Ferric pyrophosphate citrate

Identification

Name
Ferric pyrophosphate citrate
Accession Number
DB13995
Description

Ferric pyrophosphate citrate is a soluble iron replacement product. Free iron presents several side effects as it can catalyze free radical formation and lipid peroxidation as well as the presence of interactions of iron in plasma. The ferric ion is strongly complexed by pyrophosphate and citrate.1 FPC is categorized in Japan as a second class OTC drug.6 This category is given to drugs with ingredients that in rare cases may cause health problems requiring hospitalization or worst.7 It is also FDA approved since 2015.Label

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 1321.571
Monoisotopic: 1321.556531
Chemical Formula
C18H24Fe4O42P6
Synonyms
  • Ferric pyrophosphate citrate
  • FPC
  • SFP
  • Tetraferric nonahydrogen citrate pyrophosphate
  • Triferic
External IDs
  • H-61
  • H61

Pharmacology

Indication

Ferric pyrophosphate citrate is indicated for the treatment of iron loss or iron deficiency to maintain hemoglobin and to reduce the prescribed dose of erythropoiesis-stimulating agent (ESA) required to maintain desired hemoglobin levels.8

Iron deficiency appears when the dietary intake does not meet the body's requirement or when there is chronic external blood loss. During acute blood loss, body iron stores are sufficient for accelerated erythropoiesis and restoration of iron homeostasis. But when the altered homeostasis remains for weeks to months then some supplement is needed. Some causes of iron deficiency include ectoparasitism, endoparasitism, hematuria, epistaxis, hemorrhagic skin, coagulopathy, thrombocytopenia, thrombocytopathia and gastrointestinal hemorrhage.2

Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Iron supplementation typically results in increases in serum iron, transferrin-bound iron, and iron-stored in the form of ferritin in hepatocytes and macrophages. The available iron is usually used in bone marrow for the synthesis of hemoglobin.8

Mechanism of action

The usage of ferric pyrophosphate is based on the strong complex formation between these two species. Besides, the capacity of pyrophosphate to trigger iron removal from transferrin, enhance iron transfer from transferrin to ferritin and promote iron exchange between transferrin molecules. These properties make it a very suitable compound for parenteral administration, iron delivery into circulation and incorporation into hemoglobin.1

TargetActionsOrganism
AFerritin light chain
binder
Humans
AFerritin heavy chain
binder
Humans
AHemoglobin subunit alpha
binder
Humans
AHemoglobin subunit beta
binder
Humans
Absorption

The results of the present studies show that ferric pyrophosphate is as well absorbed in adults. The absorption of iron depends upon the route of entry. Ferric pyrophosphate has a very high bioavailability of 83-94%.3 The AUC and Cmax have a dose-dependent pharmacokinetic response, being of 675-1840 mcg.h/dL and 113-261 mcg/dL respectively when given in a dose from 2.5 to 10 mg. The time to reach maximum dose is approximate 4.5 hours.4

Volume of distribution

The apparent volume of distribution of ferric pyrophosphate after 4 hours of intravenous administration ranged from 0.765 to 0.859 L.Label

Protein binding

The main action site of ferric pyrophosphate is in the serum and thus it is highly bound to its targets such as ferritin and hemoglobin.4

Metabolism

Metabolism of ferric pyrophosphate resembles physiological processing of iron delivered into circulation after absorption by the gut. This is suggested due to the direct ability to trigger iron transfer to transferrin, between transferrin molecules and between transferrin and ferritin without the need of prior metabolism by the reticuloendothelial system.1

Route of elimination

After metabolism as endogenous iron, the excretion of ferric pyrophosphate follows the same pattern. In the body, iron is retained and in the absence of bleeding the excretion is very small. Most of the iron is absorbed in the gut and does not reach the feces. The excretion of iron can be done in urine, feces, sweat, hair, and nails.5

Half-life

The half-life of ferric pyrophosphate is 1.48 hours.4

Clearance

The mean clearance rate of ferric pyrophosphate can range between 0.406 to 0.556 L/hour.4

Adverse Effects
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Toxicity

Ferric pyrophosphate was showed to be clastogenic in the in vitro chromosomal aberration assay in presence of metabolic activation. It was not showed to have mutagenic or fertility effects and its carcinogenic potential have not been studied yet.Label

