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

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.