Pharmacokinetics of single and repeat doses of icatibant

Leach, J. K.; Spencer, Kelly; Mascelli, Maryann; McCauley, Thomas G.

doi:10.1002/cpdd.138

Cited by 19 publications

(17 citation statements)

References 24 publications

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“…In hereditary angioedema, a single 30 mg dose of icatibant is capable of reducing symptoms in minute to a few hours [42]. As icatibant has a short half-life (6 h) [43], we used a 30 mg/dose every 8 h for four days, which proved safe, as no increased adverse effects were reported.…”

Section: Discussionmentioning

confidence: 99%

Safety and Outcomes Associated with the Pharmacological Inhibition of the Kinin–Kallikrein System in Severe COVID-19

Mansour

Palma

Ulaf

et al. 2021

Viruses

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Background: Coronavirus disease 19 (COVID-19) can develop into a severe respiratory syndrome that results in up to 40% mortality. Acute lung inflammatory edema is a major pathological finding in autopsies explaining O2 diffusion failure and hypoxemia. Only dexamethasone has been shown to reduce mortality in severe cases, further supporting a role for inflammation in disease severity. SARS-CoV-2 enters cells employing angiotensin-converting enzyme 2 (ACE2) as a receptor, which is highly expressed in lung alveolar cells. ACE2 is one of the components of the cellular machinery that inactivates the potent inflammatory agent bradykinin, and SARS-CoV-2 infection could interfere with the catalytic activity of ACE2, leading to the accumulation of bradykinin. Methods: In this case control study, we tested two pharmacological inhibitors of the kinin–kallikrein system that are currently approved for the treatment of hereditary angioedema, icatibant, and inhibitor of C1 esterase/kallikrein, in a group of 30 patients with severe COVID-19. Results: Neither icatibant nor inhibitor of C1 esterase/kallikrein resulted in changes in time to clinical improvement. However, both compounds were safe and promoted the significant improvement of lung computed tomography scores and increased blood eosinophils, which are indicators of disease recovery. Conclusions: In this small cohort, we found evidence for safety and a beneficial role of pharmacological inhibition of the kinin–kallikrein system in two markers that indicate improved disease recovery.

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Section: Discussionmentioning

confidence: 99%

Safety and Outcomes Associated with the Pharmacological Inhibition of the Kinin–Kallikrein System in Severe COVID-19

Mansour

Palma

Ulaf

et al. 2021

Viruses

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“…In adolescent patients, blood samples were also collected 0.75 and 1 hour after dosing. Plasma icatibant concentrations were measured using a validated liquid chromatography with tandem mass spectrometry method as described previously 6 …”

Section: Methodsmentioning

confidence: 99%

“…Plasma icatibant concentrations were measured using a validated liquid chromatography with tandem mass spectrometry method as described previously. 6 PopPK Analysis of Icatibant Various compartment models were developed to optimally assess the concentration-time profiles of icatibant in the full population. The impact of covariates such as body weight and age were then analyzed to evaluate the PK of icatibant in pediatric patients with HAE.…”

Section: Clinical Studiesmentioning

confidence: 99%

“…2 Icatibant is a synthetic decapeptide that is approved for the treatment of attacks of angioedema in adult patients with HAE 3 ; it inhibits the bradykinin B2 receptor with high specificity and potency, and its long biological half-life is sufficient to allow systemic administration by subcutaneous injection. 4,5 In adults, a single subcutaneous injection of 30 mg icatibant results in achievement of maximum plasma concentrations within 1 hour of administration 6 and produces a rapid and durable response for relief of symptoms of HAE attacks irrespective of edema location. 7,8 Repeated use of icatibant over time for the treatment of multiple HAE attacks in adults produces a consistent response for each attack, with no diminution of efficacy.…”

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confidence: 99%

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Population Pharmacokinetics and Exposure‐Response Analyses to Guide Dosing of Icatibant in Pediatric Patients With Hereditary Angioedema

