Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1    Pharmacodynamic properties
Pharmacotherapeutic group: immune sera and immunoglobulins: immunoglobulins, normal human, for intravascular administration; ATC code: J06BA02.
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 1000 donations. It has a distribution of immunoglobulin G subclasses closely proportional to that in native human plasma. Adequate doses of this medicinal product may restore abnormally low immunoglobulin G levels to the normal range.
The mechanism of action in indications other than replacement therapy is not fully elucidated.

Clinical efficacy and safety
Four clinical trials were performed with Ig VENA: three trials on efficacy and safety in patients with Primary Immunodeficiency (PID), Immune Thrombocytopenia (ITP) and Chronic Inflammatory Demyelinating Poliradiculoneuropathy (CIDP); and one study on safety and tolerance of Ig VENA at increased infusions rates in patients with Immunodeficiency (ID) or ITP.

A phase III, prospective, open-label study in patients with primary Immunodeficiency syndromes (KB028) evaluated the pharmacokinetic profile of Ig VENA as the primary objective. Secondary objectives were therapeutic efficacy in terms of prophylaxis of episodes of infection, and safety in terms of short term-tolerability. Fifteen patients out of 16 enrolled, aged 28-60 years old, were evaluated for efficacy and were treated for 24 weeks with Ig VENA (total of 140 infusions).
The pharmacokinetic profile of Ig VENA showed a terminal half-life fairly consistent with the data reported in the literature, being 26.4 days. One patient developed pneumonia after 18 weeks of therapy with Ig VENA but this patient suffered of severe pulmonary infections also in the previous 10 years. No serious infections were reported for the other patients enrolled.
The data generated in KB028 study indicate that Ig VENA is safe and effective for treatment of primary immunodeficiency syndromes.

The ITP Study (KB027) was a phase III, open-label, prospective trial for the evaluation of efficacy and tolerability of Ig VENA in adult patients with chronic idiopathic thrombocytopenic purpura.
The primary objective was the evaluation of platelet count increase. Secondary objectives were: reduction in haemorrhagic events, duration of platelet response, and the incidence of AEs. Fifteen patients received a total dose of 2 g/kg each, subdivided into 5 daily infusions of 400 mg/kg on consecutive days. A second cycle of 2 g/kg body weight was given to one patient within the first 14 days. The total number of infusions applied was 80.
All enrolled patients achieved a platelet count ≥ 50x109/L, except one who received a second cycle of therapy but did not achieve the target platelet count (response rate 93.3%, 90% CI from 68.1 to 99.8). No adverse events were reported.
The results obtained from KB027 study provided evidence of tolerability and therapeutic efficacy of Ig VENA in ITP patients.
In the phase III study KB057 for the evaluation of tolerability and safety of Ig VENA at increased infusion rates, 43 adult patients were enrolled: 38 ID and 5 ITP patients who received Ig VENA at the dosages approved according to both indications.
Thirty-seven ID patients were observed for 3 infusions and 1 ID patient for 2 infusions. Four ITP patients received their planned dose over 2 daily infusions, while 1 patient was infused over 3 days.
(total of 124 infusions).
At infusion 2, twenty-eight patients out of 43 were infused at the maximum speed of 8 ml/kg/hr; 13 patients out of 43 reached only a maximum infusion speed of 6 ml/kg/hr, because their infusion was finished before they could be ramped up to the next increment in infusion speed. During the clinical trial, two patients did not reach 8 ml/kg/h because they developed 3 adverse events during the infusion at lower infusion rates.
Results obtained from this study show that Ig VENA administered at increasing infusion speed was well tolerated both in patients with ID and in those with ITP and that the infusion speed could be ramped up to a maximum of 6 ml/kg/hr and, in a limited number of patients, to 8 ml/kg/hr.
Adverse drug reactions were reported in less than 10% of ID patients and were reactions generally related with IVIg administration (e.g. pyrexia, back pain, myalgia, asthenia, somnolence and fatigue).
No serious ADR was reported as well as local reactions at the infusion site.

