Pharmacokinetic Evidence Supporting Subcutaneous Use of Protein C Concentrate in Patients with Protein C Deficiency

Abstract

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.

Keywords

population pharmacokinetics - protein C concentrate - protein C deficiency - replacement therapy - subcutaneous

Data Availability Statement

Takeda does not plan to share data supporting the results reported in this article.

Authors' Contributions

Z.L. and J.S. contributed to the study concept and design and data acquisition, analysis, and interpretation.

I.C.S. and A.T. contributed to data analysis and interpretation. All authors revised the manuscript critically for intellectual content. All authors gave their final approval for the manuscript to be published and agreed to take responsibility for the integrity of all aspects of the work.

Publikationsverlauf

Eingereicht: 21. Mai 2025

Angenommen: 16. Oktober 2025

Artikel online veröffentlicht:
11. November 2025

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