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AluminiumAluminium can cause a decrease in the absorption of Ferric pyrophosphate citrate resulting in a reduced serum concentration and potentially a decrease in efficacy.
Aluminum hydroxideAluminum hydroxide can cause a decrease in the absorption of Ferric pyrophosphate citrate resulting in a reduced serum concentration and potentially a decrease in efficacy.
CinoxacinFerric pyrophosphate citrate can cause a decrease in the absorption of Cinoxacin resulting in a reduced serum concentration and potentially a decrease in efficacy.
CiprofloxacinFerric pyrophosphate citrate can cause a decrease in the absorption of Ciprofloxacin resulting in a reduced serum concentration and potentially a decrease in efficacy.
DelafloxacinFerric pyrophosphate citrate can cause a decrease in the absorption of Delafloxacin resulting in a reduced serum concentration and potentially a decrease in efficacy.
EnoxacinFerric pyrophosphate citrate can cause a decrease in the absorption of Enoxacin resulting in a reduced serum concentration and potentially a decrease in efficacy.
Ferric ammonium citrateFerric ammonium citrate can cause a decrease in the absorption of Ferric pyrophosphate citrate resulting in a reduced serum concentration and potentially a decrease in efficacy.
Ferric carboxymaltoseFerric carboxymaltose can cause a decrease in the absorption of Ferric pyrophosphate citrate resulting in a reduced serum concentration and potentially a decrease in efficacy.
Ferric cationFerric cation can cause a decrease in the absorption of Ferric pyrophosphate citrate resulting in a reduced serum concentration and potentially a decrease in efficacy.
Ferric maltolFerric maltol can cause a decrease in the absorption of Ferric pyrophosphate citrate resulting in a reduced serum concentration and potentially a decrease in efficacy.
Additional Data Available
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  • Severity
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Food Interactions
No interactions found.

Products

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Active Moieties
NameKindUNIICASInChI Key
Ferric cationionic91O4LML61120074-52-6VTLYFUHAOXGGBS-UHFFFAOYSA-N
International/Other Brands
Incremin (Pfizer)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
TrifericSolution5.44 mg/1mLHemodialysisRockwell Medical, Inc2015-02-06Not applicableUS flag
TrifericSolution272 mg/50mLHemodialysis; IntravenousRockwell Medical, Inc2015-09-04Not applicableUS flag
TrifericPowder272 mg/272mgParenteralRopack Inc.2016-11-28Not applicableUS flag
TrifericPowder272 mg/1IntravenousRockwell Medical, Inc2016-04-25Not applicableUS flag
Triferic AVNUSolution1.5 mg/1mLIntravenousRockwell Medical Inc.2020-03-30Not applicableUS flag
Additional Data Available
  • Application Number
    Application Number
    Available for Purchase

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code
    Available for Purchase

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories

Drug Categories
Classification
Not classified

Chemical Identifiers

UNII
UBY79OCO9G
CAS number
1802359-96-1
InChI Key
SXAWSYZURCZSDX-UHFFFAOYSA-B
InChI
InChI=1S/3C6H8O7.4Fe.3H4O7P2/c3*7-3(8)1-6(13,5(11)12)2-4(9)10;;;;;3*1-8(2,3)7-9(4,5)6/h3*13H,1-2H2,(H,7,8)(H,9,10)(H,11,12);;;;;3*(H2,1,2,3)(H2,4,5,6)/q;;;4*+3;;;/p-12
IUPAC Name
tetrairon(3+) bis((phosphonooxy)phosphonic acid) tris(2-hydroxypropane-1,2,3-tricarboxylate) (hydrogen phosphonooxy)phosphonate
SMILES
[Fe+3].[Fe+3].[Fe+3].[Fe+3].OP(O)(=O)OP(O)(O)=O.OP(O)(=O)OP(O)(O)=O.OP([O-])(=O)OP([O-])([O-])=O.OC(CC([O-])=O)(CC([O-])=O)C([O-])=O.OC(CC([O-])=O)(CC([O-])=O)C([O-])=O.OC(CC([O-])=O)(CC([O-])=O)C([O-])=O

References

General References
  1. Gupta A, Amin NB, Besarab A, Vogel SE, Divine GW, Yee J, Anandan JV: Dialysate iron therapy: infusion of soluble ferric pyrophosphate via the dialysate during hemodialysis. Kidney Int. 1999 May;55(5):1891-8. doi: 10.1046/j.1523-1755.1999.00436.x. [PubMed:10231452]
  2. Naigamwalla DZ, Webb JA, Giger U: Iron deficiency anemia. Can Vet J. 2012 Mar;53(3):250-6. [PubMed:22942439]
  3. Fidler MC, Walczyk T, Davidsson L, Zeder C, Sakaguchi N, Juneja LR, Hurrell RF: A micronised, dispersible ferric pyrophosphate with high relative bioavailability in man. Br J Nutr. 2004 Jan;91(1):107-12. [PubMed:14748943]
  4. Pratt RD, Swinkels DW, Ikizler TA, Gupta A: Pharmacokinetics of Ferric Pyrophosphate Citrate, a Novel Iron Salt, Administered Intravenously to Healthy Volunteers. J Clin Pharmacol. 2017 Mar;57(3):312-320. doi: 10.1002/jcph.819. Epub 2016 Oct 3. [PubMed:27557937]
  5. Underwood E. (1977). Trace elements in human and animal nutrition (4th ed.). Academic press.
  6. KEGG [Link]
  7. Nippon [Link]
  8. FDA Reports [Link]
ChemSpider
34994433
ChEMBL
CHEMBL3833317
Wikipedia
Iron(III)_pyrophosphate
FDA label
Download (336 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3RecruitingTreatmentEnd Stage Renal Disease (ESRD)1
2TerminatedTreatmentIron-Refractory Iron-Deficiency Anemia1
1CompletedTreatmentAnemia / Chronic Kidney Disease (CKD) / Peritoneal dialysis therapy1
1CompletedTreatmentEnd Stage Renal Disease (ESRD)2
1CompletedTreatmentIron-refractory, Iron-deficiency Anemia (IRIDA)1
1, 2CompletedTreatmentEnd Stage Renal Disease (ESRD)2
1, 2Not Yet RecruitingTreatmentEnd Stage Renal Disease (ESRD)1
1, 2RecruitingTreatmentEnd Stage Renal Disease (ESRD)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
PowderIntravenous272 mg/1
PowderParenteral272 mg/272mg
SolutionHemodialysis5.44 mg/1mL
SolutionHemodialysis; Intravenous272 mg/50mL
SolutionIntravenous1.5 mg/1mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US6779468No2004-08-242016-12-31US flag
US7816404No2010-10-192029-04-17US flag
US6689275No2004-02-102016-12-31US flag
US7857977No2010-12-282027-09-08US flag
Additional Data Available
  • Filed On
    Filed On
    Available for Purchase

