Pharmacokinetics of C1 Esterase Inhibitor, Human (Pasteurized) in Subjects with Hereditary Angioedema.

Hereditary and acquired deficiencies in C1 inhibitor (C1-INH) function can result in potentially life-threatening attacks of hereditary angioedema (HAE). A highly purified and pasteurized C1-INH concentrate has been used effectively as prophylaxis against and treatment for angioedema attacks in patients with hereditary C1-INH deficiencies, but relatively little is known about its pharmacokinetic properties.

Objective: To evaluate the pharmacokinetics and in vivo recovery (IVR) of C1-INH concentrate (Berinert^®P) in two groups of patients with hereditary angioedema (HAE) receiving this preparation either as individual replacement therapy (IRT, regular, immediate treatment of first HAE symptoms in patients with frequent and severe attacks) or as on-demand treatment.

Methods: Forty subjects (15 under IRT, 25 under on-demand treatment) with HAE received intravenous injections of C1-INH (542–1,617 U) in an attack-free interval in a prospective, open, uncontrolled, single-center study. Blood was sampled for determination of C1-INH with a commercially available functional chromogenic assay for up to 72 hours after dosing. Pharmacokinetic parameters were calculated using a single-compartment model and IVR was determined using standard methods.

Results: The mean (± SD) time to maximum plasma concentration (T_max) for C1-INH administered in patients under IRT was 1.3 ± 2.1 hours, the area under the time versus plasma concentration curve (AUC) was 20.5 ± 19.1 hour•U/mL, the elimination half-life (t½) was 33.3 ± 19.8 hours, mean residence time (MRT) was 48.0 ± 28.5 hours, total body clearance (Cl) was 1.1 ± 0.6 mL/kg/hour, and volume of distribution at steady state (V_ss) was 39.5 ± 9.9 mL/kg. The respective values for patients treated on demand were 2.9 ± 6.5 hours, 20.0 ± 14.5 hour•U/mL, 43.9 ± 22.4 hours, 63.4 ± 32.3 hours, 1.2 ± 1.0 mL/kg•hour, and 51.4 ± 10.9 mL/kg. The mean IVRs for IRT and on-demand treatment were 108.2 ± 48.3% and 85.8 ± 28.3%, respectively. Children tended to have slightly lower half-life and a slightly higher Vss compared to adults.

Conclusions: C1-INH concentrate has a short T_max and a long, t½ and MRT consistent with the rapid onset of clinical efficacy for this preparation in subjects suffering angioedema attacks and the ability to effectively carry out IRT with injections administered every 2–5 days. This analysis provides to our knowledge the most comprehensive pharmacokinetic evaluation in subjects with HAE.