scale for the FAS Population. Both capsule and liquid suspension composition of ferric trimaltol in fasted and fed 10 conditions were readily absorbed with mean baseline corrected serum iron concentrations returning to near baseline at 10 hours. Table 6Error! Reference source not found, presents a summary of PK parameters for baseline corrected serum iron for the FAS Population. 15 The mean range of Cmax for baseline corrected serum iron was 33.250 to 89.938 ng / mL and the mean range of AUCiast net was 2.503 to 691.392 h*ng / mL. Table 6: Summary of PK Parameters for Baseline Corrected Serum Iron - FAS Population Formulation / Condition Statistic Cmax (ng / mL) Tmax (h) AUClast Above Baseline (h*ng / mL) AUClast Below Baseline (h*ng / mL) AUClast Net (h*ng / mL) Ferric trimaltol capsule / fed n 32 32 32 32 32 Mean 44.469 7.398 372.434 316.284 56.150 SD 73.0572 9.1629 714.8305 442.3182 964.9572 Median 12.000 3.500 90.140 92.024 16.478 Minimum 0.00 0.00 0.00 0.00 -1630.63 Maximum 294.00 24.00 3015.52 1630.63 3014.69 Geometric mean 23.568 5.444 95.588 83.884 277.905 Geometric CV% 277.0 177.1 2198.6 1144.3 311.9 Ferric trimaltol liquid suspension / fed n 32 32 32 32 32 Mean 40.219 5.461 342.700 340.197 2.503 SD 52.9715 7.4920 582.2122 480.5673 889.0745 Median 21.000 3.500 91.797 102.320 -48.998 Minimum 0.00 0.00 0.00 0.00 -1808.55 Maximum 225.00 24.00 2450.64 1808.55 2446.53 Geometric mean 24.170 3.512 96.398 164.466 408.765 Geometric CV% 225.0 173.7 1365.5 374.2 408.9 Ferric trimaltol capsule / fasted n 32 32 32 32 32 Mean 89.938 3.726 834.344 142.952 691.392 SD 50.9927 4.0687 634.1700 259.9277 791.8671 Median 79.000 2.000 711.958 39.437 666.514 Minimum 18.00 1.00 36.70 0.00 -967.51 Maximum 202.00 24.00 2488.17 1190.03 2480.06 Geometric mean 75.407 2.868 578.593 46.918 694.206 Geometric CV% 70.7 71.5 128.7 569.7 114.8 Ferric trimaltol liquid suspension / fasted n 32 32 32 32 32 Mean 33.250 3.211 301.905 311.342 -9.436 SD 23.0637 2.7534 330.3642 467.2600 693.2830 Median 27.000 2.000 143.782 114.808 66.665 Minimum 0.00 0.00 0.00 0.00 -2296.38 Maximum 83.00 10.00 1244.42 2296.38 1244.33 Geometric mean 27.069 2.326 149.131 116.369 300.328 Geometric CV% 86.4 108.3 302.2 2102.5 148.2 The actual collection times were used for the calculation of PK parameters. The Linear Up Log Down method (equivalent to the Linear Up / Log Down option in WinNonlin Professional) was used in the computation of AUC, if applicable. The Az was presented for subjects who exhibited a terminal elimination phase in their concentration-time profiles. If Az was not assigned, the values of associated PK parameters (eg, Az, AUCinf, or t / ,) were not calculated. Az = apparent terminal elimination rate constant; AUC = area under the plasma concentration curve; AUCinf = area under the plasma concentration curve for 0 to infinity; AUCiast = area under the plasma concentration curve from 0 up to the last measurable concentration (non-below) quantification limit after dosing; Cmax = maximum observed concentration; CV = coefficient of variation; FAS = Full Analysis Set; PK = pharmacokinetic(s); SD = standard deviation; t / ,= apparent terminal elimination half-life; Tmax = time to maximum plasma concentration. Baseline corrected serum iron comparative analysis Table 7Error! Reference source not found, presents an analysis of PK parameters for baseline corrected serum iron in the fasted condition for the FAS Population. For the fasted condition, the ratio of geometric LS mean (90% Cl) was 34.73% (24.71, 48.83) for Cmax- Table 7: Analysis of PK Parameters for Baseline Corrected Serum Iron in Fasted Condition - 10 FAS Population Parameter Statistic Ferric Trimaltol Capsule / Fasted (N =32) Ferric Trimaltol Liquid suspension / Fasted (N = 32) Cmax (ng / mL) n 32 32 Geometric LS mean 75.41 26.19 Treatment comparison [1] ferric trimaltol liquid suspension / fasted vs capsule / fasted Ratio of geometric LS mean (%) 34.73 90% Cl for ratio (%) (24.71, 48.83) AUCiast net (h*ng / mL) n 32 32 Median 666.51 66.67 QI, Q3 176.07, 1234.28 -531.17, 501.64 Treatment comparison [2] ferric trimaltol liquid suspension / fasted vs capsule / fasted Median of differences -644.75 90% Cl (%) (-945.69, -374.04) Values of 0 or below for baseline corrected serum iron were excluded from this analysis. 1. An ANOVA model was performed on the In-transformed PK parameters (Cmax) of the 2 formulations including terms for sequence (treatment sequence), treatment (formulation / condition), and period as fixed effects, and subjects nested within a sequence as a random effect. The estimates were back-transformed into original scale. Ratio was defined as Cmax(liquid suspension) / Cmax(capsule). 2. Median of differences and 90% Cl statistics were from the nonparametric Hodges-Lehman estimation method with treatment (formulation / condition) as the class variable. Difference was defined as AUCiast(liquid suspension) - AUCiast(capsule). ANOVA = analysis of variance; AUCiast = area under the plasma concentration curve from 0 up to the last measurable concentration (non-below) quantification limit after dosing; Cl = confidence interval; Cmax = maximum observed concentration; FAS = Full Analysis Set; In = natural logarithm; LS = least squares; N / A = not applicable; PK = pharmacokinetic(s); QI = quartile 1; Q3 = quartile 3; vs = versus. Table 8 presents an analysis of PK parameters for baseline corrected serum iron in fed condition for the FAS Population. 5 For the fed condition, the ratio of geometric LS mean (90% Cl) was 111.55% (76.01, 163.71) for Cmax- Table 8: Analysis of PK Parameters for Baseline Corrected Serum Iron in Fed Condition - FAS Population Parameter statistic Ferric Trimaltol Capsule / Fed (N =32) Ferric Trimaltol Liquid suspension / Fed (N =32) Cmax (ng / mL) n 32 32 Geometric LS mean 20.82 23.23 Treatment comparison [1] ferric trimaltol liquid suspension / fed vs capsule / fed Ratio of geometric LS mean (%) 111.55 90% Cl for ratio (%) (76.01, 163.71) AUCiast net (h*ng / mL) N 32 32 Median 16.48 -49.00 QI, Q3 -496.38, 328.38 -539.01, 483.79 Treatment comparison [2] ferric trimaltol liquid suspension / fed vs capsule / fed Median of differences -15.78 90% Cl (%) (-288.29, 326.47) Values of 0 or below for baseline corrected serum iron were excluded from this analysis. 