PB1074 - Population pharmacokinetics of subcutaneous protein C concentrate in patients with protein C deficiency

Background: Although protein C concentrate (Baxalta US Inc., a Takeda company, Lexington, MA, USA) is only approved for intravenous administration, subcutaneous administration has been reported in clinical practice.

Aims: To develop a population pharmacokinetic (PopPK) model and simulate for subcutaneous protein C concentrate dosing regimens in patients with severe congenital or acquired protein C deficiency.

Methods: The PopPK model for subcutaneous protein C concentrate administration was based on a previously developed intravenous 1-compartment linear model with first-order elimination, endogenous protein C production, and allometric scaling of clearance and volume of distribution. Following subcutaneous administration, absorption was described by a constant rate (i.e., zero-order) of administration into the depot compartment, followed by first-order absorption into the central compartment, with estimated duration of zero-order administration, absorption rate constant, and bioavailability. Simulations of the pharmacokinetic profiles of subcutaneous protein C concentrate were conducted across nine clinical dosing scenarios involving an initial dose of either 60 or 120 IU/kg with 3 subsequent doses and maintenance dosing of 45–120 IU/kg either every 6 or 12 hours. Target peak (maximum concentration; Cmax) and trough (trough concentration; Ctrough) levels were 100 IU/dL and 25 IU/dL, respectively, based on the product label.

Results: The dataset included 86 observations from 13 patients receiving subcutaneous protein C concentrate (female, n=7; median [range] age, 0.17 [0.003-18] years). Model-based simulations predicted that, at steady-state (approximately 11 days), >90% of patients would attain Ctrough >25 IU/dL for all dosing scenarios and between 24.44–68.28% of patients would reach Cmax >100 IU/dL. Steady-state was governed by the maintenance dose, regardless of the initial dose or the 3 subsequent doses. Subcutaneous bioavailability was estimated to be 79%.

Conclusion(s): The pharmacokinetics of subcutaneous protein C concentrate were well described by the PopPK model. Model-based simulations support the use of subcutaneous dosing regimens to achieve target levels of protein C.