Bradykinin B2 Receptor (B2R)

Icatibant (10–30 μM) increases the effects of angiotensin III, but not II (contraction mediated by angiotensin AT1 receptors), and Lys-des-Arg9-bradykinin, but not des-Arg9-bradykinin (effects mediated by the bradykinin B1 receptors) (see reference 3).

Icatibant (0.3, or 1.5 mg/kg, subcutaneous administration twice daily in mice) significantly reduces the risk of ulcerative colitis[2].

Female mice of the CBA/J (H-2^k) strain
0.06, 0.3, or 1.5 mg/kg.
Subcutaneous administration twice daily

Absorption, Distribution and Excretion
Following subcutaneous injection of 30 mg icatibant, the absolute bioavailability is approximately 97%. The peak plasma concentration (Cmax) after a single subcutaneous injection of 30 mg was 974 ± 280 ng/mL. The AUC was 2165 ± 568 ng∙hr/mL. No accumulation of icatibant occurred after multiple administrations. The pharmacokinetics of icatibant have been characterized in healthy subjects and patients through intravenous and subcutaneous administration studies. The pharmacokinetic profile of icatibant in patients with hereditary angioedema (HAE) is similar to that in healthy subjects. Following subcutaneous injection of 30 mg icatibant, the absolute bioavailability is approximately 97%. In healthy subjects (N=96), following a single subcutaneous injection of 30 mg icatibant, the mean (± standard deviation) peak plasma concentration (Cmax) was observed at approximately 0.75 hours later. Following a single 30 mg dose, the mean area under the concentration-time curve (AUC0-∞) was 2165 ± 568 ng·hr/mL. No accumulation of icotiban was observed after three 30 mg doses administered at 6-hour intervals. The inactive metabolites of icotiban are primarily excreted in the urine, with less than 10% of the dose excreted unchanged. The steady-state volume of distribution (Vss) after subcutaneous administration was 29.0 ± 8.7 L. The plasma clearance after subcutaneous administration was 245 ± 58 mL/min. Metabolites/Metabolites: Icatibant is metabolized to inactive metabolites by proteolytic enzymes. The cytochrome P450 enzyme system does not participate in the metabolism of icotiban. Biological Half-Life: The mean elimination half-life after subcutaneous administration was 1.4 ± 0.4 hours.

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
There is currently no information regarding the secretion of atebandin into breast milk. Because atebandin is a protein molecule with a molecular weight of 1305 Da, its concentration in breast milk is likely very low. Furthermore, it is likely to be partially destroyed in the infant's gastrointestinal tract, so the amount absorbed by the infant may be minimal. One patient has been reported to have used this medication safely while breastfeeding. Wait 6 hours after administration before breastfeeding to minimize the amount of medication secreted into breast milk.
◉ Effects on Breastfed Infants
A woman with hereditary angioedema began on-demand subcutaneous injections of 30 mg atebandin at 4 months of age to treat an episode of hereditary angioedema and continued breastfeeding for 1 year while taking atebandin. The dose was administered at night before the infant's longest sleep period, and breastfeeding should not resume until at least 6 hours after administration. If facial and neck swelling and abdominal pain occur, immediately self-medicate with itiband and replace breast milk with formula. Two years later, during her second pregnancy, she used a C1 esterase inhibitor until the baby was one month old, after which she resumed itiband treatment.
◉ Effects on lactation and breast milk
As of the revision date, no relevant published information was found.

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Protein binding
There is currently no information on itiband protein binding.

[1]. Hoe 140 a new potent and long acting bradykinin-antagonist: in vitro studies. Br J Pharmacol. 1991 Mar;102(3):769-73.

[2]. Effect of Icatibant, a Bradykinin B2 Receptor Antagonist, on the Development of Experimental Ulcerative Colitis in Mice. Dig Dis Sci. 1999 Apr;44(4):845-51.

[3]. The Bradykinin B2 Receptor Antagonist Icatibant (Hoe 140) Blocks Aminopeptidase N at Micromolar Concentrations: Off-Target Alterations of Signaling Mediated by the Bradykinin B1 and Angiotensin Receptors. Eur J Pharmacol. 2006 Dec 3;551(1-3):108-11.

Icatibant is a synthetic decapeptide composed of five non-protein amino acids that antagonizes the β2 receptor, exhibiting an affinity similar to bradykinin. It resists degradation by bradykinin lyase and is 2-3 times more potent than earlier β2 receptor antagonists, thus representing a novel class of drugs. Because bradykinin is associated with swelling in hereditary angioedema (HAE), Icatibant was previously investigated as a potential treatment for HAE; specifically, mice lacking the β2 receptor showed reduced swelling, confirming bradykinin's involvement in the pathophysiology of the disease. Icatibant received FDA approval on August 25, 2011, and EMA approval in 2008 for the treatment of hereditary angioedema. FDA approval was based on positive results from three double-blind, randomized, controlled clinical trials (FAST 1, 2, and 3). In these trials, the median time to near-complete symptom resolution was 8 hours in the treated group, compared to 36 hours in the placebo group.
Icatibant is a bradykinin B2 receptor antagonist. Icatibant's mechanism of action is as a bradykinin B2 receptor antagonist.
Icatibant is an antagonist of the human bradykinin B2 receptor (B2R) and is used to treat hereditary angioedema (HAE). After administration, Icatibant targets and binds to B2R, thereby preventing bradykinin from binding to B2R. This may prevent bradykinin/B2R-mediated vasodilation, thereby reducing increased vascular permeability and the swelling, inflammation, and pain associated with HAE. This may also prevent or improve pulmonary edema unrelated to hereditary angioedema (HAE) and improve associated hypoxemia.
See also: Icatibant acetate (in saline form).