1. An ANOVA model was performed on the In-transformed PK parameters (Cmax) of the 2 formulations including terms for sequence (treatment sequence), treatment (formulation / condition), and period as fixed effects, and subjects nested within a sequence as a random effect. The estimates were back-transformed into original scale. Ratio was defined as Cmax(liquid suspension) / Cmax(capsule). 2. Median of differences and 90% Cl statistics were from the nonparametric Hodges-Lehman estimation method with treatment (formulation / condition) as the class variable. Difference was defined as AUCiast(liquid suspension) - AUCiast(capsule). ANOVA = analysis of variance; AUCiast = area under the plasma concentration curve from 0 up to the last measurable concentration (non-below) quantification limit after dosing; Cl = confidence interval; Cmax = maximum observed concentration; FAS = Full Analysis Set; In = natural logarithm; LS = least squares; N / A = not applicable; PK = pharmacokinetic(s); QI = quartile 1; Q3 = quartile 3; vs = versus. Baseline corrected serum iron food effect analysis Table 9Error! Reference source not found, presents an analysis of PK parameters for baseline corrected serum iron for fasted versus fed conditions by formulation for the FAS Population. For the capsule formulation, the ratio of geometric LS mean (90% Cl) was 362.18% (251.15, 522.28) for Cmax. For the liquid suspension formulation, the ratio of geometric LS mean (90% Cl) was 112.77% 10 (78.65, 161.69) for Cmax. Table 9: Analysis of PK Parameters for Baseline Corrected Serum Iron for Fasted vs Fed Condition by Formulation - FAS Population Formulation Parameter Statistic Ferric Trimaltol Fed (N =32) Ferric Trimaltol Fasted (N =32) Capsule Cmax (ng / mL) n 32 32 Geometric LS mean 20.82 75.41 Treatment comparison [1] ferric trimaltol fasted vs fed Ratio of geometric LS mean (%) 362.18 90% Cl for ratio (%) (251.15, 522.28) AUCiast net (h*ng / mL) n 32 32 Median 16.48 666.51 QI, Q3 -496.38, 328.38 176.07, 1234.28 Treatment comparison [2] ferric trimaltol fasted vs fed Median of differences 719.30 90% Cl (386.52, 1043.59) Liquid suspension composition Cmax (ng / mL) n 32 32 Geometric LS mean 23.23 26.19 Treatment comparison [1] ferric trimaltol fasted vs fed Ratio of geometric LS mean (%) 112.77 90% Cl for ratio (%) (78.65, 161.69) AUCiast net (h*ng / mL) n 32 32 Median -49.00 66.67 QI, Q3 -539.01, 483.79 -531.17, 501.64 Treatment comparison [2] ferric trimaltol fasted vs fed Median of differences 57.22 90% Cl (-262.14, 352.72) Values of 0 or below for baseline corrected serum iron were excluded from this analysis. 1. An ANOVA model was performed on the In-transformed PK parameters (Cmax) of the 2 formulations including terms for sequence (treatment sequence), treatment (formulation / condition), and period as fixed effects, and subjects nested within a sequence as a random effect. The estimates were back-transformed into original scale. Ratio was defined as Cmax(fasted) / Cmax(fed). 2. Median of differences and 90% Cl statistics were from the nonparametric Hodges-Lehman estimation method with treatment (formulation / condition) as the class variable. Difference was defined as AUCiast(fasted) - AUCiast(fed). ANOVA = analysis of variance; AUCinf = area under the plasma concentration curve for 0 to infinity; AUCiast = area under the plasma concentration curve from 0 up to the last measurable concentration (non-below) quantification limit after dosing; Cl = confidence interval; Cmax = maximum observed concentration; FAS = Full Analysis Set; In = natural logarithm; LS = least squares; N / A = not applicable; PK = pharmacokinetic(s); QI = quartile 1; Q3 = quartile 3; vs = versus. Plasma maltol glucuronide Maltol is absorbed dose proportionally from ferric trimaltol. The maltol component of ferric trimaltol is rapidly metabolized to the glucuronide metabolite and is excreted in the urine. Plasma maltol glucuronide is therefore a surrogate measurement for the uptake of iron from ferric trimaltol and can be measured using high performance liquid chromatography. Plasma maltol glucuronide concentrations Figure 4Error! Reference source not found, presents a plot of mean plasma maltol glucuronide concentration (ng / mL) by formulation / condition group on linear scale and semilog scale for the FAS Population. Both capsule and liquid suspension of ferric trimaltol in fasted and fed conditions were readily absorbed with mean plasma maltol glucuronide concentration returningto baseline orslightly below at 6 hours. After 1 hour post-dose, the mean plasma maltol glucuronide concentration of the ferric trimaltol liquid suspension composition / fasted was higher than all other treatments studied. Plasma maltol glucuronide PK parameters Table 10 presents a summary of PK parameters for plasma maltol glucuronide for the FAS Population. The mean range of Cmax for plasma maltol glucuronide was 3579.063 to 7685.0 ng / mL and the mean range of AUCiast for plasma maltol glucuronide was 7335.39 to 10,410.89 h*ng / mL. The mean Cmax and AUCiast for plasma maltol glucuronide was higher in both ferric trimaltol capsule and liquid suspension composition in the fasted condition compared to the same formulations in the fed condition. Table 10: Summary of PK Parameters for Plasma Maltol Glucuronide - FAS Population Formulation / Condition Statistic Cmax (ng / mL) Tmax (h) Tlag (h) Az (1 / h) 1½ (h) AUClast (h*ng / mL) AUCinf (h*ng / mL) Ferric trimaltol capsule / fed n 32 32 32 15 15 32 15 Mean 3579.063 2.532 0.594 0.871 0.848 7335.39 8659.46 SD 1668.2120 1.0000 0.3284 0.2217 0.2354 2449.530 