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

Mechanism of action

The IG 10% component provides the therapeutic effect of this medicinal product. The rHuPH20 facilitates the dispersion and absorption of IG 10%.

Human normal immunoglobulin contains mainly immunoglobulin G (IgG) with a broad spectrum of opsonising and neutralizing antibodies against infectious agents. Human normal immunoglobulin contains the IgG antibodies present in the normal population. It is usually prepared from pooled human plasma from not fewer than 1000 donations. It has a distribution of IgG subclasses closely proportional to that in native human plasma. Adequate doses of human normal immunoglobulin may restore abnormally low IgG levels to the normal range.

Recombinant human hyaluronidase is a soluble recombinant form of human hyaluronidase that increases the permeability of the subcutaneous tissue by temporarily depolymerizing hyaluronan. Hyaluronan is a polysaccharide found in the intercellular matrix of the connective tissue. It is depolymerized by the naturally occurring enzyme hyaluronidase. Unlike the stable structural components of the interstitial matrix, hyaluronan has a very fast turnover with half-life of approximately 0.5 days. The rHuPH20 of HyQvia acts locally. The effects of the hyaluronidase are reversible, and permeability of the subcutaneous tissue is restored within 24 to 48 hours.

Clinical efficacy and safety

Efficacy and safety of HyQvia was assessed in a phase 3 study (160603) in 83 patients with PID.
Patients were treated with it at either 3- or 4-week treatment intervals for a total of 12-months (following a brief titration period). The dose was based on the previous treatment with intravenous IG 10% (320 to 1000 mg/kg body weight /4-weeks) and was individually adapted, ensuring adequate IgG levels throughout the study.

The results of the study showed a rate of validated, acute, serious bacterial infections per year during HyQvia treatment of 0.025 (upper limit of the one-sided 99% confidence interval 0.046). The overall rate of infections was less during HyQvia administration than during the 3-months intravenous administration of IG 10%: the point estimate of the annualized rate of all infections was 2.97 (95% CI: 2.51 to 3.47) for HyQvia and 4.51 (95% CI: 3.50 to 5.69) for intravenous IG 10% infusions.

Nearly all of the subjects were able to attain the same dose interval with HyQvia as they had for intravenous administration. Seventy-eight (78) of 83 (94%) subjects attained the same 3- or 4-week dosing whereas one decreased from 4-to 3-weeks, one from 4-to 2-weeks and one from 3-to 2-weeks (2-subjects withdrew during the titration period).

The median number of infusion sites per month for HyQvia was 1.09, which is slightly lower than the median number of intravenous IG 10% infusion sites used in this study (1.34), and considerably lower than the median number of infusion sites in the study of subcutaneous administration of IG 10% (21.43).

Sixty-six (66) patients who completed the pivotal phase 3 study participated in an extension study (160902) for the evaluation of long-term safety, tolerability, and efficacy of HyQvia in PID.
The overall combined exposure of PID patients in both studies was 187.69 patient years; the longest exposure for adults was 3.8-years and 3.3-years for paediatric patients.
Study 161302 (EU):

This non-interventional post-authorisation safety study on the long-term safety of HyQvia in subjects treated with HyQvia was carried out for approximately 6 years. A total of 111 adult subjects were enrolled in the study. The mean age of the study population was 46.2 (standard deviation [SD]=14.69) years, and 14.2% (n=15) of the subjects were 65 years or older. Over half of the subjects were female (n=60, 56.6%), of whom 56.7% were of childbearing potential This study confirms the known safety profile of HyQvia.

Study 161406 (US):

This non-interventional post-authorisation safety study on the long-term safety of HyQvia was carried out for approximately 6 years. A total of 253 adult subjects with PID were enrolled. The median age was 57.0 years, 30.4% (n=77) were 65 years or older, and 79.1% (n=200) were female, 22.5% (n=45) of whom were of childbearing potential. This study confirms the known safety profile of HyQvia.

Paediatric population

In the pivotal studies, HyQvia was evaluated in 24 paediatric patients, including 13 patients between 4 and < 12 years and 11 between 12 and < 18 years, who were treated for up to 3.3-years with an overall safety experience equivalent to 48.66 patient years (as described in section Clinical efficacy and safety). No appreciable differences in the pharmacodynamic effects or efficacy and safety of HyQvia were observed between paediatric patients and adults. See sections 4.2 and 4.8.

The medicinal product was evaluated in 42 paediatric subjects (age 2 to <18 years), in a Phase 4, non-controlled, multicentre study in paediatric subjects who had received prior immunoglobulin therapy. No new safety concerns were identified in paediatric subjects with PID.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Following subcutaneous administration of HyQvia in PID patients, peak serum IgG levels are achieved in the recipient’s circulation after approximately 3 to 5 days.
IgG and IgG complexes are broken down in cells of the reticuloendothelial system.

PID

The pharmacokinetics (PK) of HyQvia were evaluated in a clinical study (160601, 160602 and 160603) in patients with PID aged 12 years and older. Data from the PID clinical studies show that serum IgG trough levels can be maintained by dosing regimens of 320 to 1000 mg/kg body weight/4-weeks given at intervals of 3- or 4-weeks.

The pharmacokinetic results are presented in the table below, as compared to data for intravenous administration of IG 10% obtained in the same study.

Table 2: Pharmacokinetic Parameters of HyQvia Compared to Intravenous Administration of IG 10%
HyQvia                     IVIG 10%
Parameter                                         Median (95% Cl)            Median (95% Cl) N=60                       N=68
Cmax [g/l]                                        15.5 (14.5; 17.)           21.9 (20.7; 23.9) 
Cmin [g/l]                                        10.4 (9.4 to 11.2)         10.1 (9.5 to 10.9) 
AUC per week [g*days/l]                           90.52 (83.8 to 9)          93.9 (89.1 to 102.1) 
Tmax [days]                                       5.0 (3.3 to 5.1)           0.1 (0.1 to 0.1) HyQvia                     IVIG 10%
Parameter                                        Median (95% Cl)            Median (95% Cl) N=60                       N=68
Apparent clearance or clearance [mL/kg/day]      1.6 (1.4 to 1.79)          1.4 (1.2 to 1.4) 
Terminal half-life [days]                        45.3 (41.0 to 60.2)        35.7 (32.4 to 40.4) 
Paediatric population

In the clinical study with HyQvia, no differences in the plasma IgG trough levels were observed between adult and paediatric patients.