Icatibant - How It Works
Clinical pharmacology details from the US FDA-approved label: how Icatibant works in your body, how it's absorbed, how long it stays active, and how it's eliminated.
Mechanism of Action
12.1 Mechanism of Action Icatibant is a competitive antagonist selective for the bradykinin B2 receptor, with an affinity similar to bradykinin. Hereditary angioedema is caused by an absence or dysfunction of C1-esterase-inhibitor, a key regulator of the Factor XII/kallikrein proteolytic cascade that leads to bradykinin production. Bradykinin is a vasodilator which is thought to be responsible for the characteristic HAE symptoms of localized swelling, inflammation, and pain. Icatibant inhibits bradykinin from binding the B2 receptor and thereby treats the clinical symptoms of an acute, episodic attack of HAE.
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Icatibant is a competitive antagonist selective for the bradykinin B2 receptor, with an affinity similar to bradykinin.
Hereditary angioedema is caused by an absence or dysfunction of C1-esterase-inhibitor, a key regulator of the Factor XII/kallikrein proteolytic cascade that leads to bradykinin production.
Bradykinin is a vasodilator which is thought to be responsible for the characteristic HAE symptoms of localized swelling, inflammation, and pain.
Icatibant inhibits bradykinin from binding the B2 receptor and thereby treats the clinical symptoms of an acute, episodic attack of HAE.
12.2 Pharmacodynamics Following bradykinin challenge, intravenous administration of icatibant injection caused dose and time-dependent inhibition of development of bradykinin-induced hypotension, vasodilation, and reflex tachycardia in healthy young subjects.
Icatibant injection intravenous doses of 0.4 and 0.8 mg/kg infused over 4 hours inhibited response to bradykinin challenge for 6 to 8 hours following completion of the infusion.
Based on exposure-response analysis, a subcutaneous dose of 30 mg icatibant injection is predicted to be effective against bradykinin challenge for at least 6 hours.
The clinical significance of these findings is unknown.
The effect of icatibant injection 30 and 90 mg following a single subcutaneous injection on QTc interval was evaluated in a randomized, placebo-, and active-controlled (moxifloxacin 400 mg) four-period crossover thorough QT study in 72 healthy subjects.
In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on individual correction method (QTcI) was below 10 ms, the threshold for regulatory concern.
The dose of 90 mg is adequate to represent the high exposure clinical scenario.
12.3 Pharmacokinetics The pharmacokinetics of icatibant injection has been characterized in studies using both intravenous and subcutaneous administration to healthy subjects and patients.
The pharmacokinetic profile of icatibant injection in patients with HAE is similar to that in healthy subjects.
The absolute bioavailability of icatibant injection following a 30 mg subcutaneous dose is approximately 97%.
Following subcutaneous administration of a single 30 mg dose of icatibant injection to healthy subjects (N=96), a mean (± standard deviation) maximum plasma concentration (C max ) of 974 ± 280 ng/mL was observed after approximately 0.75 hours.
The mean area under the concentration-time curve (AUC 0-∞ ) after a single 30 mg dose was 2165 ± 568 ng·hr/mL, with no evidence of accumulation of icatibant following three 30 mg doses administered 6 hours apart.
Following subcutaneous administration, plasma clearance was 245 ± 58 mL/min with a mean elimination half-life of 1.4 ± 0.4 hours and volume of distribution at steady state (V ss ) of 29.0 ± 8.7 L.
Icatibant is extensively metabolized by proteolytic enzymes to inactive metabolites that are primarily excreted in the urine, with less than 10% of the dose eliminated as unchanged drug.
Icatibant is not degraded by oxidative metabolic pathways, is not an inhibitor of major cytochrome P450 (CYP) isoenzymes (CYP 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4) and is not an inducer of CYP 1A2 and 3A4.
Special populations Hepatic Impairment The pharmacokinetic parameters of icatibant injection were found to be generally comparable between healthy subjects (n=8) and mild to moderate (Child Pugh scores of 5 to 8) hepatic impaired patients (n=8) following a dose of 0.15 mg/kg/day as continuous intravenous infusion over 3 days.
Pharmacokinetics
12.3 Pharmacokinetics The pharmacokinetics of icatibant injection has been characterized in studies using both intravenous and subcutaneous administration to healthy subjects and patients. The pharmacokinetic profile of icatibant injection in patients with HAE is similar to that in healthy subjects. The absolute bioavailability of icatibant injection following a 30 mg subcutaneous dose is approximately 97%. Following subcutaneous administration of a single 30 mg dose of icatibant injection to healthy subjects (N=96), a mean (± standard deviation) maximum plasma concentration (C max ) of 974 ± 280 ng/mL was observed after approximately 0.75 hours. The mean area under the concentration-time curve (AUC 0-∞ ) after a single 30 mg dose was 2165 ± 568 ng·hr/mL, with no evidence of accumulation of icatibant following three 30 mg doses administered 6 hours apart. Following subcutaneous administration, plasma clearance was 245 ± 58 mL/min with a mean elimination half-life of 1.4 ± 0.4 hours and volume of distribution at steady state (V ss ) of 29.0 ± 8.7 L. Icatibant is extensively metabolized by proteolytic enzymes to inactive metabolites that are primarily excreted in the urine, with less than 10% of the dose eliminated as unchanged drug. Icatibant is not degraded by oxidative metabolic pathways, is not an inhibitor of major cytochrome P450 (CYP) isoenzymes (CYP 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4) and is not an inducer of CYP 1A2 and 3A4. Special populations Hepatic Im