2325.957 Median 3320.000 2.000 0.500 0.845 0.821 7083.68 8243.22 Minimum 1450.00 1.00 0.25 0.47 0.52 3614.0 5581.7 Maximum 8810.00 4.00 1.50 1.33 1.48 13907.3 14493.6 Geometric mean 3257.667 2.329 0.510 0.845 0.821 6950.16 8391.56 Geometric CV% 45.8 45.0 61.8 26.6 26.6 34.6 26.1 Ferric trimaltol liquid suspension / fed n 32 32 32 28 28 32 28 Mean 3597.500 1.258 0.016 0.699 1.024 7802.52 8307.73 SD 1776.4390 0.6140 0.0615 0.1284 0.1929 2582.848 2529.238 Median 3085.000 1.000 0.000 0.699 0.992 7509.30 8029.38 Minimum 1200.00 0.50 0.00 0.43 0.66 4179.7 4363.1 Maximum 8710.00 3.00 0.25 1.05 1.60 13365.3 14276.7 Geometric mean 3229.145 1.123 0.250 0.688 1.008 7401.77 7948.95 Geometric CV% 49.7 51.6 0.0 18.5 18.5 34.1 31.1 Ferric trimaltol capsule / fasted n 32 32 32 28 28 32 28 Mean 5126.250 1.164 0.258 0.756 0.996 9083.82 9429.45 SD 1996.0748 0.3842 0.1185 0.2063 0.3150 2902.863 3113.479 Median 5115.000 1.000 0.250 0.768 0.903 8786.42 9062.82 Minimum 1970.00 0.75 0.00 0.40 0.64 4392.4 4643.0 Maximum 9490.00 2.00 0.75 1.09 1.74 16640.8 17773.4 Geometric mean 4721.725 1.109 0.266 0.727 0.954 8641.43 8954.29 Geometric CV% 44.8 31.8 23.6 30.1 30.1 33.4 33.8 Ferric trimaltol liquid suspension / fasted n 32 32 32 31 31 32 31 Mean 7685.000 0.781 0.000 0.858 0.888 10410.89 10699.16 SD 1920.3797 0.2082 0.0000 0.2522 0.2956 2631.072 2751.908 Median 8365.000 0.750 0.000 0.903 0.768 10488.18 10831.54 Minimum 3350.00 0.50 0.00 0.44 0.49 5000.1 5359.8 Maximum 9900.00 1.50 0.00 1.43 1.59 16445.3 17130.7 Geometric mean 7400.668 0.756 0.820 0.846 10077.39 10349.29 Geometric CV% 30.2 26.1 32.2 32.2 26.9 27.1 The actual collection times were used for the calculation of PK parameters. The Linear Up Log Down method (equivalent to the Linear Up / Log Down option in WinNonlin Professional) was used in the computation of AUC, if applicable. The Az was presented for subjects who exhibited a terminal elimination phase in their concentration-time profiles. If Az was not assigned, the values of associated PK parameters (eg, Az, AUCinf, or t / J were not calculated. Az = apparent terminal elimination rate constant; AUC = area under the plasma concentration curve; AUCinf = area under the plasma concentration curve for 0 to infinity; AUCiast = area under the plasma concentration curve from 0 up to the last measurable concentration (non-below) quantification limit after dosing; Cmax = maximum plasma concentration; CV = coefficient of variation; FAS = Full Analysis Set; PK = pharmacokinetic(s); SD = standard deviation; tx, = apparent terminal elimination half-life; Tiag = delay between the time of dosing and time of appearance of concentration in the sampling compartment; Tmax = time to maximum plasma concentration. Plasma maltol glucuronide comparative analysis Table 11 presents an analysis of PK parameters for plasma maltol glucuronide in the fasted condition for the FAS Population. 5 For the fasted condition, the ratios of Cmax, AUCiast, and AUCinf geometric LS means (90% Cl) were 156.74% (139.27, 176.39), 116.62% (110.72, 122.83), and 114.00% (109.81, 118.35) comparing the liquid suspension versus capsule formulations. These findings indicate that, in the fasted condition, there was a formulation effect with respect to Cmax but ferric trimaltol 10 had similar PK when administered as a liquid suspension composition or capsule with respect to AUCiast and AUCinf. Table 11: Analysis of PK Parameters for Plasma Maltol Glucuronide in Fasted Condition - FAS Population Parameter Statistic Ferric Trimaltol Capsule / Fasted (N = 32) Ferric Trimaltol Liquid suspension / Fasted (N = 32) Cmax (ng / mL) n 32 32 Geometric LS mean 4721.72 7400.67 Treatment comparison ferric trimaltol liquid suspension / fasted vs capsule / fasted Ratio of geometric LS mean (%) 156.74 90% Cl for ratio (%) (139.27, 176.39) AUCiast (h*ng / mL) n 32 32 Geometric LS mean 8641.43 10077.39 Treatment comparison ferric trimaltol liquid suspension / fasted vs capsule / fasted Ratio of geometric LS mean (%) 116.62 90% Cl for ratio (%) (110.72, 122.83) AUCmf (h*ng / mL) n 28 31 Geometric LS mean 9066.18 10335.29 Treatment comparison ferric trimaltol liquid suspension / fasted vs capsule / fasted Ratio of geometric LS mean (%) 114.00 90% Cl for ratio (%) (109.81, 118.35) An ANOVA model was performed on the In-transformed PK parameters (Cmax, AUCiast, and AUCinf) of the 2 formulations including terms for sequence (treatment sequence), treatment (formulation / condition), and period as fixed effects, and subjects nested within a sequence as a random effect. The estimates were back-transformed into original scale. Ratios were defined as Cmax(liquid suspension) / Cmax(capsule), AUCiast(liquid suspension) / AUCiast(capsule), and AUCinf(liquid suspension) / AUCmf(capsule) in the fasted condition. ANOVA = analysis of variance; AUCinf = area under the plasma concentration curve for 0 to infinity; AUCiast = area under the plasma concentration curve from 0 up to the last measurable concentration (non-below) quantification limit after dosing; Cl = confidence interval; Cmax = maximum observed concentration; FAS = Full Analysis Set; In = natural logarithm; LS = least squares; PK = pharmacokinetic(s); vs = versus. Table 12 presents an analysis of PK parameters for plasma maltol glucuronide in fed condition for the FAS Population. 