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Drug Indications
Icatibant is indicated for the treatment of acute exacerbations of hereditary angioedema (HAE) in adults aged 18 years and older.
FDA Label
Firazyr is indicated for the treatment of acute exacerbations of hereditary angioedema (HAE) in adults with C1 esterase inhibitor deficiency.
Icatibant Accord is indicated for the treatment of acute exacerbations of hereditary angioedema (HAE) in adults, adolescents, and children aged 2 years and older with C1 esterase inhibitor deficiency.
Treatment of ACE Inhibitor-Induced Angioedema

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Mechanism of Action
Icatiban is a competitive ACE inhibitor. Icatiban is a selective antagonist of the bradykinin B2 receptor with a similar affinity to bradykinin. Hereditary angioedema (HAE) is caused by the absence or dysfunction of a C1 esterase inhibitor, a key regulator of the factor XII/kallikrein proteolytic cascade that ultimately leads to the production of bradykinin. Bradykinin is a vasodilator and is considered to be the cause of the characteristic symptoms of HAE (localized swelling, inflammation, and pain). Icatibant inhibits the binding of bradykinin to the B2 receptor, thereby treating the clinical symptoms of acute HAE exacerbations.

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Pharmacodynamics
In healthy young subjects, intravenous Icatibant dose- and time-dependently inhibited bradykinin-induced hypotension, vasodilation, and reflex tachycardia following a bradykinin challenge test. Intravenous infusion of 0.4 and 0.8 mg/kg icatibant inhibited the response to the bradykinin challenge test 4 hours later, with the inhibition lasting 6 to 8 hours. Based on exposure-response analysis, subcutaneous injection of 30 mg icatibant is expected to effectively inhibit the bradykinin challenge test for at least 6 hours. The clinical significance of these findings is unclear. A randomized, placebo-controlled, active drug-controlled (moxifloxacin 400 mg) four-period crossover QT interval study evaluated the effects of single subcutaneous injections of 30 mg and 90 mg icatibant on the QT interval in 72 healthy subjects. This study has confirmed the ability to detect minute effects, with the upper limit of the one-sided 95% confidence interval for the maximum placebo-corrected baseline QTc interval based on the individualized correction method (QTcI) being less than 10 ms, below the threshold of concern to regulatory agencies. A dose of 90 mg is sufficient to represent a clinically high exposure.

C59H89N19O13S

1304.5225

1303.66

C, 54.32; H, 6.88; N, 20.40; O, 15.94; S, 2.46

130308-48-4

Icatibant acetate; 138614-30-9

6918173

White to off-white solid powder

1.6±0.1 g/cm3

1.742

-2.63

15

18

30

92

2720

12

S1C([H])=C([H])C([H])=C1C([H])([H])[C@@]([H])(C(N([H])[C@@]([H])(C([H])([H])O[H])C(N1C([H])([H])C2=C([H])C([H])=C([H])C([H])=C2C([H])([H])[C@]1([H])C(N1C([H])(C(N([H])[C@]([H])(C(=O)O[H])C([H])([H])C([H])([H])C([H])([H])/N=C(\N([H])[H])/N([H])[H])=O)C([H])([H])[C@]2([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[C@]12[H])=O)=O)=O)N([H])C(C([H])([H])N([H])C([C@]1([H])C([H])([H])[C@]([H])(C([H])([H])N1C([C@]1([H])C([H])([H])C([H])([H])C([H])([H])N1C([C@]([H])(C([H])([H])C([H])([H])C([H])([H])/N=C(\N([H])[H])/N([H])[H])N([H])C([C@@]([H])(C([H])([H])C([H])([H])C([H])([H])/N=C(\N([H])[H])/N([H])[H])N([H])[H])=O)=O)=O)O[H])=O)=O

QURWXBZNHXJZBE-SKXRKSCCSA-N

InChI=1S/C59H89N19O13S/c60-37(14-5-19-67-57(61)62)48(82)72-38(15-6-20-68-58(63)64)52(86)75-22-8-18-43(75)54(88)77-30-35(80)26-44(77)50(84)70-28-47(81)71-40(27-36-13-9-23-92-36)49(83)74-41(31-79)53(87)76-29-34-12-2-1-10-32(34)24-46(76)55(89)78-42-17-4-3-11-33(42)25-45(78)51(85)73-39(56(90)91)16-7-21-69-59(65)66/h1-2,9-10,12-13,23,33,35,37-46,79-80H,3-8,11,14-22,24-31,60H2,(H,70,84)(H,71,81)(H,72,82)(H,73,85)(H,74,83)(H,90,91)(H4,61,62,67)(H4,63,64,68)(H4,65,66,69)/t33-,35+,37+,38-,39-,40-,41-,42-,43-,44-,45-,46+/m0/s1

(2S)-2-[[(2S,3aS,7aS)-1-[(3R)-2-[(2S)-2-[[(2S)-2-[[2-[[(2S,4R)-1-[(2S)-1-[(2S)-2-[[(2R)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]-4-hydroxypyrrolidine-2-carbonyl]amino]acetyl]amino]-3-thiophen-2-ylpropanoyl]amino]-3-hydroxypropanoyl]-3,4-dihydro-1H-isoquinoline-3-carbonyl]-2,3,3a,4,5,6,7,7a-octahydroindole-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoic acid

Firazyr; Icatibant

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O: ~100 mg/mL (~76.7 mM)

Solubility in Formulation 1: 50 mg/mL (38.33 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)