Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: immune sera and immunoglobulins, specific immunoglobulins, ATC code: J06BB09.

Megalotect CP is an immunoglobulin preparation from plasma of donors with a high antibody titer against the CMV. It has a defined and high titer of high avidity anti-CMV antibodies. It also contains IgG antibodies against other pathogens representative of the large number of normal persons who contributed to the plasma pools from which the product was derived. It has a distribution of IgG subclasses closely proportional to that in native human plasma.
Mechanism of action
Megalotect CP is a CMV-specific polyclonal immunoglobulin preparation that binds to CMV surface antigens thereby neutralizing the potential of CMV from entering host cells and presenting the CMV particle for phagocytosis. Megalotect CP antibodies also modulate and interact with immune cells (dendritic cells, monocytes, B- and T-cells) exerting a positive immunological balance in addition to the virostatic inhibition of CMV replication.

Pharmacodynamic effects
The primary mode of action of Megalotect CP is the binding of circulating virus. These CMV-specific antibodies block the infection of different cell types including all CMV genotypes and of virus variants that are resistant to virostatics. Furthermore, Megalotect CP can activate CMV-reactive immune cells for long-lasting CMV-specific immune responses. It also has additional immunomodulating properties independent of CMV that have been implicated with a reduction of organ rejection.


Clinical efficacy and safety
The clinical efficacy of CMVIG was investigated in different settings, including patients who received solid organ and stem cell transplants. In renal transplantation, CMVIG reduced the incidence of CMV infection from 41.7% (control group) to 21.1% (Megalotect group). Other examples include lung transplantation, where the incidence of CMV disease was reduced from 43.3% (control group) to 13.2% (Megalotect group), and bone marrow transplantation, where the incidence of interstitial pneumonitis was reduced from 26.1% to 3.8%.

Renal transplantation
A prospective, randomized controlled study investigated the efficacy of hyperimmunoglobulin prophylaxis for CMV infection in renal transplant patients. 74 patients were enrolled who received a cadaveric kidney for the first time. The mean follow-up was 45 months. Patients received immunosuppressive regimen consisting of methylprednisolone and cyclosporin A. In the treatment group 38 patients received a dose of 2 ml/kg Megalotect i.v. just before transplantation and then on days 1, 2, 4, 18, 32, 46, 60, 74 and 88 after transplantation. The control group consisted of 36 patients who did not receive Megalotect. In the treatment group overall 8/38 patients (21.1%) had CMV infection and 5/38 patients (13.2%) had CMV disease, whereas in the control group overall 15/36 patients (41.7%) had CMV infection and 6/36 patients (16.7%) had CMV disease.


Paediatric population
A retrospective study investigated the efficacy and safety of acyclovir plus Megalotect prophylaxis and early therapy with ganciclovir in CMV high-risk renal transplant paediatric patients (79 patients with a mean age of 14.1 ± 4.9 years, range 2.5 – 20). The minimum follow-up period was 12 months. The immunosuppressive regimen included cyclosporin A and steroids, with the addition of azathioprine in 4 patients who received a living donor-related kidney. Acute rejection episodes were treated with i.v.
methylprednisolone pulses. 39 R- patients received 150 mg/kg Megalotect on the first postoperative day, 100 mg/kg on days 15 and 30 and 50 mg/kg on days 45, 60 and 120 after transplantation and oral acyclovir. 40 R+ patients received only oral acyclovir at the same dosage as R- patients. In the presence of CMV infection, 10 mg/kg body weight per day i.v. ganciclovir was administered for at least 2 weeks, or until negative antigenemia was obtained. In the R- group receiving Megalotect treatment, of the 33 CMV seronegative recipients (R-) who received the graft from a CMV seropositive donor (D+) 18 (54.5 %) experienced a CMV infection and in 6 CMV seronegative recipients (R-) who received the graft from a CMV negative donor no infection occurred. In the R+ group only receiving acyclovir, of the 28 CMV R +, who received a graft from a CMV D+, 11 (39.3 %) experienced CMV infection and of the 12 R +, who received a graft from a CMV D- donor one recipient experienced a CMV infection (8.3%).

Heart transplantation
An open-label, comparative, retrospective study investigated the combined prophylaxis of Megalotect plus ganciclovir versus Megalotect alone in 207 adult high-risk heart transplant recipients (mean age 52.2 years) receiving an allograft from seropositive donors (D+/R-). All patients received polyclonal rabbit antithymocyte globulin as induction therapy. Cyclosporin A, azathioprine, and prednisone were used as maintenance immunosuppressive therapy. Acute allograft rejection episodes were treated with a daily bolus of prednisone for 3 consecutive days. In group A 96 patients received Megalotect alone and in group B 111 patients received Megalotect with ganciclovir. 100 mg/kg Megalotect were administered i.v. before transplantation and on postoperative days 1, 7, 14, 21 and 28. Patients with CMV disease were treated with ganciclovir for 21 days in combination with a reduction of the immunosuppressive therapy.
Additional Megalotect was administered at weekly intervals. In group A 53.1% had CMV infection and 32.3% (31/96 patients) had CMV disease. In group B 65.8% had CMV infection and 11.7% (13/111 patients) had CMV disease. Four CMV-associated deaths were observed in group A; 3 patients died of severe CMV sepsis, and 1 patient died of CMV encephalitis. There were no CMV-associated deaths observed in group B, which reflects a statistically significant benefit of combined Megalotect and ganciclovir versus sole Megalotect prophylaxis (P=0.0326).

