# Presentation: 507881

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

**Christy S. John, Ph.D**
** ****Division of Clinical Pharmacology V Office of Clinical Pharmacology**
**Office of Translational Sciences**
**CDER, FDA**

## OVERVIEW

**Chemistry and dosing regimen**
**Iron transport and storage**
**Pharmacokinetic profile**
**Pharmacodynamic profile**
**Conclusions**

## INJECTAFER 

## INJECTAFER (Ferric carboxymaltose)

**Single Dose Vials ( 2mL and 10 mL; 50 mg iron in each mL)**
**Supplied as a dark brown, sterile, aqueous, isotonic solution**
**Injected undiluted or infused following dilution in 250 mL saline**

## Dosing Regimen

**Proposed Dose:  15mg/kg; Maximum single weekly doses of 1,000 mg**
**Total Dose:  Maximum Total Dose of 2,500 mg given over 3 weeks**
**Administered either by rapid intravenous (IV) push injection or by IV infusion. **
**600 to 1,000 mg doses: IV infusion over ≥ 15 minutes or undiluted IV push injection over 15 minutes**
_**<**_** 500 mg doses: undiluted IV push injection at 100 mg per minute **

##  Iron Transport and Storage

_**PK Parameter:**_
**Total Serum Iron Concentration**
_**PD Parameters:**_
**Transferrin Saturation: TS is estimated by measures of total iron binding capacity (TIBC) and serum iron**
**Serum ferritin: an iron-storage protein**

## Dose Escalation PK/PD Study 

**A single-center, randomized, double-blind, placebo-controlled multiple dose study**
**Study included single IV doses of 100, 500, 800 and 1,000 mg via IV infusion or bolus (Injectafer; n = 6, placebo; n = 2)**
**A total of 32 patients were studied**

## Total Serum Iron Concentrations Vs. Time

## PK Parameters: Total Serum Iron 

| Outcome | 100 mg  | 500 mg  | 800 mg | 1,000 mg |
| --- | --- | --- | --- | --- |
| Cmax
(μg/mL) | 37 
(4) | 157 
(19) | 324 
(64) | 333 
(42) |
| AUC0-72
(μg-h/mL) | 432
(75) | 2365
(332) | 5252
(1042) | 6415
(1516) |
| CL
(mL/min) | 4.4 
(0.9) | 3.5
 (0.5) | 2.59 
(0.5) | 2.7 
(0.6) |
| Average (SD)

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

## PD for Injectafer: Serum Ferritin

| Parameters
 | Serum Ferritin  |  |  |  |
| --- | --- | --- | --- | --- |
|  | 100 mg | 500 mg | 800 mg | 1,000 mg |
| Pre-dose
(ng/mL) | 2 
(2) | 5
(7)  | 4 
(3) | 3
(2) |
| Max. Conc. (ng/mL) | 49 
(20)  | 423 
(400) | 488 
(165) | 652 
(218)  |
| Peak (Hours) | 48 | 96
 | 120 | 120
 |
| Average (Standard Deviation) |  |  |  |  |

**Normal Ferritin Concentrations:**
**Male: ~ 12 - 300 ng/mL **
**Female: ~ 12 - 150 ng/mL **

## PD for Injectafer: Transferrin Saturation

## Summary: PK/PD Study 

**Serum Iron Concentrations **
**increased with increasing Injectafer doses **
**increase in AUC was higher than expected for dose proportionality**
**Serum Ferritin Concentrations **
**increased with increasing Injectafer doses**
**More than twice upper bound for normal serum ferritin with 1000 mg Injectafer dose**
**Transferrin Saturation Increased/assay problems**

## CONCLUSIONS

**	**
**	****Clinical pharmacology data indicated increased levels of serum iron, serum ferritin and transferrin saturation in blood after Injectafer administration**
**	****Data support the ability of Injectafer to replenish body iron stores**
**	****Higher Injectafer doses produce ferritin levels that exceed normal human values**
**	**