Icatibant

HAE (an autosomal dominant disease) is caused by an absence or dysfunction of C1-esteraseinhibitor. HAE attacks are accompanied by an increased release of bradykinin, which is the key mediator in the development of the clinical symptoms.

HAE manifests as intermittent attacks of subcutaneous and/or sub mucosal oedema involving the upper respiratory tract, the skin and the gastrointestinal tract. An attack usually lasts between 2 to 5 days.

Icatibant is a selective competitive antagonist at the bradykinin type 2 (B2) receptor. It is a synthetic decapeptide with a structure similar to bradykinin, but with 5 non-proteinogenic amino acids. In HAE increased bradykinin concentrations are the key mediator in the development of the clinical symptoms.

Pharmacodynamic effects

In healthy young subjects, icatibant administered in doses of 0.8 mg/kg over 4 hours; 1.5 mg/kg/day or 0.15 mg/kg/day for 3 days, development of bradykinin-induced hypotension, vasodilatation and reflex tachycardia was prevented. Icatibant was shown to be a competitive antagonist when the bradykinin challenge dose was increased 4-fold.

The pharmacokinetics of icatibant has been characterized by studies using both intravenous and subcutaneous administration to healthy volunteers and patients. The pharmacokinetic profile of icatibant in patients with HAE is similar to that in healthy volunteers.

Absorption

Following subcutaneous administration, the absolute bioavailability of icatibant is 97%. The time to maximum concentration is approximately 30 minutes.

Distribution

Icatibant volume of distribution (Vss) is about 20-25 L. Plasma protein binding is 44%.

Biotransformation

Icatibant is extensively metabolized by proteolytic enzymes to inactive metabolites that are primarily excreted in the urine.

In vitro studies have confirmed that icatibant is not degraded by oxidative metabolic pathways and 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.

Elimination

Icatibant is mainly eliminated by metabolism with less than 10% of the dose eliminated in the urine as unchanged drug. Clearance is about 15-20 l/h and independent of dose. The terminal plasma half-life is about 1-2 hours.

Special populations

Elderly

Data suggest an age-related decline in clearance resulting in about 50-60% higher exposure in older people (75-80 years) compared to patients aged 40 years.

Gender

Data suggest that there is no difference in the clearance between females and males after correcting for body weight.

Hepatic and Renal Impairment

Limited data suggest that icatibant exposure is not influenced by hepatic or renal impairment.

Race

Information on individual race effect is limited. Available exposure data suggest no difference in the clearance between non-White (n=40) and White (n=132) subjects.

Paediatric population

The pharmacokinetics of icatibant were characterized in paediatric HAE patients in study HGT-FIR086. Following a single subcutaneous administration (0.4 mg/kg up to a maximum of 30 mg), the time to maximum concentration is approximately 30 minutes and the terminal half-life is about 2 hours. There are no observed differences in the exposure to icatibant between HAE patients with and without an attack. Population pharmacokinetic modelling using both adult and paediatric data showed that clearance of icatibant is related to body weight with lower clearance values noted for lower body weights in the paediatric HAE population. Based on modelling for weight banded dosing, the predicted exposure to icatibant in the paediatric HAE population is lower than the observed exposure in studies conducted with adult HAE patients.

Repeated-dose studies of up to 6-months duration in rats and 9-months duration in dogs have been conducted. In both rats and dogs, there was a dose-related reduction in circulating sex hormone levels and the repeated use of icatibant reversibly delayed sexual maturation.

Maximum daily exposures defined by area under the curve (AUC) at the No Observed Adverse Effect Levels (NOAEL) in the 9-month study in dog were 2.3 times the AUC in adult humans after a subcutaneous dose of 30 mg. A NOAEL was not measurable in the rat study, however, all of the findings from that study showed either completely or partially reversible effects in treated rats. Adrenal gland hypertrophy was observed at all doses tested in rats. Adrenal gland hypertrophy was seen to reverse after cessation of icatibant treatment. The clinical relevance of the adrenal gland findings is unknown.

Icatibant had no effect on the fertility of male mice (top dose 80.8 mg/kg/day) and rats (top dose 10 mg/kg/day).

In a 2 year study to evaluate the carcinogenic potential of icatibant in rats, daily doses giving exposure levels up to approximately 2-fold that achieved after a therapeutic dose in humans had no effect on the incidence or morphology of tumours. Results do not indicate a carcinogenic potential for icatibant.

In a standard battery of in vitro and in vivo tests icatibant was not genotoxic.

Icatibant was not teratogenic when administered by SC injection during early embryonic and fetal development in rat (top dose 25 mg/kg/day) and rabbit (top dose 10 mg/kg/day). Icatibant is a potent antagonist of bradykinin and therefore, at high dose levels, treatment can have effects on the uterine implantation process and subsequent uterine stability in early pregnancy. These uterine effects also manifest in late stage pregnancy where icatibant exhibits a tocolytic effect resulting in delayed parturition in the rat, with increased fetal distress and perinatal death at high doses (10 mg/kg/day).

A 2-week subcutaneous dose range finding study in juvenile rats identified 25 mg/kg/day as a maximally tolerated dose. In the pivotal juvenile toxicity study in which sexually immature rats were treated daily with 3 mg/kg/day for 7 weeks, atrophy of testes and epididymides were observed; the observed microscopic findings were partially reversible. Similar effects of icatibant on reproductive tissue were seen in sexually mature rats and dogs. These tissue findings were consistent with reported effects on gonadotrophins and during the subsequent treatment-free period appear to be reversible.

Icatibant did not elicit any cardiac conduction change in vitro (hERG channel) or in vivo in normal dogs or in various dog models (ventricular pacing, physical exertion and coronary ligation) where no associated hemodynamic changes were observed. Icatibant has been shown to aggravate induced cardiac ischemia in several non-clinical models, although a detrimental effect has not consistently been shown in acute ischemia.