Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties

Pharmacotherapeutic group: Somatropin and somatropin agonists. ATC: H01AC01.

Mechanism of action
Norditropin NordiFlex contains somatropin, which is human growth hormone produced by recombinant DNA-technology. It is an anabolic peptide of 191 amino acids stabilised by two disulphide bridges with a molecular weight of approximately 22,000 Daltons.


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The major effects of somatropin are stimulation of skeletal and somatic growth and pronounced influence on the body’s metabolic processes.

Pharmacodynamic effects

When growth hormone deficiency is treated a normalisation of body composition takes place resulting in an increase in lean body mass and a decrease in fat mass.
Somatropin exerts most of its actions through insulin-like growth factor 1 (IGF-1), which is produced in tissues throughout the body but predominantly by the liver.
More than 90% of IGF-1 is bound to binding proteins (IGFBPs) of which IGFBP-3 is the most important.

A lipolytic and protein sparing effect of the hormone becomes of particular importance during stress.

Somatropin also increases bone turnover indicated by an increase in plasma levels of biochemical bone markers. In adults bone mass is slightly decreased during the initial months of treatment due to more pronounced bone resorption, however, bone mass increases with prolonged treatment.

Clinical efficacy and safety

In clinical trials in short children born SGA doses of 0.033 and 0.067 mg/kg/day have been used for treatment until final height. In 56 patients who were continuously treated and have reached (near) final height, the mean change from height at start of treatment was +1.90 SDS (0.033 mg/kg/day) and +2.19 SDS (0.067 mg/kg/day). Literature data from untreated SGA children without early spontaneous catch-up suggest a late growth of 0.5 SDS. Long-term safety data are still limited.

A growth promoting effect was observed following 104 weeks (primary endpoint) and 208 weeks treatment with once-daily dosing of Norditropin 0.033 mg/kg/day and 0.066 mg/kg/day in 51 children aged 3 to <11 years with short stature due to Noonan syndrome.

A statistically significant increase from baseline in mean height SDS at 104 weeks (primary endpoint) was observed with 0.033 mg/kg/day (0.84 SDS) and 0.066 mg/kg/day (1.47 SDS).
A mean difference of 0.63 SDS [95 % CI: 0.38; 0.88] was observed between the groups at 104 weeks; the difference was greater after 208 weeks with an mean difference of 0.99 SDS [95 % CI: 0.62; 1.36] (figure 1).


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Change from baseline in height SDS   2.0                                                                                                                                           2.0 


Change from baseline in height SDS
1.5                                                                                                                                           1.5 


1.0                                                                                                                                           1.0 


0.5                                                                                                                                           0.5 


0.0                                                                                                                                           0.0 0     12      26    39          52   65     78       91   104      117   130       143     156   169       182   195    208 

Norditropin 0.033 mg/kg/day                Norditropin 0.066 mg/kg/day 
Full analysis set, LOCF imputed data.
Error bars are 1*SEM.



Figure 1                                           Height SDS (national) change from baseline to week 208 
The mean height velocity and height velocity SDS increased markedly from baseline during the first year of treatment with a greater increase with 0.066 mg/kg/day than with 0.033 mg/kg/day. The mean height velocity SDS was maintained above 0 in both groups after a two-year treatment and also after four years of treatment in the 0.066 mg/kg/day group. The height velocity SDS was greater with 0.066 mg/kg/day than with 0.033 mg/kg/day throughout the trial period (figure 2).


Group = Norditropin 0.033 mg/kg/day                           Group = Norditropin 0.066 mg/kg/day 
5.01
Height velocity SDS



2.80                                                                       2.65 

1.44
0.92
0.58


-0.39
-0.73
-1.70
-1.99



Baseline                                                        Baseline Time since randomisation (weeks)
Full analysis set, LOCF imputed data.
Baseline: Height velocity from 1 year prior to screening to week 0.
Error bars are 1*SEM.

Figure 2                                           Height velocity SDS (national) from baseline to week 208 
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Final height data were collected in 24 paediatric patients (18 included in a two-year prospective, open label, randomised, parallel group study and six who had followed the protocol without randomisation). After the initial two-years prospective study, Norditropin continued until final height. At the end of the treatment the majority of the subjects (16/24) achieved a final height within the normal national reference range (> 2 SDS).

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
I.v. infusion of Norditropin (33 ng/kg/min for 3 hours) to nine growth hormone deficient patients, gave the following results: serum half-life of 21.1±1.7 min., metabolic clearance rate of 2.33±0.58 ml/kg/min. and a distribution space of 67.6±14.6 ml/kg.

S.c. injection of Norditropin SimpleXx (Norditropin SimpleXx is the cartridge containing the solution for injection in Norditropin NordiFlex) 2.5 mg/m2 in 31 healthy subjects (with endogenous somatropin suppressed by continuous infusion of somatostatin) gave the following results:
Maximal concentration of human growth hormone (42-46 ng/ml) after approximately 4 hours.
Thereafter human growth hormone declined with a half-life of approximately 2.6 hours.
In addition the different strengths of Norditropin SimpleXx were demonstrated to be bioequivalent to each other and to Norditropin for reconstitution after subcutaneous injection to healthy subjects.