5 For the fed condition, the ratios of Cmax, AUCiast, and AUCinf geometric LS means (90% Cl) were 99.12% (88.08, 111.55), 106.50% (101.11, 112.17), and 97.59% (93.01, 102.39), respectively, comparing the liquid suspension versus capsule formulations, indicating ferric trimaltol had similar PK when administered as a liquid suspension or capsule. Table 12: Analysis of PK Parameters for Plasma Maltol Glucuronide in Fed Condition - FAS Population Parameter Statistic Ferric Trimaltol Capsule / Fed (N = 32) Ferric Trimaltol Liquid suspension / Fed (N = 32) Cmax (ng / mL) n 32 32 Geometric LS mean 3257.67 3229.14 Treatment comparison ferric trimaltol liquid suspension / fed vs capsule / fed Ratio of geometric LS mean (%) 99.12 90% Cl for ratio (%) (88.08, 111.55) AUCiast (h*ng / mL) n 32 32 Geometric LS mean 6950.16 7401.77 Treatment comparison ferric trimaltol liquid suspension / fed vs capsule / fed Ratio of geometric LS mean (%) 106.50 90% Cl for ratio (%) (101.11, 112.17) AUCinf (h*ng / mL) n 15 28 Geometric LS mean 8079.97 7885.16 Treatment comparison ferric trimaltol liquid suspension / fed vs capsule / fed Ratio of geometric LS mean (%) 97.59 90% Cl for ratio (%) (93.01, 102.39) An ANOVA model was performed on the In-transformed PK parameters (Cmax, AUCiast, and AUCinf) of the 2 formulations including terms for sequence (treatment sequence), treatment (formulation / condition), and period as fixed effects, and subjects nested within a sequence as a random effect. The estimates were back-transformed into original scale. Ratios were defined as Cmax(liquid suspension) / Cmax(capsule), AUCiast(liquid suspension) / AUCiast(capsule), and AUCinf(liquid suspension) / AUCmf(capsule) in the fed condition. ANOVA = analysis of variance; AUCinf = area under the plasma concentration curve for 0 to infinity; AUCiast = area under the plasma concentration curve from 0 up to the last measurable concentration (non-below) quantification limit after dosing; Cl = confidence interval; Cmax = maximum observed concentration; FAS = Full Analysis Set; In = natural logarithm; LS = least squares; PK = pharmacokinetic(s); vs = versus. Plasma maltol glucuronide food effect analysis Table 13Error! Reference source not found, presents an analysis of PK parameters for plasma maltol glucuronide for fasted versus fed conditions by formulation for the FAS Population. For the capsule formulation, the ratios of Cmax, AUCiast, and AUCinf geometric LS means (90% 5 Cl) were 144.94% (128.79, 163.12), 124.33% (118.04, 130.96), and 112.21% (106.89, 117.78), respectively, comparing fasted versus fed conditions. These findings indicate that a food effect was observed for ferric trimaltol capsule with respect to Cmax but a definite food effect was not observed with respect to AUCiast or AUCinf. 10 For the liquid suspension formulation, the ratios of Cmax, AUCiast, and AUCinf geometric LS means (90% Cl) were 229.18% (203.65,257.92), 136.15% (129.26, 143.40), and 131.07% (126.25, 136.08) comparing fasted versus fed conditions. These findings indicate that a food effect was observed for ferric trimaltol liquid suspension composition with respect to Cmax, AUCiast, and AUCinf. 15 Table 13: Analysis of PK Parameters for Plasma Maltol Glucuronide for Fasted vs Fed Condition by Formulation - FAS Population Formulation Parameter Statistic Ferric Trimaltol Fed (N = 32) Ferric Trimaltol Fasted (N = 32) Capsule Cmax (ng / mL) n 32 32 Geometric LS mean 3257.67 4721.72 Treatment comparison ferric trimaltol fasted vs fed Ratio of geometric LS mean (%) 144.94 90% Cl for ratio (%) (128.79, 163.12) AUCiast (h*ng / mL) n 32 32 Geometric LS mean 6950.16 8641.43 Treatment comparison ferric trimaltol fasted vs fed Ratio of geometric LS mean (%) 124.33 90% Cl for ratio (%) (118.04, 130.96) AUCmf (h*ng / mL) n 15 28 Geometric LS mean 8079.97 9066.18 Treatment comparison ferric trimaltol fasted vs fed Ratio of geometric LS mean (%) 112.21 90% Cl for ratio (%) (106.89, 117.78) Liquid suspension composition Cmax (ng / mL) n 32 32 Geometric LS mean 3229.14 7400.67 Treatment comparison ferric trimaltol fasted vs fed Ratio of geometric LS mean (%) 229.18 90% Cl for ratio (%) (203.65, 257.92) AUCiast (h*ng / mL) n 32 32 Geometric LS mean 7401.77 10077.39 Treatment comparison ferric trimaltol fasted vs fed Ratio of geometric LS mean (%) 136.15 90% Cl for ratio (%) (129.26, 143.40) AUCinf (h*ng / mL) n 28 31 Geometric LS mean 7885.16 10335.29 Treatment comparison ferric trimaltol fasted vs fed Ratio of geometric LS mean (%) 131.07 90% Cl for ratio (%) (126.25, 136.08) An ANOVA model was performed on the In-transformed PK parameters formulations including terms for sequence (treatment sequence), treatrr period as fixed effects, and subjects nested within a sequence as a randorr transformed into original scale. Ratios were defined as Cmax(fasted) / Cmax(fed), AUCiast(fasted) / AUCiast(fed), ANOVA = analysis of variance; AUCinf = area under the plasma concentrati area under the plasma concentration curve from 0 up to the last measi quantification limit after dosing; Cl = confidence interval; Cmax = maximum Analysis Set; In = natural logarithm; LS = least squares; PK = pharmacokinel Cmax, AUCiast, and AUCinf) of the 2 lent (formulation / condition), and effect. The estimates were back- ind AUCinf(fasted) / AUCinf(fed). an curve for 0 to infinity; AUCiast = jrable concentration (non-below) observed concentration; FAS = Full ic(s); vs = versus. Transferrin Saturation (TSAT) Transferrin binds, transports and stores serum iron. Transferrin saturation (TSAT) is a medical laboratory value measured as a percentage. This value is the ratio of serum iron and total iron binding capacity for the human body. This value also tells a clinician how much serum iron is actually bound. It is therefore a measure of iron status as low TSAT indicates iron deficiency. It is a routine medical laboratory parameter measured using an established method. TSAT concentrations Figure 5Error! Reference source not found, presents a plot of mean TSAT (%) by formulation / condition group on linear scale and semi-log scale for the FAS Population. Both capsule and liquid suspension of ferric trimaltol in fasted and fed conditions resulted in an increase in TSAT, with mean TSAT concentrations returning to baseline or slightly below at 24 hours. After 1 hour post-dose, the mean TSAT concentration of the ferric trimaltol capsule / fasted condition was higher than all other treatments studied. TSAT PK parameters Table 14 presents a summary of PK parameters for TSAT for the FAS Population. The mean range of