Mechanism of Action

Suppression of Rh Isoimmunization

The mechanism by which Rh₀(D) immune globulin suppresses immunization to Rh₀(D)-positive RBCs is not completely known.

In a clinical study of Rh₀(D)-negative healthy male volunteers, both the intravenous and intramuscular administration of a 1500 IU (300 mcg) dose of Rhophylac® 24 hours after injection of 15 mL of Rh₀(D)-positive RBCs resulted in an effective clearance of Rh₀(D)-positive RBCs. On average, 99% of injected RBCs were cleared within 12 hours following intravenous administration and within 144 hours following intramuscular administration.

ITP

Rhophylac® has been shown to increase platelet counts and to reduce bleeding in non-splenectomized Rh₀(D)-positive subjects with chronic ITP. The mechanism of action is thought to involve the formation of Rh₀(D) immune globulin RBC complexes, which are preferentially removed by the reticuloendothelial system, particularly the spleen. This results in Fc receptor blockade, thus sparing antibody-coated platelets.10

Pharmacokinetics

Suppression of Rh Isoimmunization

In a clinical study comparing the pharmacokinetics of intravenous versus intramuscular administration, 15 Rh₀(D)-negative pregnant women received a single 1500 IU (300 mcg) dose of Rhophylac® at Week 28 of gestation.11

Following intravenous administration, peak serum levels of Rh₀(D) immune globulin ranged from 62 to 84 ng/mL after 1 day (i.e., the time the first blood sample was taken following the antepartum dose). Mean systemic clearance was 0.20 ± 0.03 mL/min, and half-life was 16 ± 4 days.

Following intramuscular administration, peak serum levels ranged from 7 to 46 ng/mL and were achieved between 2 and 7 days. Mean apparent clearance was 0.29 ± 0.12 mL/min, and half-life was 18 ± 5 days. The absolute bioavailability of Rhophylac® was 69%.

Regardless of the route of administration, Rh₀(D) immune globulin titers were detected in all women up to at least 9 weeks following administration of Rhophylac®.

ITP

Pharmacokinetic studies with Rhophylac® were not performed in Rh₀(D)-positive subjects with ITP. Rh₀(D) immune globulin binds rapidly to Rh₀(D)-positive erythrocytes.12

Clinical Studies

Suppression of Rh Isoimmunization

In two clinical studies, 447 Rh₀(D)-negative pregnant women received a 1500 IU (300 mcg) dose of Rhophylac® during Week 28 of gestation. The women who gave birth to an Rh₀(D)-positive baby received a second 1500 IU (300 mcg) dose within 72 hours of birth.

• Study 1 – Eight of the women who participated in the pharmacokinetic study (see Clinical Pharmacology ) gave birth to an Rh₀(D)-positive baby and received the postpartum dose of 1500 IU (300 mcg) of Rhophylac®.11 Antibody tests performed 6 to 8 months later were negative for all women. This suggests that no Rh₀(D) immunization occurred.
• Study 2 – In an open-label, single-arm clinical study at 22 centers in the US and United Kingdom, 432 pregnant women received the antepartum dose of 1500 IU (300 mcg) of Rhophylac® either as an intravenous or intramuscular injection (two randomized groups of 216 women each).13 Subjects received an additional 1500 IU (300 mcg) dose if an obstetric complication occurred between the routine antepartum dose and birth or if extensive fetomaternal hemorrhage was measured after birth. Of the 270 women who gave birth to an Rh₀(D)-positive baby, 248 women were evaluated for Rh₀(D) immunization 6 to 11.5 months postpartum. None of these women developed antibodies against the Rh₀(D) antigen.

ITP

In an open-label, single-arm, multicenter study, 98 Rh₀(D)-positive adult subjects with chronic ITP and a platelet count of 30 x 10⁹L or less were treated with Rhophylac®. Subjects received a single intravenous dose of 250 IU (50 mcg) per kg body weight.

The primary efficacy endpoint was the response rate defined as achieving a platelet count of ≥ 30 x 10⁹L as well as an increase of >20 x 10⁹L within 15 days after treatment with Rhophylac®. Secondary efficacy endpoints included the response rate defined as an increase in platelet counts to ≥ 50 x 10⁹L within 15 days after treatment and, in subjects who had bleeding at baseline, the regression of hemorrhage defined as any decrease from baseline in the severity of overall bleeding status.

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