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Also known as: C1 esterase inhibitor C1-inh

Mechanism of Action

C1 inhibitor is a member of the serine protease inhibitor, or serpin, superfamily of proteins. The main function of serpins is to regulate the activity of serine proteases. C1 inhibitor is a single chain glycoprotein found in plasma which, in its mature state, consists of 478 amino acids with an apparent molecular weight of 105 kD.

C1 inhibitor inhibits the complement system by binding C1r and C1s, two of the active enzyme subunits of the first component of the complement system (C1) in the classical pathway, as well as to mannose-binding lectin-associated serine proteases in the lectin pathway. The primary substrate of the activated C1 enzyme is C4; uninhibited C1 results in diminished C4 levels. C1 is the most important inhibitor of contact activation and regulates the contact system and the intrinsic coagulation pathway by binding to and inactivating kallikrein and factor XIIa. Because these pathways are part of enzyme amplification cascades, without C1 inhibitor, spontaneous or trigger-induced activation of these pathways can lead to unopposed activation and swelling.

Pharmacodynamic Properties

Pharmacodynamic effects

In clinical studies, the intravenous administration of C1 inhibitor resulted in a significant increase in systemic levels of antigenic and functional C1 inhibitor within 1 hour after administration. Administration of C1 inhibitor increases serum levels of C1 inhibitor activity and temporarily restores the natural regulation of the contact, complement, and fibrinolytic systems thereby controlling the swelling or the propensity to swell.

Low serum C4 levels often correlate with HAE attacks. Treatment with C1 inhibitor resulted in elevation of C4 levels at 12 hours. There was a statistically significant (p=0.0017) difference in the changes in mean values from baseline between treatment groups at 12 hours, demonstrating the association of C1 inhibitor treatment with an increase in C4 activity (C1 inhibitor + 2.9 mg/dl versus placebo + 0.1 mg/dl).

Pharmacokinetic Properties

A randomised, parallel group, open-label pharmacokinetic study of C1 inhibitor was performed in subjects with non-symptomatic HAE. The subjects received either a single intravenous dose of 1000 Units(*) or a 1000 Units(*) dose followed by a second dose of 1000 Units(*) 60 minutes later. The mean pharmacokinetic parameters for functional C1 inhibitor derived from baseline-corrected concentration data are presented in the following table.

Mean Pharmacokinetic Parameters for Functional C1 Inhibitor Following Administration of C1 inhibitor:

ParametersSingle Dose (1000 Units*) Double Dose (1000 Units dose followed by a second 1000 Units dose 60 minutes later)
Cbaseline (U/ml) 0.31 ± 0.20 (n=12) 0.33 ± 0.20 (n=12)
Cmax (U/ml) 0.68 ± 0.08 (n=12) 0.85 ± 0.12 (n=13)
Baseline-corrected Cmax (U/ml) 0.37 ± 0.15 (n=12) 0.51 ± 0.19 (n=12)
tmax (hr) [median (range)] (n=12) (n=13)
AUC(0-t) (U*hr/ml) 74.5 ± 30.3 (n=12) 95.9 ± 19.6 (n=13)
Baseline-corrected AUC(0-t) (U*hr/ml) 24.5 ± 19.1 (n=12) 39.1 ± 20.0 (n=12)
CL (ml/min) 0.85 ± 1.07 (n=7) 1.17 ± 0.78 (n=9)
Elimination half-life (hr) 56 ± 35 (n=7) 62 ± 38 (n=9)

n=number of subjects evaluated.

* Historically assigned potency values are expressed in in-house Units (U).

After intravenous administration of a single dose of C1 inhibitor to HAE subjects, the serum concentration of functional C1 inhibitor doubled within 1 to 2 hours. The maximum serum concentration (Cmax) and area under the serum concentration-time curve (AUC) appeared to increase from the single to double dose, although the increase was not dose-proportional. The mean elimination half-life of functional C1 inhibitor after administration of C1 inhibitor was 56 hours for a single dose and 62 hours for the double dose.

Because C1 inhibitor is an endogenous human plasma protein, it is not subject to metabolism by Cytochrome P450 iso-enzymes, excretion, or pharmacokinetic drug-drug interactions exhibited by many low molecular weight compounds. The expected consequence of metabolism of a glycoprotein is via degradation to small peptides and individual amino acids. As such, the pharmacokinetics and excretion of C1 inhibitor are not expected to be altered by renal or hepatic impairment.

Paediatric population

Functional C1 inhibitor activity was measured in children in the two open label studies. Mean increases from baseline in functional C1 inhibitor activity measured 1 hour post-dose in children 2 to <18 years of age ranged from 20% to 88% in Study LEVP 2006-1 (treatment) and from 22% to 46% in Study LEVP 2006-4 (prevention) compared with 21% to 66% and 25% to 32% in adults, respectively. Two additional studies evaluated plasma levels in children (6-11 years).

In study 624-203, plasma C1 INH antigen and functional activity from 9 patients were obtained following a single IV dose of 500 Units(*), 1000 Units(*), or 1500 Units(*) C1 inhibitor based on body weight. Increases in C1 INH antigen levels and functional activity above the baseline values at 1 hour and 24 hours post-dose were demonstrated.

In Study 0624-301, plasma C1 INH antigen and functional activity were measured from 6 patients pre-dose and 1h following IV administration of two dose levels of C1 inhibitor (500 Units(*) and 1000 Units(*)) every 3 or 4 days for 12 weeks. Both C1 inhibitor doses resulted in relevant plasma levels of C1 INH antigen and functional activity.

Preclinical Safety Data

Non-clinical data reveal no special hazard for humans based on conventional studies of general toxicity and toxicity to reproduction. No genotoxicity studies were performed as the active substance is unlikely to interact directly with DNA or other chromosomal material. No studies on fertility, early embryonic and post-natal development, or carcinogenicity studies were conducted because chronic dosing in animals would be expected to be associated with development of neutralising antibodies to the human protein.

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