A Novel Three Dose Regimen of Daclizumab in Liver Transplant Recipients with Hepatitis C: A Pharmaco

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A Novel Three Dose Regimen of Daclizumab in Liver
Transplant Recipients with Hepatitis C A
Pharmacokinetic and Pharmacodynamic Study

• Washburn K, Teperman LW, Heffron TG, Douglas DD,
  Gay S, Katz E, and Klintmalm BG

Kenneth Washburn, MD Transplant Center University
of Texas Health Science Center
Supported by a research grant from Roche
Laboratories, Inc
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Introduction
Daclizumab

• Humanized IL-2R monoclonal antibody
• Binds CD25 subunit of activated lymphocytes
  suppressing T-cell activation
• Approved for the prevention of acute rejection in
  renal transplantation

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Introduction
Clinical Trials In Liver Transplant

• Most trials have tested single dose or two dose
  regimen
• Koch et al, 2003
• PK/PD of 2 dose regimen(1 mg/kg on day 0 0.5
  mg/kg on day 4)
• 28 patients, post liver transplant
• CD25 reduction 28 days post transplant
• Half-life of 99 hrs
• Total body clearance of 57 mL/hr

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Objective

• Study the PK and PD of Daclizumab in hepatitis
  C liver transplant recipients using a 3 dose
  regimen

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Methods
Design Procedure
Hep C 3 Liver Study 312 patients
Tacrolimus Corticosteroid
Tacrolimus Corticosteroid MMF
Tacrolimus Daclizumab MMF
Daclizumab Sub-study 30 patients
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MethodsDaclizumab Dosing Regimen
2mg/kg
2mg/kg
1mg/kg
Day 1
Day 3
Day 8
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Methods
Design Procedure

• Daclizumab samples were drawn on days
• - Peak
• - Peak and Trough
• - Peak and Trough
• 30 - Trough

Peak 30 min post dose Trough 60 min pre dose
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MethodsAssays

• BeadChip assay for daclizumab
  concentration
• Flow cytometry for
• CD25 saturation

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Results
Demographics
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Results Daclizumab Concentration
5mg/mL
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Results CD25 T-Cells (Saturation)
Third dose
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Results CD25 T-Cells (Saturation)
Weight
Age
Race
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Results Saturation vs. Concentration
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Summary

• This regimen of daclizumab efficiently
  establishes a therapeutic serum concentration of
  daclizumab, and a significant reduction of CD25
  lymphocyte subsets for at least 30 days.
• The third dose at day 8 appears to help in
  maintaining the therapeutic effect of daclizumab
  on the CD25 lymphocyte subsets.
• The concentration effect plot demonstrated that
  the maximum suppression effect of daclizumab on
  the CD25 lymphocyte subset was achieved with
  daclizumab concentration at or above 5mg/mL.

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Conclusion

• The dosing regimen of daclizumab on days 1, 3,
  and 8 post liver transplant provids a high
  therapeutic serum concentration of daclizumab,
  and an effective reduction of CD25 lymphocyte
  subset, lasting for at least 30 days.