Cmax for TSAT was 30.188 to 43.031 ng / mL with all treatments displaying an approximate mean serum Cmax of 30 ng / mL besides ferric trimaltol capsule / fasted, which had a mean Cmax of 43.031 ng / mL. This trend was also noted in AUCiast of ferric trimaltol capsule / fasted, which had a mean AUCiast of 644.62 h*ng / mL compared to the mean range of other treatments (484.64 to 513.62 h*ng / mL). The appearance of the Cmax for TSAT, noted asTmax, was slightly delayed in both ferric trimaltol capsule and liquid suspension composition in the fed condition compared to the same formulations in the fasted condition. Table 14: Summary of PK Parameters for TSAT - FAS Population Formulation / Condition Statistic Cmax (ng / mL) Tmax (h) AUClast (h*ng / mL) Ferric trimaltol capsule / fed n 32 32 32 Mean 32.750 6.227 509.90 SD 18.4793 8.0283 201.915 Median 27.000 3.500 481.76 Minimum 13.00 0.00 194.1 Maximum 84.00 24.00 963.4 Geometric mean 28.887 4.160 474.25 Geometric CV% 52.1 175.8 40.2 Ferric trimaltol liquid suspension composition / fed n 32 32 32 Mean 30.344 5.580 484.64 SD 12.5970 7.4414 153.990 Median 27.500 4.000 482.25 Minimum 13.00 0.00 227.9 Maximum 63.00 24.00 775.1 Geometric mean 27.946 3.498 459.44 Geometric CV% 43.3 168.6 35.2 Ferric trimaltol capsule / fasted n 32 32 32 Mean 43.031 3.585 644.62 SD 12.9428 4.0712 176.724 Median 40.500 2.000 631.73 Minimum 18.00 1.00 315.4 Maximum 79.00 24.00 1203.4 Geometric mean 41.180 2.732 622.44 Geometric CV% 31.3 72.4 27.4 Ferric trimaltol liquid suspension composition / fasted n 32 32 32 Mean 30.188 4.391 513.62 SD 9.3892 4.6839 193.642 Median 30.000 3.000 513.44 Minimum 14.00 0.00 230.8 Maximum 64.00 24.00 1270.8 Geometric mean 28.906 3.008 483.53 Geometric CV% 30.5 132.4 36.1 The actual collection times were used for the calculation of PK parameters. The Linear Up Log Down method (equivalent to the Linear Up / Log Down option in WinNonlin Professional) was used in the computation of AUC, if applicable. The Az was presented for subjects who exhibited a terminal elimination phase in their concentration-time profiles. If Az was not assigned, the values of associated PK parameters (eg, Az, AUCinf, or t / ,) were not calculated. Az = apparent terminal elimination rate constant; AUC = area under the plasma concentration curve; AUCinf = area under the plasma concentration curve for 0 to infinity; AUCiast = area under the plasma concentration curve from 0 up to the last measurable concentration (non-below) quantification limit after dosing; Cmax = maximum observed concentration; CV = coefficient of variation; FAS = Full Analysis Set; PK = pharmacokinetic(s); SD = standard deviation; t / ,= apparent terminal elimination half-life; Tmax= time to maximum plasma concentration; TSAT = transferrin saturation. TSAT comparative analysis Table 15 presents an analysis of PK parameters for TSAT in the fasted condition for the FAS Population. 5 For the fasted condition, the ratios of Cmax and AUCiast geometric LS means (90% Cl) were 70.19% (62.22, 79.19) and 77.68% (70.54, 85.54), respectively, comparing the liquid suspension versus capsule formulations. These findings indicate that, in the fasted condition, there was a formulation effect with respect to Cmax but a definitive formulation effect was not 10 observed with respect to AUCiast. Table 15: Analysis of PK Parameters for TSAT in Fasted Condition - FAS Population Parameter Statistic Ferric Trimaltol Capsule / Fasted (N =32) Ferric Trimaltol Liquid suspension / Fasted (N =32) Cmax (ng / mL) n 32 32 Geometric LS mean 41.18 28.91 Treatment comparison ferric trimaltol liquid suspension / fasted vs capsule / fasted Ratio of geometric LS mean (%) 70.19 90% Cl for ratio (%) (62.22, 79.19) AUCiast (h*ng / mL) n 32 32 Geometric LS mean 622.44 483.53 Treatment comparison ferric trimaltol liquid suspension / fasted vs capsule / fasted Ratio of geometric LS mean (%) 77.68 90% Cl for ratio (%) (70.54, 85.54) An ANOVA model was performed on the In-transformed PK parameters (Cmax and AUCiast) of the 2 formulations including terms for sequence (treatment sequence), treatment (formulation / condition), and period as fixed effects, and subjects nested within a sequence as a random effect. The estimates were back-transformed into original scale. Ratios were defined as Cmax(liquid suspension) / Cmax(capsule) and AUCiast(liquid suspension) / AUCiast(capsule) in the fasted condition. ANOVA = analysis of variance; AUCiast = area under the plasma concentration curve from 0 up to the last measurable concentration (non-below) quantification limit after dosing; Cl = confidence interval; Cmax = maximum observed concentration; FAS = Full Analysis Set; In = natural logarithm; LS = least squares; PK = pharmacokinetic(s); vs = versus. Table 16 presents an analysis of PK parameters for TSAT in the fed condition for the FAS Population. 5 For the fed condition, the ratios of Cmax and AUCiast geometric LS means (90% Cl) were 96.74% (85.75, 109.14) and 96.88% (87.97, 106.68), respectively, comparing the liquid suspension versus capsule formulations. These findings indicate that, in the fed condition, ferric trimaltol had similar PK when administered as a liquid suspension or capsule with respect to Cmax and AUCiast- 10 Table 16: Analysis of PK Parameters for TSAT in Fed Condition - FAS Population Parameter Statistic Ferric Trimaltol Capsule / Fed (N = 32) Ferric Trimaltol Liquid suspension / Fed (N =32) Cmax (ng / mL) n 32 32 Geometric LS mean 28.89 27.95 Treatment comparison ferric trimaltol liquid suspension / fed vs capsule / fed Ratio of geometric LS mean (%) 96.74 90% Cl for ratio (%) (85.75, 109.14) AUCiast (h*ng / mL) n 32 32 Geometric LS mean 474.25 459.44 Treatment comparison ferric trimaltol liquid suspension / fed vs capsule / fed Ratio of geometric LS mean (%) 96.88 90% Cl for ratio (%) (87.97, 106.68) An ANOVA model was performed on the In-transformed PK parameters (Cmax and AUCiast) of the 2 formulations