Synagis (Palivizumab) - Description and Clinical Pharmacology

DESCRIPTION

Synagis® (palivizumab) is a humanized monoclonal antibody (IgG1k) produced by recombinant DNA technology, directed to an epitope in the A antigenic site of the F protein of respiratory syncytial virus (RSV). Palivizumab is a composite of human (95%) and murine (5%) antibody sequences. The human heavy chain sequence was derived from the constant domains of human IgG1 and the variable framework regions of the V_H genes Cor (1) and Cess (2). The human light chain sequence was derived from the constant domain of Ck and the variable framework regions of the V_L gene K104 with Jk -4 (3). The murine sequences were derived from a murine monoclonal antibody, Mab 1129 (4), in a process which involved the grafting of the murine complementarity determining regions into the human antibody frameworks. Synagis® (palivizumab) is composed of two heavy chains and two light chains and has a molecular weight of approximately 148,000 Daltons.

Synagis® is available in two formulations: a lyophilized powder and a liquid solution.

Lyophilized Powder: Synagis® is supplied as a sterile lyophilized product for reconstitution with sterile water for injection. Reconstituted Synagis® (100 mg/mL) is to be administered by intramuscular injection (IM) only. The reconstituted solution should appear clear or slightly opalescent with a pH of 6.0.

Each 100 mg single-use vial of Synagis® lyophilized powder is formulated in 67.5 mg of mannitol, 8.7 mg histidine and 0.3 mg of glycine and is designed to deliver 100 mg of Synagis® in 1.0 mL when reconstituted with 1.0 mL of sterile water for injection.

Each 50 mg single-use vial of Synagis® lyophilized powder is formulated in 40.5 mg mannitol, 5.2 mg of histidine and 0.2 mg of glycine and is designed to deliver 50 mg of Synagis® in 0.5 mL when reconstituted with 0.6 mL of sterile water for injection.

Liquid Solution: Synagis® (100 mg/mL) is supplied as a sterile, preservative-free solution to be administered by intramuscular injection (IM) only. The solution should appear clear or slightly opalescent with pH of 6.0.

Each 100 mg single-use vial of Synagis® liquid solution is formulated in 4.7 mg of histidine and 0.1 mg of glycine in a volume of 1.2 mL to and is designed to deliver 100 mg of Synagis® in 1.0 mL.

Each 50 mg single-use vial of Synagis® liquid solution is formulated in 2.7 mg of histidine and 0.08 mg of glycine in a volume of 0.7 mL to and is designed to deliver 50 mg of Synagis® in 0.5 mL.

CLINICAL PHARMACOLOGY

Mechanism of Action:
Synagis® (palivizumab) exhibits neutralizing and fusion-inhibitory activity against RSV. These activities inhibit RSV replication in laboratory experiments. Although resistant RSV strains may be isolated in laboratory studies, a panel of 57 clinical RSV isolates were all neutralized by Synagis® (palivizumab) (5). Synagis® (palivizumab) serum concentrations of = 40 µg/mL have been shown to reduce pulmonary RSV replication in the cotton rat model of RSV infection by 100-fold (5). The in vivo neutralizing activity of the active ingredient in Synagis® (palivizumab) was assessed in a randomized, placebocontrolled study of 35 pediatric patients tracheally intubated because of RSV disease. In these patients, palivizumab significantly reduced the quantity of RSV in the lower respiratory tract compared to control patients (6).

Pharmacokinetics:

In studies in adult volunteers Synagis® (palivizumab) had a pharmacokinetic profile similar to a human IgG1 antibody in regard to the volume of distribution and the half-life (mean 18 days). In pediatric patients less than 24 months of age, the mean half-life of Synagis® (palivizumab) was 20 days and monthly intramuscular doses of 15 mg/kg achieved mean ±SD 30 day trough serum drug concentrations of 37 ±21 µg/mL after the first injection, 57 ±41 µg/mL after the second injection, 68 ±51 µg/mL after the third injection and 72 ±50 µg/mL after the fourth injection (7). In pediatric patients given Synagis® (palivizumab) for a second season, the mean ±SD serum concentrations following the first and fourth injections were 61 ±17 µg/mL and 86 ±31µg/mL, respectively.

In 139 pediatric patients ≤24 months of age with hemodynamically significant CHD who received Synagis® and underwent cardio-pulmonary bypass for open-heart surgery, the mean ± SD serum Synagis® concentration was 98 ± 52 µg/mL before bypass and declined to 41 ± 33 µg/mL after bypass, a reduction of 58% (see DOSAGE AND ADMINISTRATION). The clinical significance of this reduction is unknown.

Specific studies were not conducted to evaluate the effects of demographic parameters on Synagis® systemic exposure. However, no effects of gender, age, body weight or race on Synagis® serum trough concentrations were observed in a clinical study with 639 pediatric patients with CHD (≤24 months of age) receiving five monthly intramuscular injections of 15 mg/kg of Synagis®.

Trough serum Synagis® concentrations were comparable between the Synagis® liquid and Synagis® lyophilized formulations administered IM at 15 mg/kg in a cross-over trial in 153 pediatric patients ≤6 months of age with a history of prematurity.

CLINICAL STUDIES

The safety and efficacy of Synagis® were assessed in two randomized, double-blind, placebo-controlled trials of prophylaxis against RSV infection in pediatric patients at high risk of an RSV-related hospitalization. Trial 1 was conducted during a single RSV season and studied a total of 1502 patients ≤24 months of age with bronchopulmonary dysplasia (BPD) or infants with premature birth (≤35 weeks gestation) who were ≤6 months of age at study entry (7). Trial 2 was conducted over four consecutive seasons among a total of 1287 patients ≤24 months of age with emodynamically significant congenital heart disease. In both trials participants received 15 mg/kg Synagis® or an equivalent volume of placebo IM monthly for five injections and were followed for 150 days from randomization. In Trial 1, 99% of all subjects completed the study and 93% completed all five injections. In Trial 2, 96% of all subjects completed the study and 92% completed all five injections. The incidence of RSV hospitalization is shown in Table 1.

In Trial 1, the reduction of RSV hospitalization was observed both in patients with BPD (34/266 [12.8%] placebo vs. 39/496 [7.9%] Synagis®), and in premature infants without BPD (19/234 [8.1%] placebo vs. 9/506 [1.8%] Synagis®). In Trial 2, reductions were observed in acyanotic (36/305 [11.8%] placebo vs. 15/300 [5.0%] Synagis®) and cyanotic children (27/343 [7.9%] placebo vs. 19/339 [5.6%] Synagis®).

The clinical studies do not suggest that RSV infection was less severe among RSV hospitalized patients who received Synagis® compared to those who received placebo.