An open-label, single center study investigated the passive immunisation against CMV in adult allograft recipients (146 patients who underwent heart transplantation between 1984 and 1991 with a median age of 47 years). The follow-up period ranged from 13 to 73 months (median 43 months). Maintenance immunosuppression consisted of cyclosporin A and prednisone. Azathioprine was added to this regimen in 11 patients because of recurrent rejection within the first year. In the treatment group 65 CMV (R-) patients received 150 mg/kg Megalotect during the operation and 100 mg/kg Megalotect at days 2, 7, 14, 28, 42, 56 and 72 after transplantation, whereas the control group consisted of 81 CMV (R+) patients who did not receive CMV prophylaxis. In the treatment group 21/65 (R-) patients (32.3%) had CMV infection and 11/65 (R-) patients (16.9%) had CMV disease. In the control group 40/81 (R+) patients (49.4%) had CMV infection and 10/81 (R+) patients (12.3%) had CMV disease.

Lung transplantation
A retrospective, single center study investigated CMV immunoglobulin for prophylaxis and treatment of CMV infection (156 adult patients who received a lung transplant between 2007 and 2011 with a mean age of 52 years (range 17-67 years) were analyzed). The median duration of follow-up was 19.2 months.
All patients received basiliximab induction, and a triple immunosuppression (tacrolimus, mycophenolate mofetil, methylprednisolone followed by prednisolone). Ganciclovir i.v. was initiated in all at-risk patients (D+/R– or R+) during the first week post-transplant. In the treatment group 23 D+/R– patients received 2 ml/kg Megalotect on days 1, 4, 8, 15, and 30 post-transplant, then monthly for a further year and valganciclovir for 6 months. In the control group 133 R+ patients received valganciclovir for 3 months. In the treatment group 14/23 (D+/R-) patients (61%) had CMV infection and 4/23 (D+/R-) patients (17.4%) had CMV disease, whereas in the control group 46/133 (R+) patients (35%) had CMV infection and 6/133 (R+) patients (4%) had CMV disease. The mortality was 4/23 (D+R-) patients (17.4%) in the treatment group and 40/133 (R+) patients (30%) in the control group.

A comparative, retrospective study investigated the combined CMV prophylaxis after lung transplantation in 68 adult lung-transplant patients (mean age 55.8 years in the treatment group and 49.2 years in the control group) with CMV seropositive allograft. The median follow-up period was 16.5 months in the control group (5.3 to 69.5 months) and 23.8 months in the study group (11.9 to 35 months). In the control group 30 patients (transplanted from 1994 to 2000) received ganciclovir alone for the first 3 postoperative months, in the treatment group 38 patients (transplanted from 2000 to 2004) received additional treatment with 1 ml/kg Megalotect in 7 doses within the first post-transplant month.

Table 1: results of the study
Treatment group       Control group
(ganciclovir +        (ganciclovir alone)
Megalotect)           (N=30)
(N=38)
1-year survival                                               81.6%                 63.3% 3-year survival                                               71.5%                 40% 1-year freedom from CMV reactivation or de novo               71.5%                 51.1% infection
3-year freedom from CMV reactivation or de novo               66.4%                 30% infection
Development of CMV disease during follow–up                   13.2%                 43.3% Development of CMV pneumonitis                                13.2%                 33.3% Occurrence of CMV syndrome                                    0%                    10% 1-year freedom from bronchiolitis obliterans syndrome         91.0%                 69.7% (BOS)
3-year freedom BOS                                            82%                   54.3% CMV related death                                             0%                    16.7% 
Bone marrow transplantation (BMT)
A randomised comparative study investigated the use of intravenous hyperimmunoglobulin in the prevention of CMV infection in 49 adult patients with leukemia who received allogenic BMT from HLA- matched siblings (mean age 22 (Megalotect) and 22.5 years (control)). The follow-up was 110 days. All patients were conditioned with cyclophosphamide and total body irradiation. In the treatment group 26 patients received 1 ml/kg Megalotect, in the control group 23 patients received 2 ml/kg normal immunoglobulin on day -7, and days 13, 33, 73 and 93 after BMT. Within the first 110 days after BMT 1/26 patients (4%) developed CMV-related interstitial pneumonitis in the treatment group and in the control group 6/23 patients (26%). Two patients in the Megalotect treated group developed CMV-related interstitial pneumonitis after cessation of treatment (Days 143 and 153).

An open-label, non-comparative study investigated the reduction of CMV disease by prophylaxis with CMV hyperimmunoglobulin plus oral acyclovir in 93 adult BMT recipients (median age 22 years, range 1-49 years). Acute GVHD was reported for 43 (48.3%) (Grade 
                
Pharmacokinetic Properties
                                
5.2   Pharmacokinetic properties
Megalotect CP 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 an equilibrium is reached between the intra- and extravascular compartments.

Megalotect CP has a half-life of 25 days. This half-life may vary from patient to patient and depends also on the clinical condition.

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