Evaluation of pharmacokinetics of intravenous protein C concentrate in protein C deficiency: implications for treatment initiation and maintenance

Abstract

Background

Dosing of intravenous protein C concentrate (Ceprotin) in patients with protein C deficiency is guided by pharmacokinetics (PK) of plasma protein C activity.

Objectives

This study aimed to characterize PK of intravenous Ceprotin in patients with severe congenital protein C deficiency (SCPCD) and severe acquired protein C deficiency (SAPCD).

Methods

An exploratory analysis was conducted to assess effects of demographic and disease-related factors on PK of Ceprotin (n = 35 patients with SCPCD or SAPCD), followed by a population PK analysis on data from 4 prospective clinical trials of Ceprotin in SCPCD or SAPCD (n = 58). Model-based simulations were conducted across 3-stage or 1-stage dosing scenarios based on label-recommended doses in acute or maintenance settings.

Results

Age, body weight, and symptomatic state of disease appeared to influence PK of Ceprotin, including endogenous production of (active) protein C. Model-based simulations predicted that after the first doses, 15% to 76% of patients in the 3-stage dosing scenarios (initial dose: 60-120 IU/kg) and 15% of patients in the 1-stage dosing scenario (60 IU/kg every 12 hours) would attain the recommended target C_max of >100 IU/dL. At steady state, ≥86% of patients were predicted to attain the recommended maintenance C_trough of >25 IU/dL. The steady-state protein C concentration was driven by the maintenance dose, regardless of the level of initial loading doses.

Conclusion

Age, body weight, and symptomatic disease state should be considered in dose optimization. Model-based simulations support the use of various combined loading and maintenance regimens to quickly and effectively achieve target protein C plasma levels.