Wang

Jomphe²,

Marier³

et al. 2020

The Journal of Clinical Pharma

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Elevated bradykinin levels are responsible for the development of clinical symptoms in patients with hereditary angioedema (HAE). Icatibant is a bradykinin type 2 receptor antagonist indicated for the acute treatment of HAE attacks. A population modeling and simulation approach was used to examine sources of variability impacting icatibant pharmacokinetics (PK) and provide guidance on icatibant dosing in pediatric patients with HAE. An exposure-response analysis was performed for the time to onset of symptom relief (TOSR). Data from 141 adults (133 healthy, 8 with HAE) who received subcutaneous icatibant 30 mg and 31 pediatric patients with HAE who received 0.4 mg/kg (capped at 30 mg) were included in the analysis. Icatibant PK was described by a 2-compartment model with linear elimination. Complete absorption of icatibant was expected within 1 hour of dosing. The apparent clearance and central volume of distribution were 15.4 L/h and 20.4 L, respectively. Icatibant PK was mainly dependent on body weight. The mean TOSR was very short (1.38 hours). A flat exposure-response was observed, confirming that the relationship plateaued at the level of exposure observed in pediatric patients. Simulations confirmed that weight band-based dosing regimens (10 mg [12-25 kg], 15 mg [26-40 kg], 20 mg [41-50 kg], 25 mg [51-65 kg], and 30 mg [>65 kg]) resulted in exposure similar to the 0.4-mg/kg dose. This analysis showed that icatibant undergoes rapid absorption, reaches levels required for therapeutic response, and promptly relieves HAE symptoms. A weight band-based dosing regimen is appropriate in pediatric patients with HAE.

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“…Although synthetic des-Arg 10 -icatibant is a potent B 1 receptor antagonist [ 5 ], it is not a spontaneous metabolite of icatibant due to the non-natural residues in position 7 and 8 (D-Tic 7 , Oic 8 ) that preclude the binding to arginine-carboxypeptidases. The in vivo metabolites of icatibant are well known and represent fragments 1–5 and 7–10 of this decapeptide [ 55 ].…”

Section: Areas Of Uncertainty: Role Of Bk B 1 Rmentioning

confidence: 99%

In Vitro Modeling of Bradykinin-Mediated Angioedema States

et al. 2020

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Kinins (peptides related to bradykinin, BK) are formed from circulating substrates, the kininogens, by the action of two proteases, the kallikreins. The only clinical application of a BK receptor ligand, the B2 receptor antagonist icatibant, is the treatment of the rare hereditary angioedema (HAE) caused by the deficiency of C1-esterase inhibitor (C1-INH). Less common forms of HAE (genetic variants of factor XII, plasminogen, kininogen) are presumably mediated by increased BK formation. Acquired forms of BK-mediated angioedema, such as that associated with angiotensin-I converting enzyme (ACE) inhibition, are also known. Antibody-based analytical techniques are briefly reviewed, and support that kinins are extremely short-lived, prominently cleared by ACE. Despite evidence of continuous activation of the kallikrein–kinin system in HAE, patients are not symptomatic most of the time and their blood or plasma obtained during remission does not generate excessive immunoreactive BK (iBK), suggesting effective homeostatic mechanisms. HAE-C1-INH and HAE-FXII plasmas are both hyperresponsive to fibrinolysis activation. On another hand, we suggested a role for the alternate tissue kallikrein–kinin system in patients with a plasminogen mutation. The role of the BK B1 receptor is still uncertain in angioedema states. iBK profiles under in vitro stimulation provide fresh insight into the physiopathology of angioedema.

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Pharmacokinetics of single and repeat doses of icatibant

Abstract: Single 30- and 90-mg subcutaneous administration of icatibant exhibited dose-proportional PK with no appreciable accumulation upon repeated 30-mg doses administered at 6-hour intervals.

Cited by 19 publications

References 24 publications

Safety and Outcomes Associated with the Pharmacological Inhibition of the Kinin–Kallikrein System in Severe COVID-19

Safety and Outcomes Associated with the Pharmacological Inhibition of the Kinin–Kallikrein System in Severe COVID-19

Population Pharmacokinetics and Exposure‐Response Analyses to Guide Dosing of Icatibant in Pediatric Patients With Hereditary Angioedema

In Vitro Modeling of Bradykinin-Mediated Angioedema States

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