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Zenapax (Daclizumab) - Description and Clinical Pharmacology

 
 



DESCRIPTION

ZENAPAX® (Daclizumab) is an immunosuppressive, humanized IgG1 monoclonal antibody produced by recombinant DNA technology that binds specifically to the alpha subunit (p55 alpha, CD25, or Tac subunit) of the human high-affinity interleukin-2 (IL-2) receptor that is expressed on the surface of activated lymphocytes.

Daclizumab is a composite of human (90%) and murine (10%) antibody sequences. The human sequences were derived from the constant domains of human IgG1 and the variable framework regions of the Eu myeloma antibody. The murine sequences were derived from the complementarity-determining regions of a murine anti-Tac antibody. The molecular weight predicted from the DNA sequence is 144 kilodaltons.

ZENAPAX 25 mg/5 mL is supplied as a clear, sterile, colorless concentrate for further dilution and intravenous administration. Each milliliter of ZENAPAX contains 5 mg of daclizumab and 3.6 mg sodium phosphate monobasic monohydrate, 11 mg sodium phosphate dibasic heptahydrate, 4.6 mg sodium chloride, 0.2 mg polysorbate 80, and may contain hydrochloric acid or sodium hydroxide to adjust the pH to 6.9. No preservatives are added.

CLINICAL PHARMACOLOGY

GENERAL

MECHANISM OF ACTION

Daclizumab functions as an IL-2 receptor antagonist that binds with high-affinity to the Tac subunit of the high-affinity IL-2 receptor complex and inhibits IL-2 binding. Daclizumab binding is highly specific for Tac, which is expressed on activated but not resting lymphocytes. Administration of ZENAPAX inhibits IL-2-mediated activation of lymphocytes, a critical pathway in the cellular immune response involved in allograft rejection.

While in the circulation, ZENAPAX impairs the response of the immune system to antigenic challenges. Whether the ability to respond to repeated or ongoing challenges with those antigens returns to normal after ZENAPAX is cleared is unknown (see PRECAUTIONS).

PHARMACOKINETICS

ADULTS

In clinical trials involving renal allograft patients treated with a 1 mg/kg IV dose of ZENAPAX every 14 days for a total of five doses, peak serum concentration (mean ± SD) rose between the first dose (21 ± 14 µg/mL) and fifth dose (32 ± 22 µg/mL). The mean trough serum concentration before the fifth dose was 7.6 ± 4.0 µg/mL. Population pharmacokinetic analysis of the data using a two-compartment open model gave the following values for a reference patient (45-year-old male Caucasian patient with a body weight of 80 kg and no proteinuria): systemic clearance = 15 mL/hour, volume of central compartment = 2.5 liter, volume of peripheral compartment = 3.4 liter. The estimated terminal elimination half-life for the reference patient was 20 days (480 hours), which is similar to the terminal elimination half-life for human IgG (18 to 23 days). Bayesian estimates of terminal elimination half-life ranged from 11 to 38 days for the 123 patients included in the population analysis. The influence of body weight on systemic clearance supports the dosing of ZENAPAX on a milligram per kilogram (mg/kg) basis. For patients studied, this dosing maintained drug exposure within 30% of the reference exposure. Covariate analyses showed that no dosage adjustments based on age, race, gender or degree of proteinuria, are required for renal allograft patients. The estimated interpatient variability (percent coefficient of variation) in systemic clearance and central volume of distribution were 15% and 27%, respectively.

PEDIATRICS

Pharmacokinetic parameters were evaluated in 61 pediatric patients treated with a 1 mg/kg IV dose of ZENAPAX every 14 days for a total of five doses. Peak serum concentration (mean ± SD) rose between the first dose (16 ± 12 µg/mL) and fifth dose (21 ± 14 µg/mL). The mean trough serum concentration before the fifth dose was 5.0 ± 2.7 µg/mL. Population pharmacokinetic analysis of the data using a two-compartment open model gave the following values for a reference patient (Caucasian patient with a body weight of 29.7 kg): systemic clearance = 10 mL/hour, volume of central compartment = 2.0 liter, volume of peripheral compartment = 1.4 liter. The estimated terminal elimination half-life for the reference patient was 13 days (317 hours). For the patients studied, this dosing maintained drug exposure within 50% of the reference exposure. Covariate analyses suggested that disposition parameters were not influenced to a clinically relevant extent by race, gender or degree of proteinuria. The estimated interpatient variability (percent coefficient of variation) in systemic clearance and central volume of distribution were 30% and 40%, respectively.