including terms for sequence (treatment sequence), treatment (formulation / condition), and period as fixed effects, and subjects nested within a sequence as a random effect. The estimates were back-transformed into original scale. Ratios were defined as Cmax(liquid suspension) / Cmax(capsule) and AUCiast(liquid suspension) / AUCiast(capsule) in the fed condition. ANOVA = analysis of variance; AUCiast = area under the plasma concentration curve from 0 up to the last measurable concentration (non-below) quantification limit after dosing; Cl = confidence interval; Cmax = maximum observed concentration; FAS = Full Analysis Set; In = natural logarithm; LS = least squares; PK = pharmacokinetic(s); TSAT = transferrin saturation; vs = versus. TSAT food effect analysis Table 17 presents an analysis of PK parameters for TSAT for fasted versus fed conditions by formulation for the FAS Population. 5 For the capsule formulation, the ratios of Cmax and AUCiast geometric LS means (90% Cl) were 142.55% (126.36, 160.82) and 131.25% (119.19, 144.53), respectively, comparing fasted versus fed conditions. These findings indicate that a food effect was observed for ferric trimaltol capsule with respect to Cmax but a definitive food effect was not observed with 10 respect to AUCiast. For the liquid suspension formulation, the ratios of Cmax and AUCiast geometric LS means (90% Cl) were 103.44% (91.69, 116.69) and 105.24% (95.57, 115.89), respectively, comparing fasted versus fed conditions. These findings indicate that the ferric trimaltol liquid suspension 5 composition had similar PK when administered in fasted or fed conditions. Table 17: Analysis of PK Parameters for TSAT for Fasted vs Fed Condition by Formulation - FAS Population Formulation Parameter Statistic Ferric Trimaltol Fed (N = 32) Ferric Trimaltol Fasted (N = 32) Capsule Cmax (ng / mL) n 32 32 Geometric LS mean 28.89 41.18 Treatment comparison ferric trimaltol fasted vs fed Ratio of geometric LS mean (%) 142.55 90% Cl for ratio (%) (126.36, 160.82) AUCiast (h*ng / mL) n 32 32 Geometric LS mean 474.25 622.44 Treatment comparison ferric trimaltol fasted vs fed Ratio of geometric LS mean (%) 131.25 90% Cl for ratio (%) (119.19, 144.53) Liquid suspension composition Cmax (ng / mL) n 32 32 Geometric LS mean 27.95 28.91 Treatment comparison ferric trimaltol fasted vs fed Ratio of geometric LS mean (%) 103.44 90% Cl for ratio (%) (91.69, 116.69) AUCiast (h*ng / mL) n 32 32 Geometric LS mean 459.44 483.53 Treatment comparison ferric trimaltol fasted vs fed Ratio of geometric LS mean (%) 105.24 90% Cl for ratio (%) (95.57, 115.89) An ANOVA model was performed on the In-transformed PK parameters (Cmax and AUCiast) of the 2 formulations including terms for sequence (treatment sequence), treatment (formulation / condition), and period as fixed effects, and subjects nested within a sequence as a random effect. The estimates were back-transformed into original scale. Ratios were defined as Cmax(fasted) / Cmax(fed) and AUCiast(fasted) / AUCiast(fed). ANOVA = analysis of variance; AUCiast = area under the plasma concentration curve from 0 up to the last measurable concentration (non-below) quantification limit after dosing; Cl = confidence interval; Cmax = maximum observed concentration; FAS = Full Analysis Set; In = natural logarithm; LS = least squares; PK = pharmacokinetic(s); TSAT = transferrin saturation; vs = versus. Other secondary PK evaluations Plasma maltol concentrations Maltol is absorbed dose proportionally from ferric trimaltol. The maltol component of ferric trimaltol is rapidly metabolized to the glucuronide metabolite and is excreted in the urine. Plasma maltol glucuronide is therefore a surrogate measurement for the uptake of iron from ferric trimaltol and can be measured using high performance liquid chromatography. The mean range of Cmax for plasma maltol was 16.944 to 34.656 ng / mL and the mean range of AUCiast for plasma maltol was 17.29 to 39.13 h*ng / mL. The mean Cmax for plasma maltol was higher in both ferric trimaltol liquid suspension composition groups compared to capsule in the fed and fasted conditions (see Figure 7). With respect to formulation, the mean Tiag was longer in the capsule formulation (fasted and fed conditions) compared to the liquid suspension formulation (fasted and fed conditions). Regarding food, both formulations showed an increase in the Tiag in the fed condition. For the fasted condition, the ratio of geometric LS mean (90% Cl) was 143.04% (113.06, 180.96) for Cmax and was 154.49% (109.69, 217.59) for AUCiast comparing liquid suspension vs capsule formulations. These findings indicate that, in the fasted condition, a definitive formulation effect was not observed with respect to Cmax and AUCiast. For the fed condition, the ratio of geometric LS mean (90% Cl) was 130.02% (99.75, 169.48) for Cmax and was 144.41% (97.87, 213.10) for AUCiast comparing liquid suspension vs capsule formulations. These findings indicate that, in the fed condition, a definitive formulation effect was not observed with respect to Cmax and AUCiast. For the capsule formulation, the ratios of Cmax and AUCiast geometric LS mean (90% Cl) were 96.89% (74.23, 126.47) and 66.89% (45.27, 98.82), respectively, comparing fasted versus fed conditions. For the liquid suspension formulation, ratios of Cmax, AUCiast, and AUCint geometric LS mean (90% Cl) were 106.59% (84.50, 134.44), 71.55% (50.99,100.40), and 117.06% (75.65, 181.13), respectively, comparing fasted versus fed conditions. Total Iron Binding Concentration (TIBC) A total iron-binding capacity (TIBC) test measures the blood's ability to attach itself to iron and transport it around the body. A transferrin test is similar. If you have iron deficiency (a lack of iron in your blood), your iron level will be low but your TIBC will be high. It is a routine medical laboratory parameter and the method of measurement is well established. The mean range of Cmax for