10.1 Mechanism of Action
Iron is essential to the synthesis of haemoglobin to maintain oxygen transport and to the function and formation of the physiologically important heme and non-heme compounds.
MONOFERRIC (ferric derisomaltose for injection) is a colloid with strongly bound iron in spheroidal iron-carbohydrate particles. The MONOFERRIC formulation contains iron in a strongly bound complex that enables a controlled and slow release of bioavailable iron to iron-binding proteins with little risk of free iron. MONOFERRIC is an iron carbohydrate complex with a matrix structure composed of alternating layers of ferric hydroxide and the carbohydrate derisomaltose. Derisomaltose consists of linear, hydrogenated isomaltooligosaccharides with an average molecular weight of 1000 Da and a narrow molecular weight distribution that is almost devoid of mono- and disaccharides.
The derisomaltose component of MONOFERRIC consists of 3-5 glucose units with an average molecular weight of approximately 1000 Da. It has no detectable branching structures as evidenced by careful 13C and 1H NMR spectroscopic analysis. Furthermore derisomaltose does not contain any reducing sugar residues, which can be involved in complex redox reactions.
The MONOFERRIC formulation contains iron in a complex with derisomaltose that releases bioavailable iron to iron-binding proteins.
Evidence of a therapeutic response can be seen within a few days of administration of MONOFERRIC as an increase in the reticulocyte count.
Serum ferritin peaks approximately 7 days after an intravenous dose of MONOFERRIC and slowly returns to stable levels after about 4 weeks.
In a subgroup of 32 patients randomised to MONOFERRIC a thorough QT monitoring of ECG was performed. Results demonstrated no effect of MONOFERRIC on QT interval durations. No clinically meaningful effect of MONOFERRIC on heart rate was observed.
MONOFERRIC pharmacokinetics was examined across four patient populations. In patients with inflammatory bowel disease (IBD), non-haematological malignancies associated with chemotherapy induced anaemia (CIA), in stage 5 chronic kidney disease on dialysis therapy and non-dialysis dependent chronic kidney disease (CKD). MONOFERRIC pharmacokinetics was examined across a dose range of 100 to 1000 mg. There is no data investigating the pharmacokinetics of single or multiple doses of MONOFERRIC above 1000 mg. There seems to be a dose-dependent increase in AUC and Cmax which is observed within all 3 patient populations; IBD, CKD, and CIA. T1/2 varies between 23.2 to 87.9 h with the highest value observed for patients dosed with 1000 mg of MONOFERRIC.
MONOFERRIC demonstrates dose proportional increases up to 500 mg. MONOFERRIC demonstrated linear pharmacokinetics up to 500 mg, with higher doses demonstrating dose dependent pharmacokinetics.
Following intravenous administration of iron complex, it is taken up by the cells in the reticuloendothelial system (RES), particularly in the liver and spleen from where iron is slowly released.
Circulating iron is removed from the plasma by cells of the RES. The iron is immediately bound to the available protein moieties to form hemosiderin or ferritin, the physiological storage forms of iron, or to a lesser extent, to the transport molecule transferrin. This iron, which is subject to physiological control, replenishes haemoglobin and depleted iron stores.
After administration of a single dose of MONOFERRIC of 100 to 1000 mg of iron in the pharmacokinetic studies, the iron injected or infused was cleared from the plasma with a half-life that ranged from 1 to 4 days. Renal elimination of iron was negligible.
Iron is not easily eliminated from the body and accumulation can be toxic. Due to the size of the complex, MONOFERRIC is not eliminated via the kidneys. Small quantities of iron are eliminated in urine and faeces.
IV iron complexes are not clinically interchangeable, as they differ in their structures, which impact their comparative pharmacokinetic profiles.
Special Populations and Conditions
- Pregnancy and Breast-feeding
In a subset of patients (n=65) in a post-partum hemorrhage study, the mean maternal milk iron level was higher in the MONOFERRIC group (72.1 μg/dL) than in the standard medical care (oral iron treatment) group (40.0 μg/dL) at day 3. However, at week 1 the mean maternal milk iron level in the MONOFERRIC group had decreased to the same level as in the standard medical care group (46.8 μg/dL and 44.2 μg/dL, respectively).
A total of 8 patients in the MONOFERRIC group had an abnormally high maternal milk iron level (i.e. > 80 μg/dL) at day 3 (81-164.4 μg/dL) compared to 1 patient in the standard medical care group (99.4 μg/dL). At week 1, the corresponding numbers were 1 patient in the MONOFERRIC group (99.8 μg/dL) and 2 patients in the standard medical care group (115.4 μg/dL).