Clinical trial conducted with Ig VENA on patients with Chronic Inflammatory Demyelinating Poliradiculoneuropathy (CIDP):
The double-blind controlled Phase III study on the tolerability and efficacy of long-term treatment with high doses intravenous immunoglobulins versus high doses intravenous methylprednisolone (IVMP) in CIDP (KB034) was conducted of a total of 46 CIDP adult patients, randomised to receive either Ig VENA (dosage: 2 g/Kg/month in 4 consecutive days for 6 months) or IVMP (dosage: 2 g/month in 4 consecutive days for 6 months).

Ten of the 21 patients treated with IVMP (47.6%) completed the 6 months of the study compared to 21/24 on Ig Vena (87.5%) (p = 0.0085). The cumulative probability of treatment discontinuation was significantly higher with IVMP than with Ig VENA at 15 days, 2 months and 6 months. Of the 11 patients who discontinued IVMP, eight did so because of progressive worsening after treatment start (5 patients) or failure to improve after two courses of therapy (3 patients), while one had adverse events (gastritis) (9.1%) and two voluntarily withdrew (18.2%). Three patients discontinued Ig VENA for progressive worsening after starting the therapy (two patients), or absence of improvement after two courses of therapy (one patient). All the patients worsening or not improving after IVMP or IVIg were shifted to the alternative therapy while the three patients who discontinued IVMP for adverse event or who voluntary withdrew after IVMP refused further therapy.

Results regarding the study secondary endpoints are summarized in the table reported below (statistically significant differences in bold):



Intention To Treat Population Per Protocol Population (PP)
(ITT)
Secondary endpoints              IgVENA      MPIV        p-value   IgVENA     MPIV       p-value 10                                10 g/200 ml                          g/200 ml
Relapses rate *                  45.8%       52.4%       0.7683    38.1%      0%         0.0317 (n 11/24)   (n 11/21)             (n 8/21)   (n 0/10)
MRC sum score [delta (p- +4.7                +1.8        0.6148    +4.0       +2.0       0.5473 value)]                  (0.0078)            (0.1250)              (0.0469)   (0.5000) INCAT (p-value)                  0.0004      0.1877      0.3444    0.0057     0.2622     0.9065 
Vibratory score - Right          <0.0001     0.6515      0.0380    0.0009     0.2160     0.4051 medial malleolus (p- value)
Fist strength right [delta (p-   +19.4       +5.4        0.0641    +16.5      +14.7      0.5012 value)]                          (0.0005)    (0.6169)              (0.0044)   (0.0156) Fist strength left [delta (p- +16.9          +8.8        0.1358    +12.7      +10.5      0.3330 value)]                       (0.0011)       (0.1170)              (0.0014)   (0.0156) Time on 10 meters [delta (p- -3.2            -0.5        0.0800    -3.5       -2.0       0.2899 value)]                      (0.0025)        (0.2051)              (0.0043)   (0.4453) ONLS scale (p-value)             0.0006      0.0876      0.4030    0.0033     0.0661     0.8884 
Rankin scale (p-value)           0.0006      0.0220      0.3542    0.0132     0.2543     0.8360 
Rotterdam scale [delta (p- +1.4              +1.3        0.6465    +1.1       +1.1       0.4056 value)]                    (0.0071)          (0.0342)              (0.0342)   (0.0859) SF-36 QoL                        +14.2       +16.7       0.3634    +11.1      +16.0      0.6518 (0.0011)    (0.0008)              (0.0091)   (0.1094)
*ITT: throughout the study (12 months); PP: follow up phase (6 months) 
Paediatric population
Published data related to efficacy and safety studies have not revealed major differences between adults and children suffering from the same disorder.

Pharmacokinetic Properties

5.2     Pharmacokinetic properties

Human normal immunoglobulin is immediately and completely bioavailable in the recipient’s circulation after intravenous administration. It is distributed relatively rapidly between plasma and extravascular fluid, after approximately 3-5 days equilibrium is reached between the intra- and extravascular compartments.
Human normal immunoglobulin has a half-life of about 26 days. This half-life may vary from patient to patient, in particular in primary immunodeficiency.

IgG and IgG-complexes are broken down in cells of the reticuloendothelial system.

Paediatric population
Published data related to PK studies have not revealed major differences between adults and children suffering from the same disorder.
There are no data on pharmacokinetic properties in paediatric patients with CIDP.