TIBC was 393.688 to 396.938 ng / mLand the mean range of AUCiast for TIBC was 8718.02 to 8880.52 h*ng / mL. These PK parameters were similar for all treatments studied. For the fasted condition, the ratio of geometric LS mean (90% Cis) was 100.10% (97.69, 102.58) for Cmax and 100.11% (99.01, 101.23) for AUCiast comparing the liquid suspension versus capsule formulations. These findings indicate that, in the fasted condition, ferric trimaltol had similar PK when administered as a liquid suspension composition or capsule with respect to Cmax and AUCiast. For the fed condition, the ratio of geometric LS mean (90% Cl) was 100.28% (97.85, 102.76) for Cmax and was 99.86% (98.76, 100.97) for AUCiast comparing the liquid suspension versus capsule formulations. These findings indicate that, in the fed condition, ferric trimaltol had similar PK when administered as a liquid suspension or capsule with respect to Cmax and AUCiast- For the capsule formulation, the ratio of geometric LS mean (90% Cl) was 100.26% (97.84, 102.74) for Cmax and 101.79% (100.67,102.93) for AUCiast comparing fasted versus fed conditions. For the liquid suspension formulation, the ratio of geometric LS mean (90% Cl) was 100.09% (97.67,102.57) for Cmax and 102.05% (100.93, 103.19) for AUCiast comparing fasted versus fed conditions. These findings indicate that the ferric trimaltol capsule and liquid suspension composition had similar PK when administered in fasted or fed conditions. Unsaturated Iron Binding Capacity (UIBC) Unsaturated iron-binding capacity (UIBC) is a blood test used along with a serum iron test and a total iron-binding capacity test (TIBC) to evaluate people suspected of having iron deficiency. UIBC is used for calculation of TIBC: TIBC [pg / dL] = UIBC [pg / dL] + Serum Iron [pg / dL], It is a routine medical laboratory parameter and the method of measurement is well established. Both capsule and liquid suspension of ferric trimaltol in fasted and fed conditions were readily absorbed with mean UIBC concentrations returning to baseline or slightly above at 24 hours. After 1 hour post-dose, the mean UIBC concentration of the ferric trimaltol capsule / fasted condition was lower than all other treatments studied. The mean range of Cmax for UIBC was 322.375 to 331.250 ng / mL. The mean range of AUCiast for UIBC was 6432.85 to 6978.71 h*ng / mL with all treatments displaying an approximate mean AUCiast of 6900 h*ng / mL besides ferric trimaltol capsule / fasted, which had a mean AUCiast of 6432.85 h*ng / mL. For UIBC in the fasted condition for the FAS Population, the ratio of geometric LS mean (90% Cl) was 99.83% (96.81, 102.94) for Cmax and 108.36% (104.76, 112.08) for AUCiast comparing the liquid suspension versus capsule formulations. These findings indicate that, in the fasted condition, ferric trimaltol had similar PK when administered as a liquid suspension or capsule with respect to Cmax and AUCiast. For UIBC in fed condition for the FAS Population, the ratio of geometric LS mean (90% Cl) was 99.52% (96.51, 102.63) for Cmax and 101.93% (98.55, 105.44) for AUCiast comparing the liquid suspension versus capsule formulations. These findings indicate that, in the fed condition, ferric trimaltol had similar PK when administered as a liquid suspension or capsule with respect to Cmax and AUCiast, respectively. For the capsule formulation, the ratio of geometric LS mean (90% Cl) was 97.80% (94.84, 100.85) for Cmax and 94.36% (91.22, 97.60) for AUCiast comparing fasted versus fed conditions. For the liquid suspension formulation, the ratio of geometric LS mean (90% Cl) was 98.09% (95.13, 101.15) for Cmax and 100.31% (96.97, 103.75) for AUCiast comparing fasted versus fed conditions. These findings indicate that the ferric trimaltol capsule and liquid suspension composition had similar PK when administered in fasted or fed conditions with respect to Cmax and AUCiast, respectively. Transferrin Transferrin is a protein that binds iron and transports it to where it is needed. When there is enough transferrin, your body can effectively use the iron you get from the diet. Iron availability dictates transferrin production, but transferrin levels are also influenced by inflammation, liver, and kidney disease. It is a routine medical laboratory parameter and the method of measurement is well established. The mean range of Cmax for transferrin was 300.688 to 304.063 ng / mL and the mean range of AUCiast for transferrin was 6701.92 to 6837.00 h*ng / mL. These PK parameters were similar for all treatments studied. For transferrin in the fasted condition for the FAS Population, the ratio of geometric LS mean (90% Cl) was 100.34% (98.12, 102.61) for Cmax and 100.97% (99.94, 102.02) for AUCiast comparing the liquid suspension versus capsule formulations. These findings indicate that, in the fasted condition, ferric trimaltol had similar PK when administered as a liquid suspension or capsule with respect to Cmax and AUCiast. For transferrin in fed condition for the FAS Population, the ratio of geometric LS mean (90% Cl) was 98.92% (96.73, 101.15) for Cmax and 99.82% (98.80, 100.85) for AUCiast comparing the liquid suspension versus capsule formulations. These findings indicate that, in the fed condition, ferric trimaltol had similar PK when administered as a liquid suspension or capsule 5 with respect to Cmax and AUCiast. For the capsule formulation, the ratio of geometric LS mean (90% Cl) was 99.43% (97.23, 101.67) for Cmax and 100.99% (99.95, 102.03) for AUCiast comparing fasted versus fed conditions. For the liquid suspension formulation, the ratio of geometric LS mean (90% Cl) 10 was 100.86% (98.63,103.14) for Cmax and 102.15% (101.10, 103.20) for AUCiast comparing fasted versus fed conditions. These findings indicate that the ferric trimaltol capsule and liquid suspension composition had similar PK when administered in fasted or fed conditions with respect to Cmax and AUCiast, respectively. 15

