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Mechanism of Action

C1 inhibitor is a normal constituent of human blood and is one of the serine proteinase inhibitors (serpins). The primary function of C1 inhibitor is to regulate the activation of the complement and intrinsic coagulation (contact system) pathway. C1 inhibitor also regulates the fibrinolytic system. Regulation of these systems is performed through the formation of complexes between the proteinase and the inhibitor, resulting in inactivation of both and consumption of the C1 inhibitor.

HAE patients have low levels of endogenous or functional C1 inhibitor. Although the events that induce attacks of angioedema in HAE patients are not well defined, it is thought by some that increased vascular permeability and the clinical manifestation of HAE attacks are primarily mediated through contact system activation. Suppression of contact system activation by C1 inhibitor through the inactivation of plasma kallikrein and factor XIIa is thought to modulate this vascular permeability by preventing the generation of bradykinin6. Administration of CINRYZE (c1 esterase inhibitor [human] freeze dried powder) increases plasma levels of C1 inhibitor activity.


In clinical studies, the intravenous administration of CINRYZE (c1 esterase inhibitor [human] freeze dried powder) demonstrated an increase in plasma levels of C1 inhibitor within approximately one hour or less of administration.

Biological activity of CINRYZE (c1 esterase inhibitor [human] freeze dried powder) was shown in 35 subjects by the subsequent increase in plasma C4 levels from an average of C4 8.1 mg/mL at baseline to C4 8.6 mg/mL 12 hours after infusion of CINRYZE (c1 esterase inhibitor [human] freeze dried powder) .


A randomized, parallel group, open label pharmacokinetics (PK) study of CINRYZE (c1 esterase inhibitor [human] freeze dried powder) was performed in patients with non-symptomatic hereditary angioedema (HAE). The patients received either a single dose of 1,000 units or 1,000 units followed by a second 1,000 units 60 minutes later. The PK results for functional C1 inhibitor are presented the following table:

Table 4: Mean pharmacokinetic parameters of Functional C1 Inhibitor

Parameters Single Dose Double Dose
Cbaseline (units/mL) 0.31 ± 0.20 (n = 12) 0.33 ± 0.20 (n = 12)
C (units/mL)max 0.68 ± 0.08 (n = 12) 0.85 ± 0.12 (n = 13)
T (hrs)max 3.9 ± 7.3 (n = 12) 2.7 ± 1.9 (n = 13)
AUC(0-t) (units*hr/mL) 74.5 ± 30.3 (n = 12) 95.9 ± 19.6 (n = 13)
CL (mL/min) 0.85 ± 1.07 (n = 7) 1.17 ± 0.78 (n = 9)
Half-life (hours) 56 ± 36 (n = 7) 62 ± 38 (n = 9)
Numbers in parenthesis are number of subjects evaluated
Single dose = 1,000 units
Double dose = 1,000 units followed by a second 1,000 units 60 minutes later
* One unit is equal to the mean C1 inhibitor concentration of 1 mL of normal human plasma

The maximum plasma concentrations (Cmax) and area under the plasma concentration-time curve (AUC) increased from the single to double dose, although the increase was not dose proportional. The mean half-lives of CINRYZE (c1 esterase inhibitor [human] freeze dried powder) were 56 hours (range 11 to 108 hours) for a single dose and 62 hours (range 16 to 152 hours) for the double dose.

Studies have not been conducted to evaluate the PK of CINRYZE (c1 esterase inhibitor [human] freeze dried powder) in special patient populations identified by gender, race, age (pediatric or geriatric), or the presence of renal or hepatic impairment.

Animal Toxicology and/or Pharmacology

Acute toxicity of CINRYZE (c1 esterase inhibitor [human] freeze dried powder) was studied in a combined acute toxicity and 7-day repeat dose/ dose range finding (DRF) study in Sprague Dawley rats. Repeat dose toxicity was studied in a 7-day repeat dose follow up to the acute dose study. The acute and repeated dose toxicity study were performed with intravenous administration of CINRYZE (c1 esterase inhibitor [human] freeze dried powder) at dose levels of 1, 7 and 28 times normal dose. No signs of toxicity were observed in the single dose study. In the repeated dose study, no signs of toxicity were observed in the two lower doses. Repeat dosing in the rat resulted in a robust neutralizing antibody response between days 1 and 14. Therefore, toxicity in animals dosed repeatedly is difficult to interpret.

In vitro and in vivo thrombogenicity studies showed a potential for clot formation when CINRYZE (c1 esterase inhibitor [human] freeze dried powder) was administered at doses 14 times the recommended clinical dose (greater than 200U/kg).