    The date on which a patent was filed with the relevant government.

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Properties

State
Solid
Experimental Properties
PropertyValueSource
boiling point (°C)309.6ºC at 760 mmHg'MSDS-online'
water solubilitySoluble FDA label
Predicted Properties
PropertyValueSource
Water Solubility7.6 mg/mLALOGPS
logP-0.72ALOGPS
logP-1.3ChemAxon
logS-1.4ALOGPS
pKa (Strongest Acidic)3.05ChemAxon
pKa (Strongest Basic)-4.2ChemAxon
Physiological Charge-3ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area140.62 Å2ChemAxon
Rotatable Bond Count21ChemAxon
Refractivity68.14 m3·mol-1ChemAxon
Polarizability14.23 Å3ChemAxon
Number of Rings0ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Binder
General Function
Iron ion binding
Specific Function
Stores iron in a soluble, non-toxic, readily available form. Important for iron homeostasis. Iron is taken up in the ferrous form and deposited as ferric hydroxides after oxidation. Also plays a ro...
Gene Name
FTL
Uniprot ID
P02792
Uniprot Name
Ferritin light chain
Molecular Weight
20019.49 Da
References
  1. Gupta A, Amin NB, Besarab A, Vogel SE, Divine GW, Yee J, Anandan JV: Dialysate iron therapy: infusion of soluble ferric pyrophosphate via the dialysate during hemodialysis. Kidney Int. 1999 May;55(5):1891-8. doi: 10.1046/j.1523-1755.1999.00436.x. [PubMed:10231452]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Binder
General Function
Iron ion binding
Specific Function
Stores iron in a soluble, non-toxic, readily available form. Important for iron homeostasis. Has ferroxidase activity. Iron is taken up in the ferrous form and deposited as ferric hydroxides after ...
Gene Name
FTH1
Uniprot ID
P02794
Uniprot Name
Ferritin heavy chain
Molecular Weight
21225.47 Da
References
  1. Gupta A, Amin NB, Besarab A, Vogel SE, Divine GW, Yee J, Anandan JV: Dialysate iron therapy: infusion of soluble ferric pyrophosphate via the dialysate during hemodialysis. Kidney Int. 1999 May;55(5):1891-8. doi: 10.1046/j.1523-1755.1999.00436.x. [PubMed:10231452]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Binder
General Function
Oxygen transporter activity
Specific Function
Involved in oxygen transport from the lung to the various peripheral tissues.
Gene Name
HBA1
Uniprot ID
P69905
Uniprot Name
Hemoglobin subunit alpha
Molecular Weight
15257.405 Da
References
  1. Gupta A, Amin NB, Besarab A, Vogel SE, Divine GW, Yee J, Anandan JV: Dialysate iron therapy: infusion of soluble ferric pyrophosphate via the dialysate during hemodialysis. Kidney Int. 1999 May;55(5):1891-8. doi: 10.1046/j.1523-1755.1999.00436.x. [PubMed:10231452]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Binder
General Function
Oxygen transporter activity
Specific Function
Involved in oxygen transport from the lung to the various peripheral tissues.LVV-hemorphin-7 potentiates the activity of bradykinin, causing a decrease in blood pressure.Spinorphin: functions as an...
Gene Name
HBB
Uniprot ID
P68871
Uniprot Name
Hemoglobin subunit beta
Molecular Weight
15998.34 Da
References
  1. Gupta A, Amin NB, Besarab A, Vogel SE, Divine GW, Yee J, Anandan JV: Dialysate iron therapy: infusion of soluble ferric pyrophosphate via the dialysate during hemodialysis. Kidney Int. 1999 May;55(5):1891-8. doi: 10.1046/j.1523-1755.1999.00436.x. [PubMed:10231452]

Drug created on February 23, 2018 13:10 / Updated on June 12, 2020 10:53

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