ION
Velphoro chewable tablets are brown, circular, bi-planar, and are embossed with “PA 500” on 1 side. Each tablet of Velphoro contains 500 mg iron (in 2,500 mg sucroferric oxyhydroxide). The Velphoro drug substance is a mixture of polynuclear iron(III)-oxyhydroxide, sucrose, and starches. The active moiety, polynuclear iron(III)-oxyhydroxide, is practically insoluble and cannot be absorbed. The inactive ingredients are woodberry flavor, neohesperidin dihydrochalcone, magnesium stearate, and silica (colloidal, anhydrous).
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
In the aqueous environment of the GI tract, phosphate binding takes place by ligand exchange between hydroxyl groups and/or water in sucroferric oxyhydroxide and the phosphate in the diet. The bound phosphate is eliminated with feces.
Both serum phosphorus levels and calcium-phosphorus product levels are reduced as a consequence of the reduced dietary phosphate absorption.
12.2 Pharmacodynamics
In vitro studies have demonstrated a robust phosphate binding capacity of Velphoro over the physiologically relevant pH range of the GI tract (1.2-7.5). The phosphate binding capacity of Velphoro peaked at pH 2.5, resulting in 96% of the available phosphate being adsorbed (phosphorus:iron concentration ratio 0.4:1).
12.3 Pharmacokinetics
The active moiety of Velphoro, polynuclear iron(III)-oxyhydroxide (pn-FeOOH), is practically insoluble and therefore not absorbed and not metabolized. Its degradation product, mononuclear iron species, can however be released from the surface of pn-FeOOH and be absorbed.
Because of the insolubility and degradation characteristics of Velphoro, no classical pharmacokinetic studies can be carried out.
The sucrose and starch components of Velphoro can be digested to glucose and fructose, and maltose and glucose, respectively. These compounds can be absorbed in the blood. One tablet is equivalent to 1.4 g of carbohydrates.
The iron uptake from radiolabelled Velphoro drug substance, 2,000 mg in 1 day, was investigated in 16 chronic kidney disease patients (8 pre-dialysis and 8 hemodialysis 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 0.43% on Day 21. In chronic kidney disease patients, the median uptake was much less, 0.04% on Day 21.
Drug Interaction Studies
In vitro
In vitro interactions were studied in aqueous solutions which mimic the physico-chemical conditions of the gastro-intestinal tract with or without the presence of phosphate (400 mg). The study was conducted at pH 3.0, 5.5 and 8.0 with incubation at 37°C for 6 hours.
Interaction with Velphoro was seen with the following drugs: alendronate, doxycycline, levothyroxine, and paricalcitol.
The following drugs did not show interaction with Velphoro: ciprofloxacin, enalapril, hydrochlorothiazide, metformin, metoprolol, nifedipine, and quinidine.
In vivo
Five in vivo drug interaction studies (N=40/study) were conducted with losartan, furosemide, digoxin, omeprazole and warfarin in healthy subjects receiving 1,000 mg Velphoro 3 times a day with meals. Velphoro did not alter the systemic exposure as measured by the area under the curve (AUC) of the tested drugs when co-administered with Velphoro or given 2 hours later.
Data from the clinical studies (Study-05A and Study-05B) show that Velphoro do |
