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Published on: March 17, 2010
Pharmacokinetic Evidence Supporting Subcutaneous Use of Protein C Concentrate in Patients with Protein C Deficiency
Zhaoyang Li1, Inmaculada C Sorribes2, Jennifer Schneider2
1Takeda Development Center Americas, Inc., Cambridge, Massachusetts, United States.
Insights
Subcutaneous (SC) protein C concentrate administration shows promising pharmacokinetic (PK) data for severe congenital protein C deficiency (SCPCD). Model simulations support various SC dosing regimens, suggesting a high loading dose may be needed for rapid therapeutic concentrations.
Area of Science:
- Pharmacokinetics and Pharmacodynamics
- Hematology
- Drug Development
Background:
- Protein C concentrate (Ceprotin®) is approved for intravenous (IV) use in severe congenital protein C deficiency (SCPCD).
- Subcutaneous (SC) administration offers potential benefits, particularly for pediatric and neonatal patients, but requires pharmacokinetic data for dose optimization.
- Current SC use of protein C concentrate is empirical, lacking robust PK data.
Purpose of the Study:
- To characterize the population pharmacokinetic (PopPK) profile of SC protein C concentrate in patients with SCPCD.
- To provide data supporting dose optimization for SC protein C concentrate in SCPCD patients.
- To evaluate the efficacy of different SC dosing regimens through simulations.
Main Methods:
- A PopPK model was developed for SC protein C concentrate, adapting a previously established IV model.
- Simulations were conducted using both three-stage (patterned on IV regimens) and one-stage (based on clinical practice) dosing scenarios.
- Target maximum (Cmax) and trough (Ctrough) concentrations were set at 100 IU/dL and 25 IU/dL, respectively.
Main Results:
- The PopPK model demonstrated robustness and accurately described SC protein C concentrate PK data.
- Simulations predicted that 6-9% of patients in three-stage scenarios and 5-45% in one-stage scenarios would achieve Cmax >100 IU/dL after the first dose.
- At steady state, over 83% of patients were predicted to maintain Ctrough >25 IU/dL across all simulated dosing scenarios.
Conclusions:
- Model-based simulations provide evidence supporting the use of various SC dosing regimens for protein C concentrate in SCPCD patients.
- SC administration can be utilized in acute or prophylactic settings across different age groups, guided by target protein C activity levels.
- A high initial loading dose may be necessary to achieve therapeutic concentrations rapidly.
Background:
Protein C concentrate (Ceprotin®; Baxalta US Inc., a Takeda company, Cambridge, MA; Takeda Manufacturing Austria AG, Vienna, Austria) is approved for intravenous (IV) use in severe congenital protein C deficiency (SCPCD), with pharmacokinetic (PK)-guided dosing. Subcutaneous (SC) administration may reduce treatment burden, especially for pediatric and neonatal patients; however, the use of SC protein C concentrate has so far been empirical, and PK data are required to support dose optimization.
Objectives:
This study aimed to characterize the population PK (PopPK) of SC protein C concentrate in patients with SCPCD.
Methods:
A PopPK model was developed for SC protein C concentrate, based on a previously developed model for IV administration. Simulations were conducted across eight three-stage dosing scenarios that patterned the IV dosing regimens in the U.S. product label (initial dose [stage 1]: 60-120 IU/kg; subsequent three doses [stage 2]: 60-80 IU/kg every 6 hours; maintenance dose [stage 3]: 45-120 IU/kg every 12 hours). Additional simulations were performed across six one-stage dosing scenarios that were based on dosing reported in clinical practice (50-60 IU/kg every 12 hours, 200-350 IU/kg every 48 hours). Target maximum ( C max ) and trough ( C trough ) concentration levels used as references were 100 IU/dL and 25 IU/dL, respectively.
Results:
The dataset included 86 observations from 13 patients with SCPCD receiving SC protein C concentrate. Model-based simulations predicted that, after the first dose, 6-9% and 5-45% of patients in the three- and one-stage dosing scenarios, respectively, would attain C max >100 IU/dL. At steady state, ≥83% of patients were predicted to attain C trough >25 IU/dL for all scenarios. In three-stage dosing scenarios, while initial (stage 1 [dose 1]) and subsequent doses (stage 2 [doses 2-4]) determined speed to steady state, exposure at steady state was driven by the maintenance dose (stage 3 [dose 5 onwards]).
Conclusions:
The PopPK model was robust and described SC protein C concentrate PK data well. Evidence provided by model-based simulations supports the use of various SC dosing regimens across age groups in acute or prophylactic settings according to the intended protein C activity levels. A high loading dose may be required to rapidly attain target therapeutic concentrations.
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