Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: immune sera and immunoglobulins: immunoglobulins, normal human, for extravascular administration, ATC code: J06BA01.

Human normal immunoglobulin contains mainly immunoglobulin G (IgG) with a broad spectrum of antibodies against infectious agents.
Human normal immunoglobulin contains the IgG antibodies present in the normal population. It is usually prepared from pooled plasma from not fewer than 1,000 donors. It has a distribution of immunoglobulin G subclasses closely proportional to that in native human plasma.

Mechanism of action
In immunodeficiency, adequate doses of Hizentra may restore abnormally low immunoglobulin G antibody levels to the normal range and thus help against infections.

PID
In the European pivotal prospective open label, single arm and multicentre study, a total of 51 subjects with primary immunodeficiency syndromes aged between 3 and 60 years old were treated with Hizentra for up to 41 weeks. The mean dose administered each week was 0.12 g/kg body weight (bw).
Sustained IgG trough levels with mean concentrations of 7.99 – 8.25 g/l were thereby achieved throughout the treatment period. Subjects received in total 1,831 weekly Hizentra infusions.

In the US prospective open label, single arm and multicentre study, a total of 49 subjects with primary immunodeficiency syndromes aged between 5 and 72 years old were treated with Hizentra for up to 15 months. The mean dose administered each week was 0.23 g/kg bw. Sustained IgG trough levels with a mean concentration of 12.53 g/l were thereby achieved throughout the treatment period.
Subjects received in total 2,264 weekly Hizentra infusions.
No serious bacterial infections were reported during the efficacy period in subjects receiving Hizentra during clinical studies.
To assess the safety and tolerability of higher infusion rates applied via the manual push and pump- assisted administration, 49 PID subjects aged 2 to 75 years were enrolled in an open-label, multicentre, parallel-arm, nonrandomised phase IV HILO (Hizentra Label Optimization) study and treated with Hizentra for at least 12 weeks (11 paediatric patients aged 2 to <18, 35 adult patients aged 18 to 65, and 3 geriatric patients aged >65 years). In the first patient group receiving Hizentra via the manual push technique (n=16), 2 to 7 infusions per week were administered with the flow rates of 30, 60 and 120 ml/hour/site (see section 4.2). In the second patient group receiving Hizentra via pump-assisted administration (n=18), weekly Hizentra infusions were administered with 25, 50, 75 and 100 ml/hour/site flow rate. In a third group, infusion volumes of 25, 40 and 50ml per site were additionally evaluated in pump-assisted administration of weekly Hizentra doses (n=15). In all three groups, each infusion parameter was used for 4 weeks, after which subjects successfully completing required minimal number of valid infusions could switch to the next higher infusion parameter.
The primary endpoint was the percentage of subjects responding to a higher infusion parameter: 


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Group                              Infusion parameter and responder rate (%) 1. manual push        30 ml/hour/site 60 ml/hour/site 120                 - flow rates                                           ml/hour/site
100.0 %          100.0 %          87.5 %            -
2. pump-assisted      25 ml/hour/site 50 ml/hour/site 75 ml/hour/site 100 ml/hour/site flow rates        77.8 %           77.8 %           66.7 %            61.1 % 3. pump-assisted      25 ml/site       40 ml/site       50 ml/site        - volumes           86.7 %           73.3 %           73.3 %            - Responder: in the pump-assisted group a subject who performed ≥3 valid infusions out of 4 for an infusion parameter; in the manual push group a subject who performed ≥60 % of valid infusions for an infusion parameter. An infusion was considered valid, if ≥95 % of the planned flow rate/volume per ≥1 infusion site was achieved.


Overall, the number of infusions without severe local reactions versus the total number of infusions (tolerability) was ≥ 0.98 in all groups for all infusion parameters. No clinically relevant differences in the serum IgG trough concentrations were observed between the baseline at day 1 and the end of the study in all subjects.

Paediatric population
The safety and effectiveness of Hizentra have been established in paediatric subjects 2 to 18 years of age. Hizentra was evaluated in 68 paediatric subjects with PID 2 to <12 years of age and in 57 paediatric subjects 12 to <18 years of age. There were no differences in the pharmacokinetics, safety and efficacy profiles as compared with adult subjects. No paediatric-specific dose adjustments were necessary to achieve the desired serum IgG levels. No differences were seen in the pharmacodynamic properties between adult and paediatric study patients with PID.

Elderly population
No overall differences in safety or efficacy were observed between PID subjects >65 years and PID subjects 18 to 65 years of age. In the clinical studies Hizentra was evaluated in 13 patients with PID>65 years of age.

Pharmacokinetic Properties

5.2     Pharmacokinetic properties

Absorption and Distribution
Following subcutaneous administration of Hizentra, peak serum levels are achieved after approximately 2 days.

Elimination
IgG and IgG-complexes are broken down in cells of the reticuloendothelial system.
PID
In a clinical phase III trial with Hizentra (n = 46), the subjects achieved sustained trough levels (median 8.1 g/l) over a period of 29 weeks when receiving median weekly doses of 0.06 to 0.24 g/kgbw.

Simulations by empirical Population Pharmacokinetic models suggested that comparable IgG exposure levels (AUC0-14days, Cmin 14days) may be obtained if Hizentra is administered subcutaneously every two weeks using double the weekly dose during maintenance therapy.
These simulations further suggested that comparable serum IgG trough levels can be achieved when the weekly maintenance dose of Hizentra is administered in proportional amounts more frequently than once a week (e.g. 2 times per week, 3 times per week, 5 times per week or daily).

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Simulation of 2-3 missed daily doses resulted in a median serum IgG level decrease of ≤ 4% compared to consistent daily dosing. By replacing the missed doses when daily dosing was resumed, the median concentration profile recovered within 2 to 3 days. However, if missed doses were not replaced when dosing was resumed, it took up to 5-6 weeks for the IgG trough levels to return to steady-state.

Paediatric population
No differences were seen in the pharmacokinetic parameters between adult and paediatric PID study patients.

Elderly population
No overall differences in the pharmacokinetic parameters were observed between PID subjects >65 years and subjects 18 to 65 years of age.