INJECTAFER INJECTAFER Pharmacokinetics (PK) and Pharmacokinetics (PK) and Pharmacodynamics (PD) Pharmacodynamics (PD)

Christy S. John, Ph.DChristy S. John, Ph.D

Division of Clinical Pharmacology V Division of Clinical Pharmacology V Office of Clinical PharmacologyOffice of Clinical Pharmacology

Office of Translational SciencesOffice of Translational Sciences

CDER, FDACDER, FDA

OVERVIEWOVERVIEW

Chemistry and dosing regimenChemistry and dosing regimen

Iron transport and storageIron transport and storage

Pharmacokinetic profilePharmacokinetic profile

Pharmacodynamic profilePharmacodynamic profile

ConclusionsConclusions

INJECTAFER INJECTAFER

INJECTAFERINJECTAFER (Ferric carboxymaltose)(Ferric carboxymaltose)

Single Dose Vials ( 2mL and 10 mL; 50 mg iron in Single Dose Vials ( 2mL and 10 mL; 50 mg iron in each mL)each mL)

Supplied as a dark brown, sterile, aqueous, Supplied as a dark brown, sterile, aqueous, isotonic solutionisotonic solution

Injected undiluted or infused following dilution in Injected undiluted or infused following dilution in 250 mL saline250 mL saline

Dosing RegimenDosing Regimen

Proposed Dose: 15mg/kg; Maximum single Proposed Dose: 15mg/kg; Maximum single weekly doses of 1,000 mgweekly doses of 1,000 mg

Total Dose: Maximum Total Dose of 2,500 Total Dose: Maximum Total Dose of 2,500 mg given over 3 weeksmg given over 3 weeks

Administered either by rapid intravenous (IV) Administered either by rapid intravenous (IV) push injection or by IV infusion. push injection or by IV infusion.

600 to 1,000 mg doses: IV infusion over ≥ 15 600 to 1,000 mg doses: IV infusion over ≥ 15 minutes or undiluted IV push injection over 15 minutes or undiluted IV push injection over 15 minutesminutes

<< 500 mg doses: undiluted IV push injection at 500 mg doses: undiluted IV push injection at 100 mg per minute 100 mg per minute

Iron Transport and StorageIron Transport and Storage

PK Parameter:PK Parameter:

– Total Serum Iron ConcentrationTotal Serum Iron Concentration

PD Parameters:PD Parameters:

– Transferrin Saturation: TS is estimated by Transferrin Saturation: TS is estimated by measures of total iron binding capacity measures of total iron binding capacity (TIBC) and serum iron(TIBC) and serum iron

– Serum ferritin: an iron-storage proteinSerum ferritin: an iron-storage protein

Dose Escalation PK/PD StudyDose Escalation PK/PD Study

A single-center, randomized, double-blind, placebo-controlled A single-center, randomized, double-blind, placebo-controlled multiple dose studymultiple dose study

Study included single IV doses of 100, 500, 800 and 1,000 mg via IV Study included single IV doses of 100, 500, 800 and 1,000 mg via IV infusion or bolus (Injectafer; n = 6, placebo; n = 2)infusion or bolus (Injectafer; n = 6, placebo; n = 2)

A total of 32 patients were studiedA total of 32 patients were studied

Total Serum Iron Concentrations Vs. TimeTotal Serum Iron Concentrations Vs. Time

PK Parameters: Total Serum IronPK Parameters: Total Serum Iron

OutcomeOutcome 100 mg 100 mg 500 mg 500 mg 800 mg800 mg 1,000 mg1,000 mg

CmaxCmax

((µg/mL)µg/mL)

37 37

(4)(4)

157 157

(19)(19)

324 324

(64)(64)

333 333

(42)(42)

AUCAUC0-720-72

((µg-h/mL)µg-h/mL)

432432

(75)(75)

23652365

(332)(332)

52525252

(1042)(1042)

64156415

(1516)(1516)

CLCL

(mL/min)(mL/min)

4.4 4.4

(0.9)(0.9)

3.53.5

(0.5)(0.5)

2.59 2.59

(0.5)(0.5)

2.7 2.7

(0.6)(0.6)

Average (SD)Average (SD)

Normal serum iron concentration range is 4-15 Normal serum iron concentration range is 4-15 µg/mL µg/mL (LabCorp)(LabCorp)

PD for Injectafer: Serum FerritinPD for Injectafer: Serum Ferritin

ParametersParameters Serum Ferritin Serum Ferritin

100 mg100 mg 500 mg500 mg 800 mg800 mg 1,000 mg1,000 mg

Pre-dosePre-dose

(ng/mL)(ng/mL)

2 2

(2)(2)

55

(7) (7)

4 4

(3)(3)

33

(2)(2)

Max. Conc. Max. Conc. (ng/mL)(ng/mL)

49 49

(20) (20)

423 423

(400)(400)

488 488

(165)(165)

652 652

(218) (218)

Peak Peak (Hours)(Hours)

4848 9696 120120 120120

Average (Standard Deviation)Average (Standard Deviation)

Normal Ferritin Concentrations:Normal Ferritin Concentrations:

Male: ~ 12 - 300 ng/mL Male: ~ 12 - 300 ng/mL

Female: ~ 12 - 150 ng/mL Female: ~ 12 - 150 ng/mL

PD for Injectafer: Transferrin SaturationPD for Injectafer: Transferrin Saturation

%Transferrin Saturation (TS) - Baseline

01020304050607080

0 20 40 60 80

Time (Hr)

%T

S-B

as

elin

e

100 mg

500 mg

800 mg

1000 mg

Summary: PK/PD Study Summary: PK/PD Study

Serum Iron Concentrations Serum Iron Concentrations – increased with increasing Injectafer doses increased with increasing Injectafer doses

– increase in AUC was higher than expected for dose increase in AUC was higher than expected for dose proportionalityproportionality

Serum Ferritin Concentrations Serum Ferritin Concentrations – increased with increasing Injectafer dosesincreased with increasing Injectafer doses

– More than twice upper bound for normal serum ferritin More than twice upper bound for normal serum ferritin with 1000 mg Injectafer dosewith 1000 mg Injectafer dose

Transferrin Saturation Increased/assay problemsTransferrin Saturation Increased/assay problems

CONCLUSIONSCONCLUSIONS

Clinical pharmacology data indicated increased Clinical pharmacology data indicated increased levels of serum iron, serum ferritin and transferrin levels of serum iron, serum ferritin and transferrin saturation in blood after Injectafer administrationsaturation in blood after Injectafer administration

Data support the ability of Injectafer to replenish Data support the ability of Injectafer to replenish body iron storesbody iron stores

Higher Injectafer doses produce ferritin levels that Higher Injectafer doses produce ferritin levels that exceed normal human valuesexceed normal human values