Claims

1. Ferric trimaltol for use in treating or preventing iron deficiency in a human patient with or without anaemia, wherein the ferric trimaltol is administered orally in combination with solid and / or liquid food.

2. Ferric trimaltol for use in treating or preventing iron deficiency according to claim 1, wherein iron deficiency is iron deficiency with or without anaemia resulting from one or more of the group consisting of nutritional deficiency, kidney disease, coeliac disease and other malabsorption disorders, inflammatory bowel disease (IBD), menorrhagia, cancer, pregnancy, heart disease and bariatric surgery.

3. Ferric trimaltol for use in treating or preventing iron deficiency according to claim 2, wherein the inflammatory bowel disease is Crohn's disease.

4. Ferric trimaltol for use in treating or preventing iron deficiency according to claim 3, wherein the Crohn's disease is not active.

5. Ferric trimaltol for use in treating or preventing iron deficiency according to claim 4, wherein the human patient has a Crohn's Disease Activity Index of <220.

6. Ferric trimaltol for use in treating or preventing iron deficiency according to claim 2, wherein the inflammatory bowel disease is ulcerative colitis.

7. Ferric trimaltol for use in treating or preventing iron deficiency according to claim 6, wherein the ulcerative colitis is not active.

8. Ferric trimaltol for use in treating or preventing iron deficiency according to claim 7, wherein the human patient has a Simple Clinical Colitis Activity Index (SCCAI) value of <4.

9. Ferric trimaltol for use in treating or preventing iron deficiency according to claim 2, wherein kidney disease does not include chronic renal disease with an estimated Glomerular Filtration Rate (eGFR) <about 60 mL / min / m2.

10. Ferric trimaltol for use in treating or preventing iron deficiency according to any one of the preceding claims, wherein the ferric trimaltol is administered in the form of a 30-90, 60-90, 15, 30, 60, 90 mg ferric iron equivalent dose once or twice a day where the human patient is an adult, or 15-30 mg ferric iron equivalent dose twice a day where the human patient is 10-17 years old, or 15 mg ferric iron equivalent dose twice a day where the human patient is 2-9 years old.

11. Ferric trimaltol for use in treating or preventing iron deficiency according to claim 10, wherein when said ferrictrimaltol is administered twice daily, the ferrictrimaltol being administered once in the morning and once during the evening.

12. Ferric trimaltol for use in treating or preventing iron deficiency according to any one of the preceding claims, wherein the ferrictrimaltol is administered for at least 24, 20, 16, 15, 14, 13,12, 8, 4 weeks.

13. Ferric trimaltol for use in treating or preventing iron deficiency according to claim 12, wherein the ferric trimaltol is subsequently administered in the range 15-120 mg ferric iron equivalent once or twice daily, or every two, three, four, five, six or seven days where the human patient is an adult, or 15-30 mg ferric iron equivalent twice a day where the human patient is 10-17 years old, or 15 mg ferric iron equivalent twice a day where the human patient is 2-9 years old, with orwithout solid and / or liquid food, optionally the ferric trimaltol is administered indefinitely as a maintenance dose.

14. Ferric trimaltol for use in treating or preventing iron deficiency according to any one of the preceding claims, wherein the solid and / or liquid food is taken by the patient up to 4, 3, 2,1, 0.5 hours before or after or simultaneously with administration of the ferric trimaltol.

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