PHARMACODYNAMICS

In vitro and in vivo data suggest that serum levels of 5 to 10 µg/mL are necessary for saturation of the Tac subunit of the IL-2 receptors to block the responses of activated T lymphocytes. At the recommended dosage regimen, daclizumab saturates the Tac subunit of the IL-2 receptor for approximately 90 and 120 days posttransplant, respectively in pediatric and adult patients. The duration of clinically significant IL-2 receptor blockade after the recommended course of ZENAPAX is not known. No significant changes to circulating lymphocyte numbers or cell phenotypes were observed by flow cytometry. Cytokine release syndrome has not been observed after ZENAPAX administration.

CLINICAL STUDIES

The safety and efficacy of ZENAPAX for the prophylaxis of acute organ rejection in adult patients receiving their first cadaveric kidney transplant were assessed in two randomized, double-blind, placebo-controlled, multicenter trials. These trials compared a dose of 1.0 mg/kg of ZENAPAX with placebo when each was administered as part of standard immunosuppressive regimens containing either cyclosporine and corticosteroids (double-therapy trial, no US sites) or cyclosporine, corticosteroids, and azathioprine (triple-therapy trial, predominantly US sites) to prevent acute renal allograft rejection. ZENAPAX dosing was initiated within 24 hours pretransplant, with subsequent doses given every 14 days for a total of five doses.

The primary efficacy endpoint of both trials was the proportion of patients who developed a biopsy-proven acute rejection episode within the first 6 months following transplantation. As shown in Table 1, this incidence was significantly lower in the group treated with ZENAPAX in both the double-therapy and triple-therapy trials.

Table 1. Efficacy Parameters
Triple-therapy Regimen Double-therapy Regimen
(cyclosporine, corticosteroids,
and azathioprine)
(cyclosporine and
corticosteroids)
Placebo (N=134) ZENAPAX (N=126) p-value Placebo (N=134) ZENAPAX (N=141) p-value
Incidence of biopsy-proven acute rejection at 6 months
No. of patients 47 (35%) 28 (22%) 0.03 63 (47%) 39 (28%)    0.001
Incidence of biopsy-proven acute rejection at 1 year
No. of patients 51 (38%) 35 (28%) n.s. 65 (49%) 39 (28%) <0.001
Graft survival at 3 years posttransplant
No. of patients with
functioning graft
111 (83%) 106 (84%) n.s. 105 (78%) 116 (82%)   n.s.
Patient survival at 3 years posttransplant
No. of patients 126 (94%) 116 (92%) n.s. 118 (88%) 135 (96%)   0.02
n.s. = not significant

Treatment with ZENAPAX was associated with better patient survival up to 3 years posttransplant in the double-therapy study. No difference in patient survival was observed in the triple-therapy study between patients treated with ZENAPAX or placebo up to 3 years posttransplant. No difference was observed for graft survival between treatment groups in both studies at 3 years posttransplant.

The incidence of delayed graft function was not different between patients treated with placebo or ZENAPAX in either study. No difference in graft function was observed 1 year and 3 years posttransplant in either study between patients treated with placebo or ZENAPAX.

In a randomized, double-blind study to assess tolerability, pharmacokinetics, and drug interactions in renal allograft recipients, ZENAPAX (50 patients) or placebo (25 patients) was added to an immunosuppressive regimen of cyclosporine, mycophenolate mofetil, and corticosteroids. In this study, the addition of ZENAPAX did not result in an increased incidence of adverse events or a change in the types of adverse events reported. The incidence of the combined endpoint of biopsy-proven or clinically presumptive acute rejection was 20% (5 of 25 patients) in the placebo group and 12% (6 of 50 patients) in the ZENAPAX group. Although numerically lower, the difference in acute rejection was not significant. However, in a randomized, double-blind, placebo-controlled trial of ZENAPAX in cardiac transplant recipients (n=434) receiving concomitant cyclosporine, mycophenolate mofetil, and corticosteroids, mortality was increased in patients randomized to receive ZENAPAX compared with those randomized to receive placebo (see WARNINGS and ADVERSE REACTIONS).

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