Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: All other therapeutic products; drugs for treatment of hyperkalaemia and hyperphosphataemia; ATC code: V03AE05

Mechanism of action

Velphoro contains a mixture of polynuclear iron(III)-oxyhydroxide (pn-FeOOH), sucrose and starches.
Phosphate binding takes place by ligand exchange between hydroxyl groups and/or water and the phosphate ions throughout the physiological pH range of the gastrointestinal tract.
Serum phosphorus levels are reduced as a consequence of the reduced dietary phosphate absorption.

Clinical efficacy

One phase 3 clinical study has been performed in patients with CKD on dialysis to investigate the efficacy and safety of Velphoro in this population. This study was an open-label, randomised, active-controlled (sevelamer carbonate), parallel group study for up to 55 weeks. Adult patients with hyperphosphataemia (serum phosphorus levels ≥1.94 mmol/L) were treated with sucroferric oxyhydroxide at a starting dose of 1,000 mg iron/day followed by an 8-week dose titration period.
Non-inferiority to sevelamer carbonate was determined at week 12. Subjects were continued on their study medication from week 12 to week 55. From week 12 to 24, dose titrations were allowed for both tolerability and efficacy reasons. Treatment of patient sub-populations from week 24 to week 27 with maintenance dose of sucroferric oxyhydroxide (1,000 to 3,000 mg iron/day) or low dose (250 mg iron/day) of sucroferric oxyhydroxide demonstrated superiority of the maintenance dose.

In Study-05A, 1,055 patients on haemodialysis (N=968) or peritoneal dialysis (N=87) with serum phosphorus ≥1.94 mmol/L following a 2-4 week phosphate binder washout period, were randomised and treated with either sucroferric oxyhydroxide, at a starting dose of 1,000 mg iron/day (N=707), or active-control (sevelamer carbonate, N=348) for 24 weeks. At the end of week 24, 93 patients on haemodialysis whose serum phosphorus levels were controlled (<1.78 mmol/L) with sucroferric oxyhydroxide in the first part of the study, were re-randomised to continue treatment with either their week 24 maintenance dose (N=44 or a non-effective low dose control 250 mg iron/day, N=49) of sucroferric oxyhydroxide for a further 3 weeks.

Following completion of Study-05A, 658 patients (597 on haemodialysis and 61 on peritoneal dialysis) were treated in the 28-week extension study (Study-05B) with either sucroferric oxyhydroxide (N=391) or sevelamer carbonate (N=267) according to their original randomization.

Mean serum phosphorus levels were 2.5 mmol/L at baseline and 1.8 mmol/L at week 12 for sucroferric oxyhydroxide (reduction by 0.7 mmol/L). Corresponding levels for sevelamer carbonate at baseline were 2.4 mmol/L and 1.7 mmol/L at week 12 (reduction by 0.7 mmol/L), respectively.

The serum phosphorus reduction was maintained over 55 weeks. Serum phosphorus levels and calcium-phosphorus product levels were reduced as a consequence of the reduced dietary phosphate absorption.

The response rates, defined as the proportion of subjects achieving serum phosphorus levels within the Kidney Disease Outcomes Quality Initiative (KDOQI) recommended range were 45.3% and 59.1% at week 12 and 51.9% and 55.2% at week 52, for sucroferric oxyhydroxide and sevelamer carbonate, respectively.

The mean daily dose of Velphoro over 55 weeks of treatment was 1,650 mg iron and the mean daily dose of sevelamer carbonate was 6,960 mg.

Post-authorisation data

A prospective, non-interventional, post-authorisation safety study (VERIFIE) has been conducted, evaluating the short- and long-term (up to 36 months) safety and effectiveness of Velphoro in adult patients on haemodialysis (N=1,198) or peritoneal dialysis (N=160), who were followed in routine clinical practice for 12 to 36 months (safety analysis set, N=1,365). During the study, 45% (N=618) of these patients were concomitantly treated with phosphate binder(s) other than Velphoro.

In the safety analysis set, the most common ADRs were diarrhoea and discoloured faeces, reported by 14% (N=194) and 9% (N=128) of patients, respectively. The incidence of diarrhoea was highest in the first week and decreased with duration of use. Diarrhoea was of mild to moderate intensity in most patients and resolved in the majority of patients within 2 weeks. Discoloured (black) faeces is expected for an oral iron-based compound, and may visually mask gastrointestinal bleeding. For 4 of the 40 documented concomitant gastrointestinal bleeding events, Velphoro-related stool discolouration was reported as causing an insignificant delay in diagnosis of gastrointestinal bleeding, without affecting patient health. In the remaining cases, no delay in diagnosis of gastrointestinal bleeding has been reported.

The results from this study showed that the effectiveness of Velphoro in a real-life setting (including concomitant use of other phosphate binders in 45% of patients), was in line with that observed in the phase 3 clinical study.

Paediatric population

No data available.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Velphoro works by binding phosphate in the gastrointestinal tract and thus the serum concentration is not relevant for its efficacy. Due to the insolubility and degradation characteristics of Velphoro, no classical pharmacokinetic studies can be carried out, e.g., determination of the distribution volume, area under the curve, mean residence time, etc.

In 2 Phase 1 studies, it was concluded that the potential for iron overload is minimal and no dose-dependent effects were observed in healthy volunteers.

Absorption

The active moiety of Velphoro, pn-FeOOH, is practically insoluble and therefore not absorbed. Its degradation product, mononuclear iron species, can however be released from the surface of pn-FeOOH and be absorbed.

The absolute absorption studies in humans were not performed. Non-clinical studies in several species (rats and dogs) showed that systemic absorption was very low (≤1% of the administered dose).

The iron uptake from radiolabelled Velphoro active substance, 2,000 mg iron in 1 day was investigated in 16 CKD patients (8 pre-dialysis and 8 haemodialysis patients) and 8 healthy volunteers with low iron stores (serum ferritin <100 mcg/L). In healthy subjects, the median uptake of radiolabelled iron in the blood was estimated to be 0.43% (range 0.16 – 1.25%) on day 21, in pre- dialysis patients 0.06% (range 0.008 – 0.44%) and in haemodialysis patients 0.02% (range 0 – 0.04%).
Blood levels of radiolabelled iron were very low and confined to the erythrocytes.

Distribution

The distribution studies in humans were not performed. Non-clinical studies in several species (rats and dogs) showed that pn-FeOOH is distributed from the plasma to the liver, spleen and bone marrow, and utilized by incorporation into red blood cells.

In patients, absorbed iron is expected to be also distributed to the target organs, i.e. liver, spleen and bone marrow, and utilized by incorporation into red blood cells.

Biotransformation

The active moiety of Velphoro, pn-FeOOH, is not metabolised. However, the degradation product of Velphoro, mononuclear iron species, can be released from the surface of polynuclear iron(III)-oxyhydroxide and be absorbed. Clinical studies have demonstrated that the systemic absorption of iron from Velphoro is low.


In vitro data suggest that the sucrose and starch components of the active substance can be digested to glucose and fructose, and maltose and glucose, respectively. These compounds can be absorbed in the blood.

Elimination

In animal studies with rats and dogs administered 59Fe-Velphoro active substance orally, radiolabelled iron was recovered in the faeces but not the urine.