Glucagon

Glucagon increases blood glucose concentration by activating hepatic glucagon receptors, thereby stimulating glycogen breakdown and release of glucose from the liver. Hepatic stores of glycogen are necessary for glucagon to produce an anti-hypoglycaemic effect.

Pharmacodynamic effects

When used in treatment of severe hypoglycaemia, an effect on blood glucose is usually seen within 10 minutes.

The onset of inhibitory effect on gastrointestinal motility occurs within 1 minute after an intravenous injection. Duration of action is in the range 5–20 minutes depending on the dose. The onset of effect occurs within 5–15 minutes after an intramuscular injection, with a duration of 10–40 minutes.

Gender and body weight had no clinically meaningful effect on the pharmacodynamics of glucagon nasal powder.

After administration of 3 mg glucagon nasal powder in adult patients with type 1 diabetes, glucose levels began to rise as early as 5 minutes (see figure 1). By 10 minutes, the median glucose level was above 3.9 mmol/L (70 mg/dL). The mean maximum glucose increase was 7.8 mmol/L (140 mg/dL).

In paediatric patients with type 1 diabetes (aged 1 to <17 years), after administration of 3 mg glucagon nasal powder, glucose levels began to rise as early as 5 minutes, with a mean maximum glucose increase of 5.7 mmol/L (102 mg/dL) to 7.7 mmol/L (138 mg/dL). The mean maximum glucose increase from baseline was 7.33 mmol/L (132 mg/dL) (1 to <4 years), 7.67 mmol/L (138 mg/dL) (4 to <8 years), 7.39 mmol/L (133 mg/dL) (8 to <12 years), and 5.67 mmol/L (102 mg/dL) (12 to <17 years) (Figure 2).

Common cold with nasal congestion with or without concomitant use of a decongestant did not impact pharmacodynamics of glucagon nasal powder.

Figure 1. Mean glucose concentration over time in adult patients with type 1 diabetes:

Figure 2. Mean glucose concentration over time in paediatric patients with type 1 diabetes:

IV / IM / SC administration

Metabolism

Glucagon is degraded enzymatically in the blood plasma and in the organs to which it is distributed. The liver and kidney are major sites of glucagon clearance, each organ contributing about 30% to the overall metabolic clearance rate.

Elimination

Glucagon has a short half-life in the blood of about 3–6 minutes. Metabolic clearance rate of glucagon in humans is approximately 10 ml/kg/min.

Nasal administration

Absorption

Glucagon absorption via the nasal route achieved mean peak plasma levels of 6 130 pg/mL at 15 minutes.

Distribution

The apparent volume of distribution of glucagon was approximately 885 L via the nasal route.

Biotransformation

Glucagon is known to be degraded in the liver, kidneys, and plasma.

Elimination

The mean half-life of glucagon was approximately 38 minutes via the nasal route.

Renal impairment

No formal studies have been performed to evaluate renal impairment.

Hepatic impairment

No formal studies have been performed to evaluate hepatic impairment.

Paediatric population

In paediatric patients (aged 1 to <17 years), glucagon absorption via the nasal route, achieved mean peak plasma levels between 10 and 20 minutes.

Common cold and use of decongestant

Based on clinical data in adults and paediatric patients, no significant effect on response is expected in case of inability to clear nasal passages, such as in the case of young children with a runny nose, because glucagon exposure is sufficient to produce a near-maximum glucose response, despite cold and/or nasal congestion.

No relevant pre-clinical data.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.