Clinical Studies

Routine Prophylaxis Trial LEVP2005-1/B

The safety and efficacy of CINRYZE (c1 esterase inhibitor [human] freeze dried powder) prophylaxis therapy to reduce the incidence, severity, and duration of HAE attacks was demonstrated in a single randomized, double blind, placebo controlled multi-center crossover study of 24 patients. Patients were screened to confirm a diagnosis of HAE and a history of at least two HAE attacks per month. 24 patients (mean age 38.1 years with a range of 9 to 73 years) were randomized to one of two treatment groups: either CINRYZE (c1 esterase inhibitor [human] freeze dried powder) prophylaxis for 12 weeks followed by 12 weeks of placebo prophylaxis; or randomized to placebo prophylaxis for 12 weeks followed by 12 weeks of CINRYZE (c1 esterase inhibitor [human] freeze dried powder) prophylaxis. Two subjects dropped out (one in each arm); 22 patients crossed over into period 2 and were included in the efficacy analysis. Patients were given blinded injections (CINRYZE (c1 esterase inhibitor [human] freeze dried powder) or placebo) every 3 to 4 days, approximately 2 times per week. Patients recorded all angioedema symptoms daily. An attack was defined as the subject-reported indication of swelling at any location following a report of no swelling on the previous day.

The efficacy determination was based on the number of attacks during the 12 week period while receiving CINRYZE (c1 esterase inhibitor [human] freeze dried powder) as compared to the number of attacks during the placebo treatment period. The effectiveness of C1 esterase inhibitor prophylaxis in reducing the number of HAE attacks was variable among the subjects as shown in table 5:

Table 5: LEVP2005-1/B Prevention of HAE Attacks Clinical Trial Results by Subject

Subject Percent Reduction in Attack Frequency
1 100%
2 100%
3 100%
4 100%
5 90%
6 88%
7 84%
8 83%
9 78%
10 76%
11 60%
12 47%
13 43%
14 43%
15 32%
16 31%
17 25%
18 21%
19 10%
20 1%
21 -8%
22 -85%

Table 6: Summary Statistics on Number of HAE Attacks in LEVP2005-1/B

  Statistic CINRYZE
Number of Attacks Mean 6.1 12.7
SD 5.4 4.8
Median 6 13.5
Min 0 6
Max 17 22
GEE Analysis Results
  Effect Assessed p-value
  Treatment Effect < 0.0001
  Sequence Effect 0.3347
  Period Effect 0.3494

Patients treated with CINRYZE (c1 esterase inhibitor [human] freeze dried powder) had a 66% reduction in days of swelling (p < 0.0001), and decreases in the average severity of attacks (p=0.0006) and the average duration of attacks (p=0.0023), as shown in table 7.

Table 7: LEVP2005-1/B Clinical Trial Secondary Efficacy Outcomes

Treatment Effect p-value
Mean Severity ofHAE Attacks (Score from 1 to 3) (SD) 1.3(0.85) 1.9 (0.36) 0.0006
Mean Duration of HAE Attacks (Days) (SD) 2.1 (1.13) 3.4 (1.4) 0.0023
Days of Swelling (SD) 10.1 (10.73) 29.6 (16.9) < 0.0001


1. Zuraw, B.2005. Current and future therapy for hereditary angioedema. Clinical Immunology. 114: 10– 16.

2. Agostoni A, Aygoren-Pursun E, Binkley KE, et al. 2004. Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. J Allergy Clin Immunol. 114(3 Suppl):S51-131.

3. Zwaan, C., Kleine, A., J. H. C. Diris, J., et al., 2002. Continuous 48-h C1-inhibitor treatment, following reperfusion therapy, in patients with acute myocardial infarction. European Heart Journal. 23:1670–1677.

4. Caliezi C, Wuillemin WA, Zeerleder S, Redondo M, Eisele B, Hack CE. C1-Esterase Inhibitor: An Anti-Inflammatory Agent and Its Potential Use in the Treatment of Diseases Other Than Hereditary Angioedema. Pharmacol Rev. 2000; 52:91-112

5. Davis AE, The pathophysiology of hereditary angioedema. Clin Immunol. 2005; 114:3-9.

6. Arzneimittelkommission der Deutschen Aertzteschaft. Schwerwiegende Thrombenbildung nach Berinert HS. Dtsch Aerztebl. 2000; 97:B-864

7. Horstick, G et al, 2002. Circulation 104:3125-3131

Last reviewed on RxList: 10/2/2009
This monograph has been modified to include the generic and brand name in many instances.


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