INJECTAFER Pharmacokinetics (PK) and Pharmacodynamics (PD)

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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

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OVERVIEW

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

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INJECTAFER
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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

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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
• lt 500 mg doses undiluted IV push injection at
  100 mg per minute

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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

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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

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Total Serum Iron Concentrations Vs. Time
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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) Average (SD) Normal serum iron concentration range is 4-15 µg/mL (LabCorp) Average (SD) Normal serum iron concentration range is 4-15 µg/mL (LabCorp) Average (SD) Normal serum iron concentration range is 4-15 µg/mL (LabCorp) Average (SD) Normal serum iron concentration range is 4-15 µg/mL (LabCorp)
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PD for Injectafer Serum Ferritin
Parameters Serum Ferritin Serum Ferritin Serum Ferritin Serum Ferritin
Parameters 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) Average (Standard Deviation) Average (Standard Deviation) Average (Standard Deviation) Average (Standard Deviation)
Normal Ferritin Concentrations Male 12 - 300
ng/mL Female 12 - 150 ng/mL
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PD for Injectafer Transferrin Saturation
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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

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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